DAT and TH expression marks human Parkinson's disease in peripheral immune cells.

Parkinson's disease (PD) is marked by a loss of dopamine neurons, decreased dopamine transporter (DAT) and tyrosine hydroxylase (TH) expression. However, this validation approach cannot be used for diagnostic, drug effectiveness or investigational purposes in human patients because midbrain tissue is accessible postmortem. PD pathology affects both the central nervous and peripheral immune systems. Therefore, we immunophenotyped blood samples of PD patients for the presence of myeloid derived suppressor cells (MDSCs) and discovered that DAT+/TH+ monocytic MDSCs, but not granulocytic MDSCs are increased, suggesting a targeted immune response to PD. Because in peripheral immune cells DAT activity underlies an immune suppressive mechanism, we investigated whether expression levels of DAT and TH in the peripheral immune cells marks PD. We found drug naïve PD patients exhibit differential DAT+/TH+ expression in peripheral blood mononuclear cells (PBMCs) compared to aged/sex matched healthy subjects. While total PBMCs are not different between the groups, the percentage of DAT+/TH+ PBMCs was significantly higher in drug naïve PD patients compared to healthy controls irrespective of age, gender, disease duration, disease severity or treatment type. Importantly, treatment for PD negatively modulates DAT+/TH+ expressing PBMCs. Neither total nor the percentage of DAT+/TH+ PBMCs were altered in the Alzheimer's disease cohort. The mechanistic underpinning of this discovery in human PD was revealed when these findings were recapitulated in animal models of PD. The reverse translational experimental strategy revealed that alterations in dopaminergic markers in peripheral immune cells are due to the disease associated changes in the CNS. Our study demonstrates that the dopaminergic machinery on peripheral immune cells displays an association with human PD, with exciting implications in facilitating diagnosis and investigation of human PD pathophysiology.

Posterior Cortical Atrophy with Right Lower Egocentric Quadrantic Neglect and Lower Vertical Allocentric Neglect.

BACKGROUND/OBJECTIVES: Whereas rare cases of hemispatial visual neglect have been reported in patients with a neurodegenerative disease, quadrantic visuospatial neglect has not been described. We report a patient with probable posterior cortical atrophy who demonstrated lower right-sided quadrantic visuospatial neglect, together with allocentric vertical neglect. METHODS/RESULTS: A 68-year-old man initially noted deficits in reading and writing. Subsequently, he developed other cognitive deficits. On vertical line bisections, he deviated upward, and on horizontal line bisections, he deviated to the left. These deviations together suggest that this man's neglect might be most severe in his right (head/body-centered) lower (below eye level) visual space. When attempting to perform vertical line bisections in all four egocentric quadrants, his upward deviations were largest in the right lower quadrant. On a cancelation test, he revealed bilateral lower (ventral) allocentric neglect but not egocentric neglect. This patient's magnetic resonance imaging revealed cortical atrophy, most prominent in the left parietal lobe. DISCUSSION: Previous research in stroke patients has demonstrated that the parietal lobes are important in mediating attention to contralateral and inferior visual space. The presence of left parietal atrophy may have induced this right lower (ventral) egocentric inattention as well as bilateral ventral allocentric inattention. Although to our knowledge there have been no prior reports of a patient with right lower quadrantic and lower vertical allocentric visuospatial neglect, patients are rarely tested for these forms of neglect, and this patient illustrates the importance of evaluating patients for these and other forms of neglect.

A novel approach to study markers of dopamine signaling in peripheral immune cells.

Human monocytes express known markers of dopamine synthesis, storage and clearance, including dopamine transporter (DAT), tyrosine hydroxylase (TH), all subtypes of dopamine receptors and vesicular monoamine transporter 2 (VMAT2). Immunohistochemical and immunofluorescent methodologies have traditionally been employed to determine DAT and TH expression in the CNS, their detection in the blood and specifically in the peripheral monocytes has not been studied by flow cytometry. Flow cytometry assays are widely used in medicine and in basic, preclinical or clinical research to quantify physical and chemical characteristics of target cell populations. Here, we have established a highly sensitive and reproducible flow cytometry panel to detect and quantify DAT and TH expression in freshly isolated or cryopreserved human peripheral monocytes. In healthy humans (n = 41 biological replicates), we show baseline DAT and TH expressing monocytes constitute ~12% of the peripheral blood mononuclear cell (PBMC) fraction when examined in fresh isolation from whole blood. Using an identical flow cytometry panel, we found that cryopreservation of PBMCs using multiple techniques resulted in altered PBMC populations as compared to fresh isolation and relative to one another. Among these, we identified an optimum cryopreservation method for detecting TH and DAT in cryopreserved PBMCs. Our data provide a sensitive and reproducible approach to examine dopamine signaling in peripheral human immune cells. This approach can be applied to study peripheral dopamine signaling under healthy and potentially under disease conditions. The use of dopamine signaling could also be explored as a technique to monitor therapeutic interventions particularly those targeting DAT and TH in the periphery.

The dopamine transporter: An unrecognized nexus for dysfunctional peripheral immunity and signaling in Parkinson's Disease.

The second-most common neurodegenerative disease, Parkinson's Disease (PD) has three hallmarks: dysfunctional dopamine transmission due, at least in part, to dopamine neuron degeneration; intracellular inclusions of α-synuclein aggregates; and neuroinflammation. The origin and interplay of these features remains a puzzle, as does the underlying mechanism of PD pathogenesis and progression. When viewed in the context of neuroimmunology, dopamine also plays a role in regulating peripheral immune cells. Intriguingly, plasma dopamine levels are altered in PD, suggesting collateral dysregulation of peripheral dopamine transmission. The dopamine transporter (DAT), the main regulator of dopaminergic tone in the CNS, is known to exist in lymphocytes and monocytes/macrophages, but little is known about peripheral DAT biology or how DAT regulates the dopaminergic tone, much less how peripheral DAT alters immune function. Our review is guided by the hypothesis that dysfunctional peripheral dopamine signaling might be linked to the dysfunctional immune responses in PD and thereby suggests a potential bidirectional communication between central and peripheral dopamine systems. This review seeks to foster new perspectives concerning PD pathogenesis and progression.

A Degenerative Form of Mixed Transcortical Aphasia.

Mixed transcortical aphasia (MTA) is characterized by decreased spontaneous speech, impaired naming, and poor comprehension, but with intact repetition. MTA has been reported to be the sequela of left hemisphere watershed infarction that isolates Wernicke's perisylvian arc. We report a 55-year-old right-handed woman who began having word-finding difficulty and then gradually developed impaired spontaneous speech, comprehension, and naming, but with intact repetition. Magnetic resonance imaging showed atrophy in the left frontal, parietal, and temporal lobes. This patient demonstrates that MTA can occur as a result of neurodegenerative disease. Further research is needed to learn whether progressive MTA is a late stage of primary progressive aphasia, examine the neuropathology associated with this syndrome, and identify treatment strategies.

MicroRNA: Relevance to stroke diagnosis, prognosis, and therapy.

Stroke is a life-threatening disease that accounts for a considerable burden of mortality in both developing and developed world. Identification of specific biomarkers for stroke and its outcomes can greatly contribute to improved care of patients. MicroRNAs (miRNAs) are known as novel biomarkers that could be used as diagnostic, prognostic, and therapeutic biomarkers. Various studies have shown that miRNAs have key roles in the pathogenesis of stroke, and its complications and outcomes. In addition, there is evidence showing that mesenchaymal stromal cell-derived exosomes containing miRNAs can be used for monitoring and treatment of various diseases such as stroke. Here, we summarized various aspects of miRNA applications in different stages of stroke.

GD2-targeted immunotherapy and potential value of circulating microRNAs in neuroblastoma.

Neuroblastoma (NB) with various clinical presentation is a known childhood malignancy. Despite significant progress in treatment of NB afflicted patients, high risk disease is usually associated with poor outcome, resulting in long-term survival of less that 50%. Known as a disease most commonly originated form the nerve roots, the variants involved in NB imitation and progression remain to be elucidated. The outcome of low to intermediate risk disease is favorable whereas the high risk NB disease with dismal prognosis, positing the necessity of novel approaches for early detection and prognostication of advanced disease. Tailored immunotherapy approaches have shown significant improvement in high-risk NB patients. It has found a link between Gangliosides and progression of NB. The vast majority of neuroblastoma tumors express elevated levels of GD2, opening new insight into using anti-GD2 drugs as potential treatments for NBs. Implication of anti-GD2 monoclonal antibodies for treatment of high risk NBs triggers further investigation to unearth novel biomarkers as prognostic and response biomarker to guide additional multimodal tailored treatment approaches. A growing body of evidence supports the usefulness of miRNAs to evaluate high risk NBs response to anti-GD2 drugs and further prevent drug-related toxicities in refractory or recurrent NBs. miRNAs and circulating proteins in body fluids (plasma and serum) present as potential biomarkers in early detection of NBs. Here, we summarize various biomarkers involved in diagnosis, prognosis and response to treatment in patients with NB. We further attempted to overview prognostic biomarkers in response to treatment with anti-GD2 drugs.

A case of posterior cortical atrophy with vertical neglect.

Posterior cortical atrophy (PCA) is a syndrome caused by a neurodegenerative disease that often presents with visuospatial deficits, and can be debilitating. PCA is often characterized by elements of Balint's syndrome and dyslexia. The most common underlying pathology has been found to be Alzheimer's disease. Signs of horizontal neglect are frequently associated with PCA, but the presence of vertical (or altitudinal) neglect has not yet been reported in a patient with PCA or other forms of neurodegenerative dementia. In this paper, we present a patient with PCA who on vertical line bisection and cancellation tests revealed upper altitudinal spatial neglect. Detection of this abnormality may have important implications for diagnosis, therapeutic interventions, and patient safety.

Polymorphisms in CD14 Gene May Modify Soluble CD14 Levels and Represent Risk Factors for Multiple Sclerosis.

BACKGROUND: Besides the central role of the adaptive immune system, a disturbance of innate immune system is also suggested to be involved in the pathogenesis of multiple sclerosis (MS). CD14, a receptor upregulated in activated microglia, is known to be an essential mediator of inflammation in innate immune responses. Therefore, in this study we aimed to assess possible roles of CD14-159 and -260 gene polymorphisms in MS susceptibility and the effects of those polymorphisms to its protein producing capacity in Iranian population. METHODS: In this case control study, CD14-159 and -260 polymorphisms were genotyped using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) in 200 MS patients and 200 healthy controls matched in age and gender. Serum levels of soluble CD14 (sCD14) was determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: There were significant differences in genotype distribution of CD14-159 and -260 polymorphisms between patients and controls (P = 0.01, for-both). Mean serum level of sCD14 was significantly higher in MS patients than in control subjects (3340.30 ± 612.50 ng/ml vs 2353.73 ± 539.07 ng/ml; P < 0.01). CONCLUSION: In summary, we conclude that CD14-159 and -260 polymorphisms are associated with the risk of MS in Iranian population and affects CD14 promoter activity, thereby regulating CD14 expression. Furthermore, our study provides preliminary evidence for the activation of innate immunity in the pathogenesis of MS. In addition, the findings of the present study suggest serum level of sCD14 as candidate biomarker of MS severity.

A Novel Approach to Discriminate Subgroups in Multiple Sclerosis.

Multiple sclerosis (MS) is an autoimmune disease of central nervous system. Since different types of immune cells are involved in MS pathogenesis, in this study we aimed to evaluate serum levels of several immunological components including soluble CD4 (sCD4), sCD8, sCD163, and immunoglobulins as markers of activity of T-cells, macrophages, and B-cells in different types of MS. Serum levels of sCD4, sCD8, and sCD163 of patients with relapsing-remitting MS (RRMS, n=61), primary progressive MS (PRMS, n=31), secondary progressive MS (SPMS, n=31), clinical isolated syndrome (CIS, n=31) and neuromyelitis optica (NMO, n=31), and healthy controls (n=49) were measured using enzyme-linked immunosorbent assay (ELISA). Serum levels of Ig-G, Ig-M, and Ig-A were determined using nephelometric technique. Serum levels of sCD4, sCD8, sCD163, Ig-G, Ig-M, and Ig-A were significantly different in five groups of cases (p<0.05). Furthermore, application of stepwise method of discriminant analysis yielded 4 significant discriminant functions of classification due to the presence of six levels of categorical variables in the analysis. The most important function explained 85.5% of the total variance with the correlation value of 0.79. Taken together, our preliminary analysis suggests that although we found some functions to discriminate most of the patients, further studies will be required to individuate immunological markers characterizing the different type of MS including RRMS, PPMS, SPMS, CIS and NMO as proved by the data on sCD4, sCD163, Ig-M, and Ig-G in blood.

Linguistic Validation of the M. D. Anderson Symptom Inventory in Persian-Speaking Iranian Cancer Patients.

CONTEXT: Various symptoms frequently affect cancer patients' quality of life. Appropriate assessment of these symptoms provides valuable data for cancer management. OBJECTIVES: This study aimed to validate the Persian version of the M. D. Anderson Symptom Inventory (MDASI-P). METHODS: This cross-sectional study was conducted at four cancer treatment centers in two cities in Iran. Breast cancer and colorectal cancer patients aged 18 years and older were consecutively included in the study. The standard forward-backward translation method was applied. Patients completed the MDASI-P along with the previously validated Persian version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). Construct validity (factor analysis), criterion validity (against the EORTC QLQ-C30), and reliability (Cronbach's alpha) were analyzed. RESULTS: A total of 146 breast cancer and 94 colorectal cancer patients were studied. Factor analysis for the symptom severity items resulted in a three-factor solution, further reduced to a two-factor solution: general symptoms and gastrointestinal symptoms. Correlation of the MDASI-P symptom severity items with corresponding EORTC QLQ-C30 symptom items (r = 0.48-0.75) and MDASI-P interference items with corresponding EORTC QLQ-C30 functioning domains (r = -0.46 to -0.23) supported the criterion validity. Cronbach's alpha was 0.90, 0.88, and 0.77 for the total questionnaire, symptom severity items, and the interference subscale, respectively. CONCLUSION: The MDASI-P is a feasible, valid, and reliable instrument for evaluation of symptoms in Persian-speaking cancer patients and can be used to improve symptom management in these patients.