Clinical correlates of pathology in the claustrum in Parkinson's disease and dementia with Lewy bodies

Dementia and visual hallucinations are common complications of Parkinson's disease (PD), yet their patho-anatomical bases are poorly defined. We studied α-synuclein (αSyn), tau and amyloid-β (Aβ) pathology in the claustrum of 20 PD cases without dementia, 12 PD cases with dementia (PDD) and 7 cases with dementia with Lewy bodies (DLB). αSyn positivity was observed in 75% of PD cases without dementia and in 100% of PDD and DLB cases. Aβ was observed in the claustrum in 25% of PD, 58% of PDD and 100% of DLB cases. Tau was negligible in all cases restricting further analysis. Compared to PD cases without dementia, PDD cases demonstrated a significantly greater αSyn burden in the claustrum (p = 0.0003). In addition, DLB cases showed a significantly increased αSyn deposition when compared to PDD (p = 0.02) and PD without dementia (p = 0.0002). A similar hierarchy, PD < PDD < DLB was seen in terms of Aβ burden in the claustrum. Comparison of αSyn and Aβ burden in those cases with and without visual hallucinations did not reveal any significant associations (p = 0.13 and 0.1, respectively). We demonstrate that pathology in the claustrum, a region of largely obscure physiological function, strongly relates to the presence of dementia in Parkinson's disease and DLB.     

Cerebrospinal fluid from patients with multiple system atrophy promotes in vitro α-synuclein fibril formation

The aggregation of α-synuclein (αS) in the central nervous system (CNS) is the hallmark of multiple system atrophy (MSA) and Lewy body diseases including Parkinson's disease (PD) and dementia with Lewy bodies (DLB) (α-synucleinopathies). To test the hypothesis that patients with α-synucleinopathies have a CNS environment favorable for αS aggregation, we examined the influence of cerebrospinal fluid (CSF) from patients with MSA (n = 20), DLB (n = 8), and PD (n = 10) on in vitro αS fibril (fαS) formation at pH 7.5 and 37 °C using fluorescence spectroscopy with thioflavin S, compared with those with hereditary spinocerebellar ataxia (hSCA) (n = 16), and tension-type headache (n = 7). CSF from MSA patients (MSA-CSF) promoted fαS formation more strongly than PD-, hSCA-, or headache-CSF. By electron microscopic analyses, the width of fαS formed in MSA-CSF was significantly greater than others. MSA may have a CSF environment particularly favorable for fαS formation.     

HLA rs3129882 variant in Chinese Han patients with late-onset sporadic Parkinson disease

Recently, the rs3129882 variant in intron 1 of HLA-DRA was found to be associated with late-onset sporadic Parkinson disease (PD) in Americans of European ancestry. To evaluate whether the same variant is related to PD in Chinese population, we investigated late-onset sporadic PD patients of Chinese Han ethanicity in Mainland China. We found significant difference in genotypic and allele distribution between patients and control subjects (χ² = 6.446, p = 0.040 for genotypic distribution; χ² = 5.762, p = 0.016 for allele distribution), suggesting this variant is associated with late-onset sporadic PD in Chinese Han population.     

Iron,copper, and iron regulatory protein 2 in Alzheimer's disease and related dementias

Accumulating evidence implicates a role for altered iron and copper metabolism in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD). However, imbalances in the levels of the various forms of iron at different stages of AD have not been examined. In this pilot study we extracted and measured the levels of loosely bound, non-heme and total iron and copper in the frontal cortex and hippocampus of patients with mild–moderate AD (n = 3), severe AD (n = 8) and dementia with Lewy bodies (DLB, n = 6), using graphite furnace atomic absorption spectrometry (GFAAS). Additionally, the expression of iron regulatory protein 2 (IRP2) was examined in relation to the pathological hallmarks of AD and DLB, amyloid plaques, neurofibrillary tangles (NFT), and Lewy bodies, by immunohistochemistry. We found significantly decreased loosely bound iron in the hippocampal white matter of mild–moderate and severe AD patients and a trend towards increased non-heme iron in the hippocampal gray matter of severe AD patients. Furthermore, decreased levels of total copper were seen in severe AD and DLB frontal cortex compared to controls, suggesting an imbalance in brain metal levels in both AD and DLB. The decrease in loosely bound iron in mild–moderate AD patients may be associated with myelin breakdown seen in the beginning stages of AD and implicates that iron dysregulation is an early event in AD pathogenesis.     

Polymorphism in the human DJ-1 gene is not associated with sporadic dementia with Lewy bodies or Parkinson's disease

Genetic analysis of early onset Parkinson's disease (PD) has indicated that the mutation DJ-1 gene is one cause of autosomal recessive PD. Its role in the development of late onset PD and other Lewy body associated disorders such as dementia with Lewy bodies (DLB) is however unknown. We have therefore determined the influence of a common polymorphism in the DJ-1 gene that shows strong linkage disequilibrium with other DJ-1 polymorphisms, in late onset PD and DLB. No alteration in the frequency of the intron 1 deletion allele was seen in PD or DLB, nor were DJ-1 genotypes altered by disease. Stratification of the cases according to the apolipoprotein E epsilon4 allele additionally failed to show any significant association. The DJ-1 gene does not appear to be a significant risk factor for late onset Lewy body disease in this population.     

Preparation and application of monoclonal antibodies against oxidized DJ-1. Significant elevation of oxidized DJ-1 in erythrocytes of early-stage Parkinson disease patients

DJ-1 was initially identified as a novel oncogene and has recently been found to be a causative gene for a familial form of Parkinson's disease (PD), viz, PARK7. Cysteine residue at position 106 (Cys-106) in DJ-1 was found to be oxidized preferentially under oxidative stress. In the present study, we developed specific antibodies against Cys-106-oxidized DJ-1 using baculovirus particles displaying the surface glycoprotein gp64-fusion protein as the immunizing agent. Western blot analysis combined with two-dimensional gel electrophoresis revealed that these antibodies specifically recognized oxidized DJ-1. Furthermore, we developed a competitive enzyme-linked immunosorbent assay (ELISA) for detecting oxidized DJ-1 and measured blood levels of oxidized DJ-1 in PD patients (n = 15). It was observed that the levels of oxidized DJ-1 in erythrocytes of unmedicated PD patients were markedly higher without overlap than those of medicated PD patients and healthy subjects. No significant difference was observed in DJ-1 levels between mediated and unmediated PD patient. These results suggest the oxidative modification of DJ-1 in PD patients and the potential application of the antibody for diagnosis of PD at early-stage.     

Vitamin D receptor gene polymorphism and its association with Parkinson's disease in Chinese Han population

Vitamin D plays an important role in neurodegenerative disorders as a crucial neuro-immunomodulator, and accumulating data have provided evidence for that vitamin D receptor (VDR) gene is a candidate gene for susceptibility to Parkinson's disease (PD). In this study, we performed a case-control study to demonstrate whether the risk for the development of onset of sporadic PD might be influenced by VDR gene polymorphisms in a Chinese cohort. Two hundred and sixty PD patients and 282 matched-healthy controls were genotyped for two representative single nucleotide polymorphisms (SNPs) in VDR gene (FokI C/T and BsmI G/A) by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) analysis in. Results from our study revealed that FokI C allele carriers were likely to associate with an increased risk of PD (P = 0.004) as well as early-onset PD (EOPD) (P = 0.010). Moreover, the frequency of FokI C allele was significantly increased in PD group and late-onset PD (LOPD) group relative to the control groups respectively (P = 0.023 and P = 0.033, respectively). For BsmI polymorphisms, no significant difference in genotype or allele distribution was found between PD patients and the controls, as well as gender- and age-related differences between PD patients and the controls subgroup. This study demonstrated a possible association between the VDR FokI T/C polymorphism and PD, indicating that VDR polymorphisms may well change genetic susceptibility to sporadic PD in a Han Chinese population.     

Assessment of ZnT3 and PSD95 protein levels in Lewy body dementias and Alzheimer's disease: association with cognitive impairment

The loss of zinc transporter 3 (ZnT3) has been implicated in age-related cognitive decline in mice, and the protein has been associated with plaques. We investigated the levels of ZnT3 and postsynaptic density protein 95 (PSD95), a marker of the postsynaptic terminal, in people with Parkinson's disease dementia (PDD, n = 31), dementia with Lewy bodies (DLB, n = 44), Alzheimer's disease (AD, n = 16), and controls (n = 24), using semiquantitative western blotting and immunohistochemistry in 3 cortical regions. Standardized cognitive assessments during life and semiquantitative scoring of amyloid β (Aβ), tau, and α-synuclein at postmortem were used to investigate the relationship between ZnT3 and PSD95, cognition and pathology. Associations were observed between ZnT3 and PSD95 levels in prefrontal cortex and cognitive impairment (p = 0.001 and p = 0.002, respectively) and between ZnT3 levels in the parietal cortex and cognitive impairment (p = 0.036). Associations were also seen between ZnT3 levels in cingulate cortex and severity of Aβ (p = 0.003) and tau (p = 0.011) pathologies. DLB and PDD were characterized by significant reductions of PSD95 (p < 0.05) and ZnT3 (p < 0.001) in prefrontal cortex compared with controls and AD. PSD95 levels in the parietal cortex were found to be decreased in AD cases compared with controls (p = 0.02) and PDD (p = 0.005). This study has identified Zn²⁺ modulation as a possible novel target for the treatment of cognitive impairment in DLB and PDD and the potential for synaptic proteins to be used as a biomarker for the differentiation of DLB and PDD from AD.     

The hOGG1 Ser326Cys polymorphism is not associated with sporadic Parkinson's disease

Parkinson's disease (PD) is one of the most common neurodegenerative disorders characterized by progressive and profound loss of dopaminergic neurons in the substantia nigra (SN) resulting in resting tremor, rigidity, bradykinesia, and postural instability. The primary cause of the disease is still unknown, but mitochondrial dysfunction and oxidative stress have been implicated in the neurodegenerative process. Oxoguanine DNA glycosylase (OGG1) removes oxidized guanine (8-oxo-G) from the DNA, thus reducing the mutagenic potential of this modified base. Increased 8-oxo-G levels and up-regulation of OGG1 have been detected in the SN of PD brains. Moreover, studies performed in OGG1 knockout mice revealed the importance of this enzyme in protecting dopaminergic neurons against the accumulation of oxidative DNA damage. A common Ser326Cys polymorphism is known in the human gene encoding OGG1 (hOGG1), and the mutant Cys326 variant has been associated with reduced glycosylase activity. In the present study we screened 139 sporadic PD patients and 211 healthy matched controls for the presence of the hOGG1 Ser326Cys polymorphism. The Cys326 allele frequency was similar between the groups (0.20 in PD patients and 0.19 in controls; p = 0.817), and no difference in genotype frequencies was observed. Moreover, the hOGG1 Ser326Cys polymorphism was not associated with disease age at onset (p = 0.791). Overall, present results suggest that the hOGG1 Ser326Cys polymorphism is not associated with sporadic PD.     

Microtubule-associated protein tau (MAPT) influences the risk of Parkinson's disease among Indians

Parkinson's disease (PD) is a neurodegenerative disease of the central nervous system and its prevalence increases with age. Microtubule-associated protein tau (MAPT), a neuronal protein is involved in the pathogenesis of several neurodegenerative diseases including PD. To determine the broader significance of this association with PD, replicative studies in distinct ethnic populations are required. In this study, we investigated MAPT for its potential association with PD using five haplotype-tagging SNPs and the del-In9 polymorphism of MAPT in 301 PD patients and 243 healthy controls from eastern India. Our case–control analysis did not show a significant association with any of the markers and PD. However, a risk haplotype [GAC + G] for PD was identified (OR = 1.563; 95% CI = 1.045–2.337; p = 0.03). In addition, haplotype AAC + A (OR = 2.787; 95% CI = 1.372–5.655; p = 0.004) was strongly associated with early onset PD (age at onset ≤40 years) and AAC + G haplotype showed a weak association (OR = 2.233; 95% CI = 1.018–4.895; p = 0.045) with late onset PD (age at onset >40 years). This observation highlights the significance of rs7521 in modifying the age at onset of PD under a common haplotype background. We also identified AGC + A as a risk haplotype for sporadic cases (OR = 2.773, 95% CI = 1.198–6.407, p = 0.016). This is the first association study from India conducted on MAPT among PD patients and provides valuable information for comparison with other ethnic groups.     

Thalamic cholinergic innervation is spared in Alzheimer disease compared to parkinsonian disorders

There are two major sources of cholinergic projections in the brain. The nucleus basalis of Meynert provides the principal cholinergic input of the cortical mantle and the pedunculopontine nucleus–laterodorsal tegmental complex (PPN–LDTC; hereafter referred to as PPN) provides the major cholinergic input to the thalamus. Cortical cholinergic denervation has previously been shown to be part of Alzheimer and parkinsonian dementia but there is less information about subcortical thalamic cholinergic denervation. We investigated thalamic cholinergic afferent integrity by measuring PPN–Thalamic (PPN–Thal) acetylcholinesterase (AChE) activity via PET imaging in Alzheimer (AD), Parkinson disease without dementia (PD), Parkinson disease with dementia (PDD) and dementia with Lewy bodies (DLB). AD (n = 13; mean age 75.4 ± 5.5), PD (n = 11; age 71.4 ± 6.4), PDD (n = 6; age 70.8 ± 4.7), DLB (n = 6; age 68.0 ± 8.6) and normal controls (NC; n = 14; age 69.0 ± 7.5) subjects underwent AChE [¹¹C]-methyl-4-piperidinyl propionate (PMP) PET imaging. PPN–Thal PET data were analyzed using the Nagatsuka method. There were no significant differences in mean age between the groups (F = 1.86, p = 0.134). Kruskal–Wallis testing demonstrated a significant group effect for PPN–Thal AChE hydrolysis rates (F = 9.62, p < 0.0001). Compared to NC, reduced thalamic k3 hydrolysis rate was noted in subjects with PDD (−19.8%; AChE k3 hydrolysis rates 0.1072 ± 0.0143 min⁻¹), DLB (−17.4%; 0.1103 ± 0.0112 min⁻¹) and PD (−12.8%; 0.1165 ± 0.0114 min⁻¹). Each of these 3 subgroups was statistically different from AD subjects (−0.7%; 0.1326 ± 0.0095 min⁻¹) who showed relatively spared thalamic k3 hydrolysis rates which were comparable to NC (0.1336 ± 0.0142 min⁻¹). Thalamic cholinergic denervation is present in PD, PDD, and DLB but not in AD. Neurodegenerative involvement of thalamic cholinergic afferent projections may contribute to disease-specific motor and cognitive abnormalities.     

Association between GBA L444P mutation and sporadic Parkinson's disease from Mainland China

Mutations in GBA gene have been reported to be in patients with Parkinson's disease (PD) from different ethnic populations, including Taiwanese Chinese. To explore whether mutation in GBA is also associated with PD in Mainland China, we have now a case control study. The occurrence of the GBA L444P mutation was analyzed in an independent cohort of PD patients and controls from Mainland China. This mutation was present in 20/616 (3.2%) of PD compared with 1/411 (0.2%) of controls (odds ratio, OR = 13.76, 95% Confidence interval, CI: 1.84–102.92, p = 0.001). All carriers harbored the heterozygous genotype. In a subset analysis, the frequency of this mutation was higher both in early onset (EOPD) and late onset PD (LOPD) than in controls. However, no difference in clinical characteristics, such as gender, age at onset, onset symptoms, Hoehn–Yahr stage and UPDRS, was found between L444P carriers and non-carriers. In addition, we also explored the potential relationship between GBA L444P mutation and LRRK2 G2385R and R1628P variants in patients with PD. But no association was found, either. In conclusion, our data suggest that the GBA L444P mutation plays an important role in the development of PD also in Han-Chinese patients from Mainland China.     

DLB and PDD: a role for mutations in dementia and Parkinson disease genes?

Based on the substantial overlap in clinical and pathological characteristics of dementia with Lewy bodies (DLB) and Parkinson disease with dementia (PDD) with Alzheimer disease (AD) and Parkinson disease (PD) we hypothesized that these disorders might share underlying genetic factors. The contribution of both sequence and copy number variants (CNVs) in known AD and PD genes to the genetic etiology of DLB and PDD however is currently unclear. Therefore, we performed a gene-based mutation analysis of all major AD and PD genes in 99 DLB and 75 PDD patients, including familial and sporadic forms, from Flanders, Belgium. Also, copy number variants in APP, SNCA, and PARK2 were determined. In the AD genes we detected proven pathogenic missense mutations in PSEN1 and PSEN2, and 2 novel missense variants in PSEN2 and MAPT. In the PD genes we identified 1 SNCA duplication, the LRRK2 R1441C founder mutation and 4 novel heterozygous missense variants with unknown pathogenicity. Our results suggest a contribution of established AD and PD genes to the genetic etiology of DLB and PDD though to a limited extent. They do support the hypothesis of a genetic overlap between members of the Lewy body disease spectrum, but additional genes still have to exist.     

Significance of association of HLA-C and HLA-E with psoriatic arthritis

Psoriatic arthritis (PsA) is a complex genetic disorder that results from an interplay between multiple genetic and environmental factors. The aim of the study was to assess the significance of the association between the HLA-C and HLA-E allelic groups and PsA. Our results confirm the association between HLA-C^∗06 and PsA (OR = 5.16, p < 0.0001). Furthermore, HLA-C^∗06-positive patients develop more severe disease (p < 0.01) and more frequently present with polyarticular pattern of PsA (p = 0.08). Additionally our study revealed that the HLA-C^∗02 allele was more frequently observed in PsA patients (OR = 5.40, p < 0.0005) and also that the HLA-E^∗01:01 allele was significantly over-represented among HLA-C^∗02-negative patients in comparison to healthy individuals (OR = 6.44, p = 0.045). Therefore these results suggest that the HLA-E and HLA-C^∗02 molecules may also play an important role in determination immune response contributing to the PsA development.     

Correlation of changes in pain intensity with synovial fluid adenosine triphosphate levels after treatment of patients with osteoarthritis of the knee with high-molecular-weight hyaluronic acid

We sought to determine whether a clinical association exists between osteoarthritis (OA)-associated knee pain and adenosine triphosphate (ATP) levels in synovial fluid (SF). A total of 28 patients with 28 primary OA knees were included. They routinely received intra-articular injection of high-molecular-weight hyaluronic acid (HA) once weekly for 5 weeks (treated group). Eight patients without knee pain who had undergone an operation for anterior or posterior cruciate ligament reconstruction 2 years ago were also examined (control group). SF and blood ATP concentrations, total amount of ATP, total SF volume, and Visual Analogue Scale (VAS) scores in all patients were measured and we compared pre-treatment values with those 1 week after the final treatment. We evaluated the correlation of change in total ATP (??ATP) and change in VAS score (??VAS), ??VAS and change in SF volume (??SF), and ATP concentration in SF and blood. In the treated group, SF ATP concentration, total amount of ATP, SF volume, and VAS score were all significantly lower post-treatment than pre-treatment (p = 0.0005, 0.0003, 0.0022, and < 0.0001, respectively). In treated group, ??VAS was significantly associated with ??ATP (r = 0.56, p = 0.0032), ??SF was significantly associated with ??VAS (r = 0.78, p < 0.0001), and total amount of SF ATP and SF volume at pre-treatment were significantly higher than the control group (p < 0.0001, p < 0.0001) We demonstrated an association between SF ATP level changes and OA knee pain, which should facilitate a further understanding of OA pain mechanisms.     

CXC chemokine expression profiles in aqueous humor of patients with different clinical entities of endogenous uveitis

Aqueous humor (AH) samples from patients with Behçet's disease (BD) (n = 29), Vogt-Koyanagi-Harada (VKH) disease (n = 21), and HLA-B27-associated uveitis (n = 8), and 42 control patients were assayed for the neutrophil chemoattractants CXCL1/GRO-α and CXCL8/IL-8 and the lymphocyte chemoattractants CXCL9/MIG, CXCL10/IP-10 and CXCL12/SDF-1 with the use of a multiplex chemokine assay. Chemokine levels except SDF-1 were significantly higher in the 3 disease groups than in normal controls. Considering all patients, mean GRO-α levels were 15-fold higher than IL-8 levels and mean IP-10 levels were 22-fold higher than MIG levels. In patients with the same disease activity, AH levels of GRO-α and IP-10 were significantly higher in patients with BD than in patients with VKH disease and HLA-B27-associated uveitis (p = 0.0474; p < 0.001, respectively). These data suggest that GRO-α and IP-10 are the predominant CXC chemokines involved in neutrophil and activated T lymphocyte chemoattraction in endogenous uveitis, particularly in BD.     

Associations of killer cell immunoglobulin like receptors with rheumatoid arthritis among North Indian population

Introduction

Rheumatoid arthritis (RA) is an autoimmune and chronic inflammatory disease of unknown etiology. Killer cell immunoglobulin-like receptors (KIR) expressed on surface of natural killer cells and CD28 null T-cells which are present in synovial membrane of RA. The present study has evaluated associations of KIR genes with RA among North Indian population from Uttar Pradesh.

Materials and methods

KIR genotypes were determined in 100 RA cases and 100 healthy controls using sequence specific primer polymerase chain reaction (PCR-SSP) method.

Results

RA cases positive for KIR3DS1 (OR = 1.17, p-value = 0.0498) and KIR2DS2 (OR = 2.21, p-value = 0.0120) showed risk associations. While, KIR2DL2 (OR = 0.40, p-value = 0.0026), KIR2DL3 (OR = 0.44, p-value = 0.0283) and KIR3DL1 (OR = 0.32, p-value = 0.0012) showed protective associations. Increased incidence of BB genotype (45%) was revealed among cases. Risk association was noted against telomeric region (OR = 2.12, p = 0.0120) genes for RA. Pair-wise linkage disequilibrium (LD) analysis among RA cases revealed KIR2DS1-2DL1 (D′ = 0.83, r² = 0.36), KIR3DL1-3DS1 (D′ = 1, r² = 0.58) and KIR2DL1-2DL2 (D′ = 1, r² = 0.61) to be in significant LD. KIR3DS1 and KIR2DS3 genes showed significant risk associations among RA patients with extra-articular manifestations (OR = 5.14, p-value = 0.0018; OR = 3.79, p-value = 0.0106) and in limited range of motion in affected joints (OR = 14.91, p-value = 0.0001; OR = 2.95, p-value = 0.0126).

Conclusion

The KIR activating genes have risk association with RA in the present study.