Cause Of Parkinsonism Research Articles

Absence/rarity of commonly reported LRRK2 mutations in Indian Parkinson's disease patients

Recent discovery of pathogenic mutations in the leucine-rich repeat kinase 2 (LRRK2) gene in Parkinson's disease (PD) patients in different ethnic groups have raised a hope of diagnostic screening and genetic counseling. We investigated the six most commonly reported mutations in LRRK2 gene among Indian PD patients, using PCR-RFLP method. Mutations G2019S, R1441C, R1441G, and R1441H were screened in 1012 individuals (PD, 800; controls, 212) while mutations I2012T and I2020T were screened in 748 PD patients. We did not observe any of these six mutations in this study sample except in a single female young onset PD patient who showed a heterozygous G2019S mutation. The absence of mutations was reconfirmed by sequencing of probands from several autosomal dominant PD families. Our observations suggest that these mutations may be a rare cause of PD among Indians and therefore of little help for diagnostic screening and genetic counseling for Indian PD patients.

POLG1 in idiopathic Parkinson disease

We studied POLG1 in 140 UK patients with idiopathic Parkinson disease (PD) and 279 Italian patients with PD and compared them to a UK control group (n = 207) and an Italian control group (n = 285). Our observations do not support a role for common POLG1 genetic variants in PD and indicate that dominant POLG1 mutations are a rare cause of parkinsonism in the general population.

Screening for mutations of the HFE gene in Parkinson's disease patients with hyperechogenicity of the substantia nigra

Iron mediated oxidative stress is known to contribute to the neurodegenerative process in Parkinson's disease (PD). Although there are hints that genes involved in brain iron metabolism might be involved in the pathogenesis of PD in some instances, it is still not known whether the increase in brain iron content constitutes a primary or secondary event in the disease cascade. Recent studies on the role of hemochromatosis gene (HFE) mutations in PD vary from a protective effect of C282Y heterozygosity, no effect of the C282Y or H63D mutation to an increased risk for PD in C282Y mutation carriers. In this study, analyzing the whole coding region of the HFE gene by dHPLC in 278 PD patients, priorly characterized by transcranial sonography for increased iron content of the substantia nigra (SN), we did not find an association of the common HFE mutations and PD. However, we identified two novel variants (K92N and I217T) each in a single PD patient. These variations were not found in any of the controls. Future studies are necessary to reveal a possible functional relevance of these mutations for PD. Our results indicate that mutations in the HFE gene are not a common cause for PD with increased iron levels of the SN.

Full Length Article

Many studies have shown that deficits in olfactory and cognitive functions precede the classical motor symptoms seen in Parkinson's disease (PD) and that olfactory testing may contribute to the early diagnosis of this disorder. Although the primary cause of PD is still unknown, epidemiological studies have revealed that its incidence is increased in consequence of exposure to certain environmental toxins. In the present study, we demonstrated that rats treated with intranasal infusion of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at low concentrations (0.1 mg/nostril) suffered progressive impairments in olfactory, cognitive and motor functions that were assessed with the olfactory discrimination, Morris water maze and open field tests, respectively. Moreover, intranasal administration of MPTP reduced the expression of the enzyme tyrosine hydroxylase in the olfactory bulb and substantia nigra of rats, resulting in a significant reduction of dopamine concentration in the olfactory bulb, prefrontal cortex and striatum, but not in the hippocampus. These results reinforce the notion that the olfactory system represents a particularly sensitive route for the transport of neurotoxins into the central nervous system that may be related to the etiology of PD. In addition, the time course of the olfactory, cognitive and motor impairments verified in rats treated intranasally with MPTP, which appears to be correlated with different stages of the human PD, suggest that the MPTP intranasal model in rats may provide new insights into the underlying mechanisms of PD pathogenesis.

The risk is in the air: Intranasal administration of MPTP to rats reproducing clinical features of Parkinson's disease

Many studies have shown that deficits in olfactory and cognitive functions precede the classical motor symptoms seen in Parkinson's disease (PD) and that olfactory testing may contribute to the early diagnosis of this disorder. Although the primary cause of PD is still unknown, epidemiological studies have revealed that its incidence is increased in consequence of exposure to certain environmental toxins. In the present study, we demonstrated that rats treated with intranasal infusion of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at low concentrations (0.1 mg/nostril) suffered progressive impairments in olfactory, cognitive and motor functions that were assessed with the olfactory discrimination, Morris water maze and open field tests, respectively. Moreover, intranasal administration of MPTP reduced the expression of the enzyme tyrosine hydroxylase in the olfactory bulb and substantia nigra of rats, resulting in a significant reduction of dopamine concentration in the olfactory bulb, prefrontal cortex and striatum, but not in the hippocampus. These results reinforce the notion that the olfactory system represents a particularly sensitive route for the transport of neurotoxins into the central nervous system that may be related to the etiology of PD. In addition, the time course of the olfactory, cognitive and motor impairments verified in rats treated intranasally with MPTP, which appears to be correlated with different stages of the human PD, suggest that the MPTP intranasal model in rats may provide new insights into the underlying mechanisms of PD pathogenesis.

Cellular and molecular mechanisms of Parkinson's disease: neurotoxins, causative genes, and inflammatory cytokines.

1. Parkinson's disease (PD) is considered to be an aging-related neurodegeneration of catecholamine (CA) systems [typically A9 dopamine (DA) neurons in the substantia nigra and A6 noradrenaline (NA) neurons in the locus coeruleus]. The main symptom is movement disorder caused by a DA deficiency at the nerve terminals of fibers that project from the substantia nigra to the striatum. Most PD is sporadic (sPD) without any hereditary history. sPD is speculated to be caused by some exogenous or endogenous substances that are neurotoxic toward CA neurons, which toxicity leads to mitochondrial dysfunction and subsequent oxidative stress resulting in the programmed cell death (apoptosis or autophagy) of DA neurons. 2. Recent studies on the causative genes of rare familial PD (fPD) cases, such as alpha-synuclein and parkin, suggest that dysfunction of the ubiquitin-proteasome system (UPS) and the resultant accumulation of misfolded proteins and endoplasmic reticulum stress may cause the death of DA neurons. 3. Activated microglia, which accompany an inflammatory process, are present in the nigro-striatum of the PD brain; and they produce protective or toxic substances, such as cytokines, neurotrophins, and reactive oxygen or nitrogen species. These activated microglia may be neuroprotective at first in the initial stage, and later may become neurotoxic owing to toxic change to promote the progression toward the death of CA neurons.4. All of these accumulating evidences on sPD and fPD points to a hypothesis that multiple primary causes of PD may be ultimately linked to a final common signal-transduction pathway leading to programmed cell death, i.e., apoptosis or autophagy, of the CA neurons.

Identification and haplotype analysis of LRRK2 G2019S in Japanese patients with Parkinson disease

LRRK2 G2019S is the most common known cause of Parkinson disease (PD) in patients of European origin, but little is known about its distribution in other populations. The authors identified two of 586 Japanese patients with PD heterozygous for the mutation who shared a haplotype distinct from that observed in Europeans. This suggests that G2019S originated from separate founders in Europe and Japan and is more widely dispersed than previously recognized.

Visual hallucinations in the diagnosis of idiopathic Parkinson’s disease: a retrospective autopsy study

Visual hallucinations (VH) in idiopathic Parkinson’s disease (PD) have classically been considered to be a complication of antiparkinsonian treatment. The cause of VH is now thought to be nerve-cell loss and Lewy-body pathology in the ventral-temporal regions of the brain. However, the use of VH as a clinical sign of PD has not been previously investigated. In this study, the authors identified 788 cases with parkinsonism archived at the Queen Square Brain Bank for Neurological Diseases. Patients had not been given standardized antemortem assessments. Clinical records were retrospectively assessed for reports of VH. The incidence of VH in pathologically diagnosed cases was calculated, and factors affecting onset of VH were investigated. The authors found evidence of VH in 50% (221 of 445) of patients with PD, in 73% (32 of 44) with dementia with Lewy bodies (DLB), and in only 7% (18 of 255) of patients with non-Lewy-body parkinsonism. The specificity of VH for Lewy-body parkinsonism (PD and DLB combined) was 92.9% (95% CI 89.1–95.8) and the positive predictive value was 93.4% (89.7–95.8). VH were associated with cognitive dysfunction (hazard ratio 5.62, 3.37–9.35), autonomic dysfunction (3.13, 1.77–5.52), axial rigidity (2.22, 1.26–3.85) within the first 2 years of disease onset, and also age of onset (1.05, 1.03–1.07). In PD, the onset of VH typically occurred in the second half of the disease course, and time to onset of VH was only weakly correlated with use of selegiline (Spearman’s rho 0.22, P = .005) and ergot dopamine agonists (0.24, P = .006) but not correlated with use of levodopa, amantadine, or anticholinergic drugs. The authors conclude that the presence of VH is helpful in the differentiation of PD from other non-Lewy-body causes of parkinsonism. They also suggest that VH be added, as a supportive criterion, to the diagnostic clinical criteria for PD.—Valérie Biousse

Parkinsonism associated with basal ganglia cryptococcal abscesses in an immunocompetent patient

Currently, infectious agents are a rare cause of parkinsonism. We report on an immunocompetent patient with persistent parkinsonism associated with cryptococcal abscesses of the basal ganglia.

S.11.03 Can cells repair the brain in Parkinson's disease?

Parkinson’s disease (PD) is a neurodegenerative movement disorder characterized by the loss of dopaminergic neurons in the substantia nigra of the midbrain. To date, a number of PD-causing genes have been found, including SNCA, LRRK2, VPS35, PARK2, PINK1, DJ-1, ATP13A2, and most recently CHCHD2. Mutations in these genes range from point mutations to larger exonic rearrangements including deletions and duplications. This study aimed to detect possible copy number variation (CNV) in the known PD-causing genes in a cohort of South African patients with PD. Multiplex Ligation-dependent Probe Amplification (MLPA) analysis was performed on a total of 210 South African PD patients, and possible CNVs were verified using quantitative real time PCR. No homozygous or compound heterozygous exon rearrangements in the genes analysed were found in the patient group. A heterozygous PARK2 exon 4 deletion was found in a sporadic patient with an age at onset of 51 years. Sanger sequencing did not reveal any additional mutations in PARK2 in this patient. Combining our results with that of previous studies in a South African cohort, the frequency of exonic rearrangements in the known PD-causing genes is only 1.8% (8/439 patients). In conclusion, CNV in the known PD-causing genes are a rare cause of PD in a South African cohort, and there may be as yet unknown genetic causes of PD that are specific to patients of African ethnicity.

Regulation of p53 by Activated Protein Kinase C-δ during Nitric Oxide-induced Dopaminergic Cell Death

Selective cell death of dopaminergic neurons in the substantia nigra is the major cause of Parkinson disease. Current evidence suggests that this cell death could be mediated by nitric oxide by-products such as nitrate and peroxynitrite. Because protein kinase C (PKC)-delta is implicated in apoptosis of various cell types, we studied its roles and activation mechanisms in nitric oxide (NO)-induced apoptosis of SN4741 dopaminergic cells. When cells were treated with sodium nitroprusside (SNP), a NO donor, endogenous PKC-delta was nitrated and activated. Immunoprecipitation revealed that p53 co-immunoprecipitated with PKC-delta and was phosphorylated at the 15th serine residue in SNP-treated cells. An in vitro kinase assay revealed that p53 was directly phosphorylated by SNP-activated PKC-delta. The p53 Ser-15 phosphorylation was suppressed in SNP-treated cells when the NO-mediated activation of PKC-delta was inhibited by rottlerin or (-)-epigallocatechin gallate. Within 3 h of p53 phosphorylation, its protein levels increased because of decreased ubiquitin-dependent proteosomal proteolysis, whereas the protein levels of MDM2, ubiquitin-protein isopeptide ligase, were down-regulated in a p53 phosphorylation-dependent fashion. Taken together, these results demonstrate that nitration-mediated activation of PKC-delta induces the phosphorylation of the Ser-15 residue in p53, which increases its protein stability, thereby contributing to the nitric oxide-mediated apoptosis-like cell death pathway. These findings may be expanded to provide new insight into the cellular mechanisms of Parkinson disease.

Deep brain stimulation: Preoperative issues

Numerous factors need to be taken into account in deciding whether a patient with Parkinson's disease (PD) is a candidate for deep brain stimulation. Patient-related personal factors including age and the presence of other comorbid disorders need to be considered. Neuropsychological and neuropsychiatric concerns relate both to the presurgical status of the patient and to the potential for surgery to result in new problems postoperatively. A number of factors related to the underlying PD need to be considered, including the specific parkinsonian motor indications (e.g., tremor, bradykinesia, gait dysfunction), previous medical therapies, including benefit from current therapy and adverse effects, and past surgical treatments. Definable causes of Parkinsonism, particularly atypical Parkinsonisms, should be considered. Finally, methods of evaluating outcomes should be defined and formalized. This is a report from the Consensus on Deep Brain Stimulation for Parkinson's Disease, a project commissioned by the Congress of Neurological Surgeons and the Movement Disorder Society (MDS). The report has been endorsed by the Scientific Issues Committee of the MDS and the American Society of Stereotactic and Functional Neurosurgery. It outlines answers to a series of questions developed to address all aspects of deep brain stimulation preoperative decision-making.

Pramipexole protects against H2O2-induced PC12 cell death

Pramipexole, a novel non-ergot dopamine (DA) agonist, has been successfully applied to the treatment of Parkinson's disease (PD). Although the specific cause of PD remains unknown, recent studies have provided evidence that oxidative stress plays a role in the parthenogenesis of the disease. In the present study, we examined the effect of pramipexole on hydrogen peroxide (H2O2, 100 microM)-induced PC12 cell death, and the intracellular mechanism of this effect. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay revealed that pretreatment of PC12 cells with pramipexole (1-100 microM) resulted in significant protection against H2O2-induced cell death in a concentration-dependent manner. The protective effect of pramipexole was not affected by pretreatment with the DA receptor antagonists sulpiride, spiperone or domperidone, suggesting that the effect of pramipexole is not mediated by DA receptors. In PC12 cells, pramipexole inhibited H2O2-induced lactate dehydrogenase (LDH) leakage, as well as H2O2-induced cytochrome c release and caspase-3 activation with the resultant apoptosis. It was also observed in PC12 cells that H2O2 stimulated phosphorylation of mitogen-activated protein (MAP) kinases, i.e., extracellular signal-regulated kinase1/2 (ERK1/2), c-Jun NH2-terminal kinase (JNK) and p38 MAP kinase. Pramipexole inhibited H2O2-induced JNK and p38 MAP kinase, but not ERK1/2 phosphorylation. Furthermore, in these cells experiments with a fluorescent probe, 2-[6-(4'-amino)phenoxy-3H-xanthen-3-on-9-yl]benzoic acid, revealed that pramipexole, the JNK inhibitor SP600125 and the p38 MAP kinase inhibitor SB203580 inhibited the generation of H2O2-induced reactive oxygen species. Caspase inhibitors Z-DEVD-FMK and Z-IETD-FMK, as well as SP600125 and SB203580, inhibited H2O2-induced PC12 cell death to a similar extent as pramipexole. These results suggest that pramipexole exerts a protective effect against oxidative stress-induced PC12 cell death in part through an inhibition of JNK and p38 MAP kinase.

Tetrahydrobiopterin causes mitochondrial dysfunction in dopaminergic cells: Implications for Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disorder associated with a selective loss of dopaminergic neurons in the substantia nigra. While the underlying cause of PD is not clearly understood, oxidative stress and mitochondrial dysfunction are thought to play a role. We have previously suggested tetrahydrobiopterin (BH4), an obligatory cofactor for the dopamine synthesis enzyme tyrosine hydroxylase and present selectively in monoaminergic neurons in the brain, as an endogenous molecule that contributes to the dopaminergic neurodegeneration. In the present study, we show that BH4 leads to inhibition of activities of complexes I and IV of the electron transport chain (ETC) and reduction of mitochondrial membrane potential. BH4 appears to be different from rotenone and MPP +, the synthetic compounds used to generate Parkinson models, in its effect on complex IV. BH4 also induces the release of mitochondrial cytochrome c. Pretreatment with the sulfhydryl antioxidant N-acetylcysteine or the quinone reductase inducer dimethyl fumarate prevents the ETC inhibition and cytochrome c release following BH4 exposure, suggesting the involvement of quinone products. Together with our previous observation that BH4 leads to generation of oxidative stress and selective dopaminergic neurodegeneration both in vitro and in vivo via inducing apoptosis, the mitochondrial involvement in BH4 toxicity further suggests possible relevance of this endogenous molecule to pathogenesis of PD.

Visual hallucinations in the diagnosis of idiopathic Parkinson’s disease: a retrospective autopsy study

Visual hallucinations (VH) and other disturbances of visual perception occur in several neurodegenerative diseases, including idiopathic Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). VH in PD are classically considered to be a complication of antiparkinsonian treatment. However, recent studies have suggested that one of the causes of VH is nerve-cell loss and Lewy-body pathology in the ventral-temporal regions of the brain. The authors retrospectively identified 788 cases with Parkinson syndrome archived at the Queen Square Brain Bank for Neurological Diseases. Patients had not been given standardized antemortem assessments. Clinical records were reviewed looking for reports of VH. The incidence of VH in pathologically diagnosed cases was calculated, and factors affecting onset of VH were investigated. The authors found evidence of VH in 50% (221 of 445) of patients with PD, in 73% (32 of 44) with dementia with Lewy bodies (DLB), and in only 7% (18 of 255) of patients with non-Lewy-body parkinsonism. The specificity of VH for Lewy-body parkinsonism (PD and DLB combined) was 92.9% (95% CI 89.1 to 95.8) and the positive predictive value was 93.4% (89.7 to 95.8). VH were associated with cognitive dysfunction (hazard ratio 5.62, 3.37 to 9.35), autonomic dysfunction (3.13, 1.77 to 5.52), axial rigidity (2.22, 1.26 to 3.85) within the first 2 years of disease onset and also age of onset (1.05, 1.03 to 1.07). In PD, the onset of VH typically occurred in the second half of the disease course, and time to onset of VH was only weakly correlated with use of selegiline (Spearman’s rho .22, P = .005) and ergot dopamine agonists (.24, P = .006) but was not correlated with use of levodopa, amantadine, or anticholinergic drugs. The authors conclude that the presence of VH is helpful in the differentiation of PD from other non-Lewy-body causes of parkinsonism.—Valérie Biousse

Parkinson's disease in diphenyl-exposed workers—A causal association?

We report a cluster of five cases of Parkinson's disease (PD) among paper mill workers exposed to a fungicide, diphenyl. The cause of PD is still unknown, but epidemiological studies have indicated an elevated risk of developing PD after exposure to pesticides. The five cases of PD were found in a group of 255 diphenyl-exposed workers, and the number of expected cases in the exposed group was estimated to be 0.9, resulting in a relative risk of 5.6 (95% CI 1.8–13). Exposure to diphenyl may have contributed to this PD cluster, but chance is an alternative explanation.

Parkinson's Disease Research Education and Clinical Centers (PADRECC): Background and overview

Parkinson's disease (PD) afflicts more than 1,000,000 people in the United States and over 50,000 veterans obtain their medical care for PD within the Veterans Health Care System. In an effort to improve care for this growing population of veterans suffering from PD, the Veteran's Health Administration established 6 Parkinson's disease Research, Education, and Clinical Centers (PADRECC) based on merit. These 6 centers offer state of the art diagnosis and treatment of PD and other movement disorders. The PADRECC also provide education for both the professional community and patients not only at the 6 sites, but also throughout the VA system through the development of a national consortium. Improving veterans' health care through research is also a priority for the PADRECC. All 6 PADRECC are participating in the largest surgical trial for the treatment of PD ever performed. Heath service researchers have already identified quality of care indicators that are now being used to evaluate care for veterans with PD. Basic researchers at the PADRECC are studying the cause of PD and are developing new therapies including stem cells. The development of the PADRECC has created an important infrastructure and attracted expertise into the VA system. They have already made great improvements in caring for veterans with PD and promises to push the field further with their research efforts.

LRRK2

It is now clear that genetic risk is important in the pathogenesis of Parkinson disease (PD). Initial studies focusing on families with clear mendelian inheritance led to the identification of five genes with a confirmed role in PD etiology: α-synuclein ( SCNA ; PARK1), parkin ( PRKN ; PARK2), PTEN-induced putative kinase 1 ( PINK1 ; PARK6), oncogene DJ-1 ( DJ-1 ; PARK7), and leucine-rich repeat kinase 2 ( LRRK2 ; PARK8). Mutations in three of these genes, SCNA , PINK1 , and DJ-1 , are rare causes of PD.1 However, the role of parkin in PD etiology has been greatly expanded. Mutations in parkin were thought initially to cause only early-onset, autosomal recessive PD.2 Further studies have shown that mutations in parkin can be found among individuals with adult-onset disease3 and suggest that heterozygous mutations in parkin might act as a susceptibility factor, increasing the risk of PD.4 LRRK2 seems likely to contribute to more typical, idiopathic PD. Mutations have been reported in patients of all ages. However, LRRK2 has posed major challenges for researchers. The most formidable is the size of the gene. LRRK2 includes 51 exons. As a result, thorough screening of this gene to identify novel mutations is costly and time-consuming. Three articles in this issue of Neurology have taken different approaches to this difficult problem. Two …

Analysis of LRRK2 G2019S and I2020T mutations in Parkinson's disease

Mutations in the leucine-rich repeat kinase 2 (LRRK2), encoding dardarin protein, have been demonstrated to be linked to autosomal dominant Parkinson's disease (PD). In the present study the entire exon 41 of LRRK2 gene was evaluated in a series of 174 PD patients recruited from Polish population, aged at the time of diagnosis 54.0 ± 39.1 years, 21 of them had positive family history of PD with mean onset of the disease of 51.9 ± 11.7 years as well as in 190 healthy controls aged 73.7 ± 6.0 years. The mutations were evaluated by direct sequencing for mutations in exon 41 of LRRK2 gene. In the studied patients no known mutations in exon 41 of LRRK2 gene, including G2019S and I2020T were found, both in PD patients as well as in the controls. It can be concluded that the G2019S and I2020T mutations in exon 41 of LRRK2 gene are rare causes of Parkinson disease in a Polish population.

Visual hallucinations in the diagnosis of idiopathic Parkinson's disease: a retrospective autopsy study

For many years, visual hallucinations (VH) in idiopathic Parkinson's disease (PD) were thought to be a complication of antiparkinsonian treatment. The cause of VH is now thought to be nerve-cell loss and Lewy-body pathology in the ventral-temporal regions of the brain. However, the use of VH as a clinical sign of PD has not been investigated. 788 cases with parkinsonism archived at the Queen Square Brain Bank for Neurological Diseases were identified for study. Patients had not been given standardised antemortem assessments. Clinical records were assessed for reports of VH. The incidence of VH in pathologically diagnosed cases was calculated, and factors affecting onset of VH were investigated. VH occurred in 50% (221/445) of patients with PD, in 73% (32/44) with dementia with Lewy bodies (DLB), and in only 7% (18/255) of patients with non-Lewy-body parkinsonism. The specificity of VH for Lewy-body parkinsonism (PD and DLB combined) was 92.9% (95% CI 89.1-95.8) and the positive predictive value was 93.4% (89.7-95.8). VH were associated with cognitive dysfunction (hazard ratio 5.62, 3.37-9.35), autonomic dysfunction (3.13, 1.77-5.52), axial rigidity (2.22, 1.26-3.85) within the first 2 years of disease onset and also age of onset (1.05, 1.03-1.07). In PD, the onset of VH typically occurred in the second half of the disease course, and time to onset of VH was only weakly correlated with use of selegiline (Spearman's rho 0.22, p=0.005) and ergot dopamine agonists (0.24, p=0.006) but not correlated with use of levodopa, amantadine, or anticholinergic drugs. The presence of VH is helpful in the differentiation of PD from other non-Lewy-body causes of parkinsonism. We propose that VH be added, as a supportive criterion, to the operational clinical criteria for the diagnosis of PD.