Protocol of a prospective study on the diagnostic value of transcranial duplex scanning of the substantia nigra in patients with parkinsonian symptoms

Background  

Parkinson's disease (PD) is the second most common neurodegenerative disorder. As there is no definitive diagnostic test, its diagnosis is based on clinical criteria. Recently transcranial duplex scanning (TCD) of the substantia nigra in the brainstem has been proposed as an instrument to diagnose PD. We and others have found that TCD scanning of substantia nigra duplex is a relatively accurate diagnostic instrument in patients with parkinsonian symptoms. However, all studies on TCD so far have involved well-defined, later-stage PD patients, which will obviously lead to an overestimate of the diagnostic accuracy of TCD.     

The quality of care delivered to Parkinson's disease patients in the U.S. Pacific Northwest Veterans Health System

Background  

Parkinson's disease (PD) is the second most common chronic neurological disorder of the elderly. Despite the fact that a comprehensive review of general health care in the United States showed that the quality of care delivered to patients usually falls below professional standards, there is limited data on the quality of care for patients with PD.     

Proteome analysis of human substantia nigra in Parkinson's disease

Background  

Parkinson's disease (PD) is the most common neurodegenerative disorder involving the motor system. Although not being the only region involved in PD, affection of the substantia nigra and its projections is responsible for some of the most debilitating features of the disease. To further advance a comprehensive understanding of nigral pathology, we conducted a tissue based comparative proteome study of healthy and diseased human substantia nigra.     

Efficacy and acceptability of selective serotonin reuptake inhibitors for the treatment of depression in Parkinson's disease: a systematic review and meta-analysis of randomized controlled trials

Background  

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressants for the treatment of depression in patients with Parkinson's Disease (PD) but data on their efficacy are controversial.     

Current clinical practice for Parkinson’s disease among Chinese physicians,general neurologists and movement disorders specialists: a national survey

Background

To explore current status and choices regarding diagnosis and treatment of Parkinson’s disease (PD) among physicians, general neurologists and movement disorders specialists in China via a national survey.

Methods

The cross-sectional questionnaire-based survey was conducted from November, 2010 to July, 2011. Six hundreds and twelve doctors from different cities in China were recruited for this study.

Results

68.6% (n=420) and 23.9% (n=146) of doctors have read the national and international guidelines, respectively. There was a larger proportion of movement disorders specialists reading the guidelines, in contrast to physicians and general neurologists (P<0.001). Up to 76.4% (n=465) and 81.8% (n=498) of doctors would choose standard oral levodopa test and conventional MRI(with T1 and T2), respectively; Whereas susceptibility weighed imaging(SWI)(16.1%; n=98), transcranial sonography (TCS) (1.8%; n=11) and functional neuroimaging test, such as single photon emission computed tomography(SPECT) (10.2%; n=62) and positron emission tomography(PET)(13.3%; n=81) were less used for suspected patients with PD in clinical practice. Doctors at different levels or from different hospitals and cities would choose different medication for motor complications and non-motor symptoms of patients with PD, in addition to initial drug selection for newly diagnosed PD. Doctors who had read the guidelines had significantly better knowledge of medication selections for PD under specific circumstances.

Conclusions

Compared with commonly employed standard oral levodopa test and conventional MRI, SWI complements MRI, TCS and functional neuroimaging were less performed for diagnosis of PD in clinical practice in China. The choices of diagnostic methods and therapeutic strategy of PD vary among physicians, general neurologists and movement disorders specialists. Guideline awareness is markedly beneficial to reasonable PD medications strategy in China.

     

Metallomic Profiling and Linkage Map Analysis of Early Parkinson's Disease: A New Insight to Aluminum Marker for the Possible Diagnosis

Background

Parkinson''s disease (PD) is the most common neurodegenerative disorder. The diagnosis of PD is challenging and currently none of the biochemical tests have proven to help in diagnosis. Serum metallomic analysis may suggest the possibility of diagnosis of PD.

Methodology/Results

The metallomic analysis was targeted on 31 elements obtained from 42 healthy controls and 45 drug naive PD patients using ICP-AES and ICP-MS to determine the concentration variations of elements between PD and normal. The targeted metallomic analysis showed the significant variations in 19 elements of patients compared to healthy control (p<0.04). The partial least squares discriminant analysis (PLS-DA) showed aluminium, copper, iron, manganese and zinc are the key elements, contributes the separation of PD patients from control samples. The correlation coefficient analysis and element-element ratio confirm the imbalance of inter-elements relationship in PD patients'' serum. Furthermore, elements linkage map analysis showed aluminium is a key element involved in triggering of phosphorus, which subsequently lead to imbalance of homeostatic in PD serum. The execution of neural network using elements concentrations provides 95% accuracy in detection of disease.

Conclusions/Significance

These results suggest that there is a disturbance in the elements homeostasis and inter-elements relationship in PD patients'' serum. The analysis of serum elements helps in linking the underlying cellular processes such as oxidative stress, neuronal dysfunction and apoptosis, which are the dominating factors in PD. Also, these results increase the prospect of detection of early PD from serum through neural network algorithm.     

Limb-shaking transient ischemic attacks: case report and review of literature

Background

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, characterized clinically by resting tremor, bradykinesia, postural instability and rigidity. The prevalence of PD is approximately 2% of the population over 65 years of age and 1.7 million PD patients (age ≥ 55 years) live in China. Recently, a common LRRK2 variant Gly2385Arg was reported in ethnic Chinese PD population in Taiwan. We analyzed the frequency of this variant in our independent PD case-control population of Han Chinese from Taiwan.

Methods

305 patients and 176 genetically unrelated healthy controls were examined by neurologists and the diagnosis of PD was based on the published criteria. The region of interest was amplified with standard polymerase chain reaction (PCR). PCR fragments then were directly sequenced in both forward and reverse directions. Differences in genotype frequencies between groups were assessed by the X ² test, while X ² analysis was used to test for the Hardy-Weinberg equilibrium.

Results

Of the 305 patients screened we identified 27 (9%) with heterozygous G2385R variant. This mutation was only found in 1 (0.5%) in our healthy control samples (odds ratio = 16.99, 95% CI: 2.29 to 126.21, p = 0.0002). Sequencing of the entire open reading frame of LRRK2 in G2385R carriers revealed no other variants.

Conclusion

These data suggest that the G2385R variant contributes significantly to the etiology of PD in ethnic Han Chinese individuals. With consideration of the enormous and expanding aging Chinese population in mainland China and in Taiwan, this variant is probably the most common known genetic factor for PD worldwide.     

Diagnostic Accuracy of Apparent Diffusion Coefficient and 123I-Metaiodobenzylguanidine for Differentiation of Multiple System Atrophy and Parkinson’s Disease

Background

It is often hard to differentiate Parkinson’s disease (PD) and parkinsonian variant of multiple system atrophy (MSA-P), especially in the early stages. Cardiac sympathetic denervation and putaminal rarefaction are specific findings for PD and MSA-P, respectively.

Purpose

We investigated diagnostic accuracy of putaminal apparent diffusion coefficient (ADC) test for MSA-P and ¹²³I-metaiodobenzylguanidine (MIBG) scintigram for PD, especially in early-stage patients.

Methods

The referral standard diagnosis of PD and MSA-P were the diagnostic criteria of the United Kingdom Parkinson’s Disease Society Brain Bank Criteria and the second consensus criteria, respectively. Based on the referral standard criteria, diagnostic accuracy [area under the receiver-operator characteristic curve (AUC), sensitivity and specificity] of the ADC and MIBG tests was estimated retrospectively. Diagnostic accuracy of these tests performed within 3 years of symptom onset was also investigated.

Results

ADC and MIBG tests were performed on 138 patients (20 MSA and 118 PD). AUC was 0.95 and 0.83 for the ADC and MIBG tests, respectively. Sensitivity and specificity were 85.0% and 89.0% for MSA-P diagnosis by ADC test and 67.0% and 80.0% for PD diagnosis by MIBG test. When these tests were restricted to patients with disease duration ≤3 years, the sensitivity and specificity were 75.0% and 91.4% for the ADC test (MSA-P diagnosis) and 47.7% and 92.3% for the MIBG test (PD diagnosis).

Conclusions

Both tests were useful in differentiating between PD and MSA-P, even in the early stages. In early-stage patients, elevated putaminal ADC was a diagnostic marker for MSA-P. Despite high specificity of the MIBG test, careful neurological history and examinations were required for PD diagnosis because of possible false-negative results.     

Predictive Value of Clinical Judgment of Tumour Progression in Phase II Trials

Background

The diagnosis of tumour progression or progressive disease (PD) is a key element for designing and interpreting contemporary phase II trials. In some cases, PD is stated by the physician and is not formally confirmed by imaging.

Purpose

In this study, we intend to analyze the value of the PD based on clinical judgment and the risk of overestimating the occurrence of PD by clinical judgment.

Methods

We have conducted a single-centre retrospective study to analyse the diagnostic accuracy of this clinical judgment compared to planned imaging including all patients enrolled in our institution in phase II trials investigating systemic treatments for advanced solid tumours between January 2008 and November 2010.

Results

The positive predictive value (PPV) and the specificity of clinical judgment of PD was very high (>90%).

Conclusions

According to this study, the clinical judgment of PD is highly predictive of radiological PD as assessed, for example, by RECIST. Physicians do not overestimate PD occurence. Clinical judgment of PD could be taken into account in the definition of PD.     

"Closing-in" phenomenon in Alzheimer's disease and subcortical vascular dementia

Background  

The 'closing-in' phenomenon is defined as a tendency to close in on a model while copying it. This is one of several constructional apraxia observed in dementia, particularly in Alzheimer's disease (AD). The aim of this study was to investigate the usefulness of it in the differential diagnosis of AD and subcortical vascular dementia (SVD) and to clarify the factors associated with it.     

A cross-sectional study of the nutritional status of community-dwelling people with idiopathic Parkinson's disease

Background  

Parkinson's disease (PD) patients have an increased risk of under-nutrition, but we are unaware of any population based prevalence studies of under-nutrition in PD. The main objective of this study was to identify the prevalence, and nature, of under-nutrition in a representative population of people with PD.     

Novel multiplex technology for diagnostic characterization of rheumatoid arthritis

Introduction  

The aim of this study was to develop a clinical-grade, automated, multiplex system for the differential diagnosis and molecular stratification of rheumatoid arthritis (RA).     

Design and baseline characteristics of the ParkFit study,a randomized controlled trial evaluating the effectiveness of a multifaceted behavioral program to increase physical activity in Parkinson patients

Background  

Many patients with Parkinson's disease (PD) lead a sedentary lifestyle. Promotion of physical activities may beneficially affect the clinical presentation of PD, and perhaps even modify the course of PD. However, because of physical and cognitive impairments, patients with PD require specific support to increase their level of physical activity.     

Metabolic profiling of Parkinson's disease: evidence of biomarker from gene expression analysis and rapid neural network detection

Background

Parkinson's disease (PD) is a neurodegenerative disorder. The diagnosis of Parkinsonism is challenging because currently none of the clinical tests have been proven to help in diagnosis. PD may produce characteristic perturbations in the metabolome and such variations can be used as the marker for detection of disease. To test this hypothesis, we used proton NMR and multivariate analysis followed by neural network pattern detection.

Methods &; Results

¹H nuclear magnetic resonance spectroscopy analysis was carried out on plasma samples of 37 healthy controls and 43 drug-naive patients with PD. Focus on 22 targeted metabolites, 17 were decreased and 5 were elevated in PD patients (p < 0.05). Partial least squares discriminant analysis (PLS-DA) showed that pyruvate is the key metabolite, which contributes to the separation of PD from control samples. Furthermore, gene expression analysis shows significant (p < 0.05) change in expression of PDHB and NPFF genes leading to increased pyruvate concentration in blood plasma. Moreover, the implementation of ¹H- NMR spectral pattern in neural network algorithm shows 97.14% accuracy in the detection of disease progression.

Conclusion

The results increase the prospect of a robust molecular definition in detection of PD through the early symptomatic phase of the disease. This is an ultimate opening for therapeutic intervention. If validated in a genuinely prospective fashion in larger samples, the biomarker trajectories described here will go a long way to facilitate the development of useful therapies. Moreover, implementation of neural network will be a breakthrough in clinical screening and rapid detection of PD.     

Bcl-2 over-expression fails to prevent age-related loss of calretinin positive neurons in the mouse dentate gyrus

Background

Mutations in LRRK2 encoding leucine-rich repeat kinase 2 are thus far the most frequent genetic cause associated with autosomal dominant and idiopathic Parkinson's disease (PD). To examine whether LRRK2 is directly associated with neuropathology of PD and other related disorders, we analyzed LRRK2 in brains of patients affected by PD and dementia with Lewy bodies (DLB) using highly specific antibodies to LRRK2.

Results

We demonstrated that anti-LRRK2 antibodies strongly labelled brainstem and cortical Lewy bodies, the pathological hallmarks of PD and DLB, respectively. In addition, anti-LRRK2 also labelled brain vasculature, axons, and neuronal cell bodies. Interestingly, the immunocytochemical profile of LRRK2 varied with different antibodies depending upon specific antigenic sites along the LRRK2 protein. All anti-LRRK2 antibodies tested that were raised against various regions of LRRK2, were found to be immunoreactive to recombinant LRRK2 on Western blots. However, only the antibodies raised against the N-terminal and C-terminal regions of LRRK2, but not the regions containing folded protein domains, were positive in immunolabeling of Lewy bodies, suggesting a differential exposure of specific antigenic sites of LRRK2 on tissue sections.

Conclusion

We conclude that LRRK2 is a component of Lewy bodies in both PD and DLB, and therefore plays an important role in the Lewy body formation and disease pathogenesis. Information on the cellular localization of LRRK2 under normal and pathological conditions will deepen our understanding of its functions and molecular pathways relevant to the progression of PD and related disorders.     

Periodontitis and Porphyromonas gingivalis in Preclinical Stage of Arthritis Patients

Purpose

To determine whether the presence of periodontitis (PD) and Porphyromonas gingivalis (Pg) in the subgingival biofilm associates with the development of rheumatoid arthritis (RA) in treatment naïve preclinical stage of arthritis patients.

Methods

We conducted a prospective cohort study of 72 consecutive patients with arthralgia who had never been treated with any anti-rheumatic drugs or glucocorticoids. Periodontal status at baseline was assessed by dentists. PD was defined stringently by the maximal probing depth≧4 mm, or by the classification by the 5th European Workshop in Periodontology (EWP) in 2005 using attachment loss. Up to eight plaque samples were obtained from each patient and the presence of Pg was determined by Taqman PCR. The patients were followed up for 2 years and introduction rate of methotrexate (MTX) treatment on the diagnosis of RA was compared in patients with or without PD or Pg.

Results

Patients with PD (probing depth≧4mm) had higher arthritis activity (p = 0.02) and higher risk for future introduction of MTX treatment on the diagnosis of RA during the follow up than patients without PD (Hazard ratio 2.68, p = 0.03). Arthritis activity and risk for MTX introduction increased with the severity of PD assessed by EWP, although not statistically significant. On the other hand, presence of Pg was not associated with arthritis activity (p = 0.72) or the risk for MTX introduction (p = 0.45).

Conclusion

In treatment naïve arthralgia patients, PD, but not the presence of Pg, associates with arthritis activity and future requirement of MTX treatment on the diagnosis of RA.     

Imaging Non-Specific Wrist Pain: Interobserver Agreement and Diagnostic Accuracy of SPECT/CT,MRI, CT,Bone Scan and Plain Radiographs

Purpose

Chronic hand and wrist pain is a common clinical issue for orthopaedic surgeons and rheumatologists. The purpose of this study was 1. To analyze the interobserver agreement of SPECT/CT, MRI, CT, bone scan and plain radiographs in patients with non-specific pain of the hand and wrist, and 2. to assess the diagnostic accuracy of these imaging methods in this selected patient population.

Materials and Methods

Thirty-two consecutive patients with non-specific pain of the hand or wrist were evaluated retrospectively. All patients had been imaged by plain radiographs, planar early-phase imaging (bone scan), late-phase imaging (SPECT/CT including bone scan and CT), and MRI. Two experienced and two inexperienced readers analyzed the images with a standardized read-out protocol. Reading criteria were lesion detection and localisation, type and etiology of the underlying pathology. Diagnostic accuracy and interobserver agreement were determined for all readers and imaging modalities.

Results

The most accurate modality for experienced readers was SPECT/CT (accuracy 77%), followed by MRI (56%). The best performing, though little accurate modality for inexperienced readers was also SPECT/CT (44%), followed by MRI and bone scan (38% each). The interobserver agreement of experienced readers was generally high in SPECT/CT concerning lesion detection (kappa 0.93, MRI 0.72), localisation (kappa 0.91, MRI 0.75) and etiology (kappa 0.85, MRI 0.74), while MRI yielded better results on typification of lesions (kappa 0.75, SPECT/CT 0.69). There was poor agreement between experienced and inexperienced readers in SPECT/CT and MRI.

Conclusions

SPECT/CT proved to be the most helpful imaging modality in patients with non-specific wrist pain. The method was found reliable, providing high interobserver agreement, being outperformed by MRI only concerning the typification of lesions. We believe it is beneficial to integrate SPECT/CT into the diagnostic imaging algorithm of chronic wrist pain.     

Biomarkers in Parkinson’s disease (recent update)

Parkinson’s disease (PD) is the second most common neurodegenerative disorder mostly affecting the aging population over sixty. Cardinal symptoms including, tremors, muscle rigidity, drooping posture, drooling, walking difficulty, and autonomic symptoms appear when a significant number of nigrostriatal dopaminergic neurons are already destroyed. Hence we need early, sensitive, specific, and economical peripheral and/or central biomarker(s) for the differential diagnosis, prognosis, and treatment of PD. These can be classified as clinical, biochemical, genetic, proteomic, and neuroimaging biomarkers. Novel discoveries of genetic as well as nongenetic biomarkers may be utilized for the personalized treatment of PD during preclinical (premotor) and clinical (motor) stages. Premotor biomarkers including hyper-echogenicity of substantia nigra, olfactory and autonomic dysfunction, depression, hyposmia, deafness, REM sleep disorder, and impulsive behavior may be noticed during preclinical stage. Neuroimaging biomarkers (PET, SPECT, MRI), and neuropsychological deficits can facilitate differential diagnosis. Single-cell profiling of dopaminergic neurons has identified pyridoxal kinase and lysosomal ATPase as biomarker genes for PD prognosis. Promising biomarkers include: fluid biomarkers, neuromelanin antibodies, pathological forms of α-Syn, DJ-1, amyloid β and tau in the CSF, patterns of gene expression, metabolomics, urate, as well as protein profiling in the blood and CSF samples. Reduced brain regional N-acetyl-aspartate is a biomarker for the in vivo assessment of neuronal loss using magnetic resonance spectroscopy and T₂ relaxation time with MRI. To confirm PD diagnosis, the PET biomarkers include [¹⁸F]-DOPA for estimating dopaminergic neurotransmission, [¹⁸F]dG for mitochondrial bioenergetics, [¹⁸F]BMS for mitochondrial complex-1, [¹¹C](R)-PK11195 for microglial activation, SPECT imaging with ¹²³Iflupane and βCIT for dopamine transporter, and urinary salsolinol and 8-hydroxy, 2-deoxyguanosine for neuronal loss. This brief review describes the merits and limitations of recently discovered biomarkers and proposes coenzyme Q₁₀, mitochondrial ubiquinone-NADH oxidoreductase, melatonin, α-synculein index, Charnoly body, and metallothioneins as novel biomarkers to confirm PD diagnosis for early and effective treatment of PD.     

Negative predictive value of SPECT for the occurrence of MACE in a medium-sized clinic in the Netherlands

Background

Single-photon emission computed tomography (SPECT) is an important prognostic tool in evaluating coronary artery disease (CAD), with a high negative predictive value (NPV) for the occurrence of major adverse cardiac events (MACE). The prognostic value of SPECT is disputed in women, patients with atrial fibrillation (AF), diabetes, left bundle branch block (LBBB) and renal impairment.

Methods

Seven hundred sixty-two patients without prior history of CAD who had SPECT without perfusion deficits were followed for 2 years for MACE. Predictive variables for the occurrence of MACE were reviewed by Cox proportional hazard regression, considering clinical information, resting-ECG data and SPECT data.

Results

The NPV of SPECT for the occurrence of MACE within 2 years was 95.8 %. Multivariate Cox regression revealed male gender as the only significant predictor for the occurrence of MACE, besides a positive stress ECG at SPECT and a low LVEF. AF, LBBB, renal impairment and diabetes had no significant effect on the prognosis after normal SPECT.

Conclusion

SPECT with normal perfusion images has great NPV in a medium-sized clinic in the Netherlands, even in patients with LBBB, AF, diabetes and renal impairment. MACE-free survival, however, was negatively influenced by male gender; we therefore propose more caution in men.