Alterations in B Cell and Follicular T-Helper Cell Subsets in Patients with Acute COVID-19 and COVID-19 Convalescents.

BACKGROUND: Humoral immunity requires interaction between B cell and T follicular helper cells (Tfh) to produce effective immune response, but the data regarding a role of B cells and Tfh in SARS-CoV-2 defense are still sparse. METHODS: Blood samples from patients with acute COVID-19 (n = 64), convalescents patients who had specific IgG to SARS-CoV-2 N-protein (n = 55), and healthy donors with no detectable antibodies to any SARS-CoV-2 proteins (HC, n = 44) were analyses by multicolor flow cytometry. RESULTS: Patients with acute COVID-19 showed decreased levels of memory B cells subsets and increased proportion plasma cell precursors compared to HC and COVID-19 convalescent patients, whereas for the latter the elevated numbers of virgin naïve, Bm2' and "Bm3+Bm4" was found if compared with HC. During acute COVID-19 CXCR3+CCR6- Tfh1-like cells were decreased and the levels of CXCR3-CCR6+ Tfh17-like were increased then in HC and convalescent patients. Finally, COVID-19 convalescent patients had increased levels of Tfh2-, Tfh17- and DP Tfh-like cells while comparing their amount with HC. CONCLUSIONS: Our data indicate that COVID-19 can impact the humoral immunity in the long-term.

Chorein Sensitive Dopamine Release from Pheochromocytoma (PC12) Cells.

BACKGROUND: Chorein, a protein supporting activation of phosphoinositide 3 kinase (PI3K), participates in the regulation of actin polymerization and cell survival. A loss of function mutation of the chorein encoding gene VPS13A (vacuolar protein sorting-associated protein 13A) leads to chorea-acanthocytosis (ChAc), a neurodegenerative disorder with simultaneous erythrocyte akanthocytosis. In blood platelets chorein deficiency has been shown to compromise expression of vesicle-associated membrane protein 8 (VAMP8) and thus degranulation. The present study explored whether chorein is similarly involved in VAMP8 expression and dopamine release of pheochromocytoma (PC12) cells. METHODS: Chorein was down-regulated by silencing in PC12 cells. Transmission electron microscopy was employed to quantify the number of vesicles, RT-PCR to determine transcript levels, Western blotting to quantify protein expression and ELISA to determine dopamine release. RESULTS: Chorein silencing significantly reduced the number of vesicles, VAMP8 transcript levels and VAMP8 protein abundance. Increase of extracellular K+ from 5 mM to 40 mM resulted in marked stimulation of dopamine release, an effect significantly blunted by chorein silencing. CONCLUSIONS: Chorein deficiency down-regulates VAMP8 expression, vesicle numbers and dopamine release in pheochromocytoma cells.

Up-regulation of hepatic alpha-2-HS-glycoprotein transcription by testosterone via androgen receptor activation.

BACKGROUND/AIMS: Fetuin-A (alpha-2-HS-glycoprotein, AHSG), a liver borne plasma protein, contributes to the prevention of soft tissue calcification, modulates inflammation, reduces insulin sensitivity and fosters weight gain following high fat diet or ageing. In polycystic ovary syndrome, fetuin-A levels correlate with free androgen levels, an observation pointing to androgen sensitivity of fetuin-A expression. The present study thus explored whether the expression of hepatic fetuin-A is modified by testosterone. METHODS: HepG2 cells were treated with testosterone and androgen receptor antagonist flutamide, and were silenced with androgen receptor siRNA. To test the in vivo relevance, male mice were subjected to androgen deprivation therapy (ADT) for 7 weeks. AHSG mRNA levels were determined by quantitative RT-PCR and fetuin-A protein abundance by Western blotting. RESULTS: In HepG2 cells, AHSG mRNA expression and fetuin-A protein abundance were both up-regulated following testosterone treatment. The human alpha- 2-HS-glycoprotein gene harbors putative androgen receptor response elements in the proximal 5 kb promoter sequence relative to TSS. The effect of testosterone on AHSG mRNA levels was abrogated by silencing of the androgen receptor in HepG2 cells. Moreover, treatment of HepG2 cells with the androgen receptor antagonist flutamide in presence of endogenous ligands in the medium significantly down-regulated AHSG mRNA expression and fetuin-A protein abundance. In addition, ADT of male mice was followed by a significant decrease of hepatic Ahsg mRNA expression and fetuin-A protein levels. CONCLUSIONS: Testosterone participates in the regulation of hepatic fetuin-A expression, an effect mediated, at least partially, by androgen receptor activation.

Upregulation of the Na⁺-coupled phosphate cotransporters NaPi-IIa and NaPi-IIb by B-RAF.

B-RAF, a serine/threonine protein kinase, contributes to signaling of insulin-like growth factor IGF1. Effects of IGF1 include stimulation of proximal renal tubular phosphate transport, accomplished in large part by Na⁺-coupled phosphate cotransporter NaPi-IIa. The related Na⁺-coupled phosphate cotransporter NaPi-IIb accomplishes phosphate transport in intestine and tumor cells. The present study explored whether B-RAF influences protein abundance and/or activity of type II Na⁺-coupled phosphate cotransporters NaPi-IIa and NaPi-IIb. cRNA encoding wild-type NaPi-IIa and wild-type NaPi-IIb was injected into Xenopus oocytes with or without additional injection of cRNA encoding wild-type B-RAF, and electrogenic phosphate transport determined by dual-electrode voltage clamp. NaPi-IIa protein abundance in Xenopus oocyte cell membrane was visualized by confocal microscopy and quantified by chemiluminescence. Moreover, in HEK293 cells, the effect of B-RAF inhibitor PLX-4720 on NaPi-IIa cell surface protein abundance was quantified utilizing biotinylation of cell surface proteins and western blotting. In NaPi-IIa-expressing Xenopus oocytes, but not in oocytes injected with water, addition of phosphate to extracellular bath generated a current (I P), which was significantly increased following coexpression of B-RAF. According to kinetic analysis, coexpression of B-RAF enhanced the maximal IP. Coexpression of B-RAF further enhanced NaPi-IIa protein abundance in the Xenopus oocyte cell membrane. Treatment of HEK293 cells for 24 h with PLX-4720 significantly decreased NaPi-IIa cell membrane protein abundance. Coexpression of B-RAF, further significantly increased IP in NaPi-IIb-expressing Xenopus oocytes. Again, B-RAF coexpression enhanced the maximal IP. In conclusion, B-RAF is a powerful stimulator of the renal and intestinal type II Na⁺-coupled phosphate cotransporters NaPi-IIa and NaPi-IIb, respectively.

Structural brain changes associated with depressive symptoms in the elderly with Alzheimer's disease.

OBJECTIVE: To examine neuroanatomical changes associated with depressive symptoms in Alzheimer's disease (AD) and the relationship between brain structure and cerebrospinal fluid (CSF) AD biomarkers in depressed and non-depressed patients. METHODS: Two independent cohorts were used in this study. The first cohort (KI) was collected from the Memory Clinic at Karolinska University Hospital and consisted of 41 AD patients. The second cohort was selected and downloaded from the Alzheimer's Disease Neuroimaging Initiative database (ADNI) and consisted of 148 patient. Patients underwent medical, neuropsychological assessment, laboratory analyses of CSF, including ß amyloid 1-42 (Aß 42), total τ (t-τ), phosphorylated τ 181 (p-τ) and brain MRI examination. In the KI cohort, depression was assessed using the Cornell Scale for Depression in Dementia, and in the ADNI cohort the Geriatric Depression Scale was applied. 3D T1-weighted MRI images were processed using automated steps for segmentation and surface reconstruction implemented in Freesurfer. General linear model analysis was used as a statistical approach. RESULTS: Cortical thinning in AD patients with depressive symptoms compared with those without was observed in the left parietal and temporal brain regions in both cohorts. Negative correlation between cortical thickness and t-τ was greater in depressed compared with non-depressed AD patients in precuneus and parahippocampal cortex. CONCLUSIONS: Our findings suggest that depressive symptoms in AD patients are associated with cortical thinning in temporal and parietal regions. In addition, our findings suggest that τ protein pathology in these areas may contribute to the development of depressive symptoms in AD.

Chorein sensitivity of actin polymerization, cell shape and mechanical stiffness of vascular endothelial cells.

BACKGROUND/AIMS: Endothelial cell stiffness plays a key role in endothelium-dependent control of vascular tone and arterial blood pressure. Actin polymerization and distribution of microfilaments is essential for mechanical cell stiffness. Chorein, a protein encoded by the VPS13A gene, defective in chorea-acanthocytosis (ChAc), is involved in neuronal cell survival as well as cortical actin polymerization of erythrocytes and blood platelets. Chorein is expressed in a wide variety of further cells, yet nothing is known about the impact of chorein on cells other than neurons, erythrocytes and platelets. The present study explored whether chorein is expressed in human umbilical vein endothelial cells (HUVECs) and addressed the putative role of chorein in the regulation of cytoskeletal architecture, stiffness and survival of those cells. METHODS: In HUVECs with or without silencing of the VPS13A gene, VPS13A mRNA expression was determined utilizing quantitative RT-PCR, cytoskeletal organization visualized by confocal microscopy, G/F actin ratio and phosphorylation status of focal adhesion kinase quantified by western blotting, cell death determined by flow cytometry, mechanical properties studied by atomic force microscopy (AFM) and cell morphology analysed by scanning ion conductance microscopy (SICM). RESULTS: VPS13A mRNA expression was detectable in HUVECs. Silencing of the VPS13A gene attenuated the filamentous actin network, decreased the ratio of soluble G-actin over filamentous F-actin, reduced cell stiffness and changed cell morphology as compared to HUVECs silenced with negative control siRNA. These effects were paralleled by a significant decrease in FAK phosphorylation following VPS13A silencing. Moreover, silencing of the VPS13A gene increased caspase 3 activity and induced necrosis in HUVECs. CONCLUSIONS: Chorein is a novel regulator of cytoskeletal architecture, cell shape, mechanical stiffness and survival of vascular endothelial cells.

Effect of carbon monoxide donor CORM-2 on vitamin D3 metabolism.

BACKGROUND/AIMS: Carbon monoxide (CO) interferes with cytochrome-dependent cellular functions and acts as gaseous transmitter. CO is released from CO-releasing molecules (CORM) including tricarbonyl-dichlororuthenium (II) dimer (CORM-2), molecules considered for the treatment of several disorders including vascular dysfunction, inflammation, tissue ischemia and organ rejection. Cytochrome P450-sensitive function include formation of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) by renal 25-hydroxyvitamin D3 1-alpha-hydroxylase (Cyp27b1). The enzyme is regulated by PTH, FGF23 and klotho. 1,25(OH)2D3 regulates Ca(2+) and phosphate transport as well as klotho expression. The present study explored, whether CORM-2 influences 1,25(OH)2D3 formation and klotho expression. METHODS: Mice were treated with intravenous CORM-2 (20 mg/kg body weight). Plasma 1,25(OH)2D3 and FGF23 concentrations were determined by ELISA, phosphate, calcium and creatinine concentrations by colorimetric methods, transcript levels by quantitative RT-PCR and protein expression by western blotting. Fgf23 mRNA transcript levels were further determined in rat osteosarcoma UMR106 cells without or with prior treatment for 24 hours with 20 µM CORM-2. RESULTS: CORM-2 injection within 24 hours significantly increased FGF23 plasma levels and decreased 1,25(OH)2D3 plasma levels, renal Cyp27b1 gene expression as well as renal klotho protein abundance and transcript levels. Moreover, treatment of UMR106 cells with CORM-2 significantly increased Fgf23 transcript levels. CONCLUSION: CO-releasing molecule CORM-2 enhances FGF23 expression and release and decreases klotho expression and 1,25(OH)2D3 synthesis. © 2013 S. Karger AG, Basel.

Sleep Mediates the Association Between Stress at Work and Incident Dementia: Study From the Survey of Health, Ageing and Retirement in Europe.

BACKGROUND: Both psychosocial stress at work and sleep disturbance may predispose impaired cognitive function and dementia in later life. However, whether sleep plays a mediating role for the link between stress at work and subsequent dementia has yet to be investigated. METHODS: Data from the Survey of Health, Ageing and Retirement in Europe were used for the study. A cohort of 7 799 dementia-free individuals (aged 71.1 ± 0.2 years) were followed up for a median of 4.1 years for incident dementia. Job demand and control were estimated using questions derived from the Karasek's Job Content Questionnaire. Sleep disturbance was ascertained by a question in the EURO-Depression scale. Cox proportional hazard models adjusted for age, sex, education, cognitive test score, and other potential covariates were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of dementia in relation to different job strain levels. RESULTS: An interaction between job demand and sleep disturbance regarding the risk of dementia was detected. Data suggested a protective role of high-level job demand for dementia in individuals with sleep disturbance (HR [95% CI]: 0.69 [0.47, 1.00]) compared with low job demand. A 4-category job strain model based on the combination of job demand and job control levels suggested that among individuals with sleep disturbance, passive job (low demand, low control) was associated with a higher risk of dementia (1.54 [1.01, 2.34]), compared to active job (high demand, high control). CONCLUSION: The link between work-related stress and risk of dementia is limited to individuals suffering sleep disturbance.

Streptococcal Arginine Deiminase Inhibits T Lymphocyte Differentiation In Vitro.

Pathogenic microbes use arginine-metabolizing enzymes as an immune evasion strategy. In this study, the impact of streptococcal arginine deiminase (ADI) on the human peripheral blood T lymphocytes function in vitro was studied. The comparison of the effects of parental strain (Streptococcus pyogenes M49-16) with wild type of ArcA gene and its isogenic mutant with inactivated ArcA gene (Streptococcus pyogenes M49-16delArcA) was carried out. It was found that ADI in parental strain SDSC composition resulted in a fivefold decrease in the arginine concentration in human peripheral blood mononuclear cell (PBMC) supernatants. Only parental strain SDSCs suppressed anti-CD2/CD3/CD28-bead-stimulated mitochondrial dehydrogenase activity and caused a twofold decrease in IL-2 production in PBMC. Flow cytometry analysis revealed that ADI decreased the percentage of CM (central memory) and increased the proportion of TEMRA (terminally differentiated effector memory) of CD4+ and CD8+ T cells subsets. Enzyme activity inhibited the proliferation of all CD8+ T cell subsets as well as CM, EM (effector memory), and TEMRA CD4+ T cells. One of the prominent ADI effects was the inhibition of autophagy processes in CD8+ CM and EM as well as CD4+ CM, EM, and TEMRA T cell subsets. The data obtained confirm arginine's crucial role in controlling immune reactions and suggest that streptococcal ADI may downregulate adaptive immunity and immunological memory.

Heterogenous CD8+ T Cell Maturation and 'Polarization' in Acute and Convalescent COVID-19 Patients.

BACKGROUND: The adaptive antiviral immune response requires interaction between CD8+ T cells, dendritic cells, and Th1 cells for controlling SARS-CoV-2 infection, but the data regarding the role of CD8+ T cells in the acute phase of COVID-19 and post-COVID-19 syndrome are still limited. METHODS: . Peripheral blood samples collected from patients with acute COVID-19 (n = 71), convalescent subjects bearing serum SARS-CoV-2 N-protein-specific IgG antibodies (n = 51), and healthy volunteers with no detectable antibodies to any SARS-CoV-2 proteins (HC, n = 46) were analyzed using 10-color flow cytometry. RESULTS: Patients with acute COVID-19 vs. HC and COVID-19 convalescents showed decreased absolute numbers of CD8+ T cells, whereas the frequency of CM and TEMRA CD8+ T cells in acute COVID-19 vs. HC was elevated. COVID-19 convalescents vs. HC had increased naïve and CM cells, whereas TEMRA cells were decreased compared to HC. Cell-surface CD57 was highly expressed by the majority of CD8+ T cells subsets during acute COVID-19, but convalescents had increased CD57 on 'naïve', CM, EM4, and pE1 2-3 months post-symptom onset. CXCR5 expression was altered in acute and convalescent COVID-19 subjects, whereas the frequencies of CXCR3+ and CCR4+ cells were decreased in both patient groups vs. HC. COVID-19 convalescents had increased CCR6-expressing CD8+ T cells. Moreover, CXCR3+CCR6- Tc1 cells were decreased in patients with acute COVID-19 and COVID-19 convalescents, whereas Tc2 and Tc17 levels were increased compared to HC. Finally, IL-27 negatively correlated with the CCR6+ cells in acute COVID-19 patients. CONCLUSIONS: We described an abnormal CD8+ T cell profile in COVID-19 convalescents, which resulted in lower frequencies of effector subsets (TEMRA and Tc1), higher senescent state (upregulated CD57 on 'naïve' and memory cells), and higher frequencies of CD8+ T cell subsets expressing lung tissue and mucosal tissue homing molecules (Tc2, Tc17, and Tc17.1). Thus, our data indicate that COVID-19 can impact the long-term CD8+ T cell immune response.

Protective Role of Mytilus edulis Hydrolysate in Lipopolysaccharide-Galactosamine Acute Liver Injury.

Acute liver injury in its terminal phase trigger systemic inflammatory response syndrome with multiple organ failure. An uncontrolled inflammatory reaction is difficult to treat and contributes to high mortality. Therefore, to solve this problem a search for new therapeutic approaches remains urgent. This study aimed to explore the protective effects of M. edulis hydrolysate (N2-01) against Lipopolysaccharide-D-Galactosamine (LPS/D-GalN)-induced murine acute liver injure and the underlying mechanisms. N2-01 analysis, using Liquid Chromatography Mass Spectrometry (LCMS) metabolomic and proteomic platforms, confirmed composition, molecular-weight distribution, and high reproducibility between M. edulis hydrolysate manufactured batches. N2-01 efficiently protected mice against LPS/D-GalN-induced acute liver injury. The most prominent result (100% survival rate) was obtained by the constant subcutaneous administration of small doses of the drug. N2-01 decreased Vascular Cell Adhesion Molecule-1 (VCAM-1) expression from 4.648 ± 0.445 to 1.503 ± 0.091 Mean Fluorescence Intensity (MFI) and Interleukin-6 (IL-6) production in activated Human Umbilical Vein Endothelial Cells (HUVECs) from 7.473 ± 0.666 to 2.980 ± 0.130 ng/ml in vitro. The drug increased Nitric Oxide (NO) production by HUVECs from 27.203 ± 2.890 to 69.200 ± 4.716 MFI but significantly decreased inducible Nitric Oxide Synthase (iNOS) expression from 24.030 ± 2.776 to 15.300 ± 1.290 MFI and NO production by murine peritoneal lavage cells from 6.777 ± 0.373 µm to 2.175 ± 0.279 µm. The capability of the preparation to enhance the endothelium barrier function and to reduce vascular permeability was confirmed in Electrical Cell-substrate Impedance Sensor (ECIS) test in vitro and Miles assay in vivo. These results suggest N2-01 as a promising agent for treating a wide range of conditions associated with uncontrolled inflammation and endothelial dysfunction.

Aggregation-based fluorescence amplification strategy: "turn-on" sensing of aminoglycosides using near-IR carbocyanine dyes and pre-micellar surfactants.

This study is aimed at developing sensing schemes without obtaining selective receptors. A series of simple carbocyanine dyes was synthesized, whose emission was quenched in water with formation of nanoparticles in the range of 20-100 nm. Fluorescence in near-IR region is "turned on" in the presence of a drug cation of middle molecular weight (400-700 Da) and sodium dodecyl sulfate (SDS), as well as anionic drugs and a cationic surfactant (cetyltrimethylammonium bromide, CTAB). Aggregates (clusters) up to 100-200 nm in size were detected using dynamic light scattering (DLS) and Rayleigh light scattering (RLS) techniques in the systems: cationic analyte-SDS, carbocyanine dye-CTAB, and in all brightly fluorescent ternary systems dye-surfactant-analyte. Small ions (<200 Da) incapable of multi-point binding do not form the aggregates or cause the emission enhancement. The "turn-on" signal is only observed at the surfactant submicellar concentrations insufficient to solubilize the dye nanoparticles. Based on these findings, we suggest a rapid and simple method for the detection of ≥4·10-5 mol/L of neomycin in urine. The proposed strategy paves the way for developing more selective methods.

MRI-Based Classification Models in Prediction of Mild Cognitive Impairment and Dementia in Late-Life Depression.

Objective: Late-life depression (LLD) is associated with development of different types of dementia. Identification of LLD patients, who will develop cognitive decline, i.e., the early stage of dementia would help to implement interventions earlier. The purpose of this study was to assess whether structural brain magnetic resonance imaging (MRI) in LLD patients can predict mild cognitive impairment (MCI) or dementia 1 year prior to the diagnosis. Methods: LLD patients underwent brain MRI at baseline and repeated clinical assessment after 1-year. Structural brain measurements were obtained using Freesurfer software (v. 5.1) from the T1W brain MRI images. MRI-based Random Forest classifier was used to discriminate between LLD who developed MCI or dementia after 1-year follow-up and cognitively stable LLD. Additionally, a previously established Random Forest model trained on 185 patients with Alzheimer's disease (AD) vs. 225 cognitively normal elderly from the Alzheimer's disease Neuroimaging Initiative was tested on the LLD data set (ADNI model). Results: MCI and dementia diagnoses were predicted in LLD patients with 76%/68%/84% accuracy/sensitivity/specificity. Adding the baseline Mini-Mental State Examination (MMSE) scores to the models improved accuracy/sensitivity/specificity to 81%/75%/86%. The best model predicted MCI status alone using MRI and baseline MMSE scores with accuracy/sensitivity/specificity of 89%/85%/90%. The most important region for all the models was right ventral diencephalon, including hypothalamus. Its volume correlated negatively with the number of depressive episodes. ADNI model trained on AD vs. Controls using SV could predict MCI-DEM patients with 67% accuracy. Conclusion: LDD patients developing MCI and dementia can be discriminated from LLD patients remaining cognitively stable with good accuracy based on baseline structural MRI alone. Baseline MMSE score improves prediction accuracy. Ventral diencephalon, including the hypothalamus might play an important role in preservation of cognitive functions in LLD.

Neuroanatomical correlates of late-life depression and associated cognitive changes.

We compared cortical thickness between patients with late-life depression (LLD) and healthy controls and between patients with early-onset (EOD) and late-onset (LOD) depression. We also tested age effects on cortical thickness in LLD and controls and if cortical thickness and hippocampal volumes were associated with cognitive performance in LLD. Three-dimensional T1-weighted magnetic resonance images were obtained in 49 LLD and 49 matched hospital controls and processed using FreeSurfer. General linear model analysis was used as a statistical approach. LLD group had thinning in the left parahippocampal, fusiform, and inferior-parietal cortex compared with controls. Age correlated with cortical thinning in controls but not in LLD. Women in the LOD groups had extensive cortical thinning in the lateral prefrontal cortex bilaterally compared with EOD women. Absence of statistically significant changes observed in men should however be treated with caution because of the low number of men in the study. Mini-Mental Status Examination score correlated with lateral prefrontal cortical thickness bilaterally and hippocampal volume in the total group of LLD and in LOD but not EOD. LLD is associated with cortical thinning, which is associated with age at depression onset, gender, and level of cognitive functioning.

Up-regulation of hERG K⁺ channels by B-RAF.

Human ether-a-go-go related-gene K⁺ channels (hERG) participate in the regulation of tumor cell proliferation and apoptosis. HERG channel activity is up-regulated by growth factors. Kinases sensitive to growth factor signaling include the serine/threonine protein kinase B-RAF. The present study thus explored whether B-RAF influences hERG channel expression and activity. To this end, hERG channels were expressed in Xenopus oocytes with or without wild-type B-RAF, hERG channel activity was determined utilizing dual-electrode voltage clamp and hERG protein abundance in the cell membrane was analyzed utilizing confocal microscopy as well as chemiluminescence. Moreover, in rhabdomyosarcoma RD cells the effect of B-RAF inhibitor PLX-4720 on hERG-mediated current was quantified by whole-cell patch clamp and hERG cell surface protein abundance by utilizing biotinylation of cell surface proteins as well as flow cytometry. As a result, co-expression of wild-type B-RAF in hERG-expressing Xenopus oocytes significantly increased hERG channel activity and hERG channel protein abundance in the cell membrane. Treatment for 24 hours of B-RAF and hERG-expressing Xenopus oocytes with B-RAF inhibitor PLX-4720 (10 µM) significantly decreased hERG-mediated current and hERG cell surface expression. Similarly, in rhabdomyosarcoma RD cells, treatment for 24 hours with B-RAF inhibitor PLX-4720 significantly decreased hERG cell membrane protein abundance and hERG-mediated current. In conclusion, B-RAF is a powerful regulator of hERG channel activity and cell surface hERG protein abundance.

Large-scale resting state network correlates of cognitive impairment in Parkinson's disease and related dopaminergic deficits.

Cognitive impairment is a common non-motor feature of Parkinson's disease (PD). Understanding the neural mechanisms of this deficit is crucial for the development of efficient methods for treatment monitoring and augmentation of cognitive functions in PD patients. The current study aimed to investigate resting state fMRI correlates of cognitive impairment in PD from a large-scale network perspective, and to assess the impact of dopamine deficiency on these networks. Thirty PD patients with resting state fMRI were included from the Parkinson's Progression Marker Initiative (PPMI) database. Eighteen patients from this sample were also scanned with (123)I-FP-CIT SPECT. A standardized neuropsychological battery was administered, evaluating verbal memory, visuospatial, and executive cognitive domains. Image preprocessing was performed using an SPM8-based workflow, obtaining time-series from 90 regions-of-interest (ROIs) defined from the AAL brain atlas. The Brain Connectivity Toolbox (BCT) was used to extract nodal strength from all ROIs, and modularity of the cognitive circuitry determined using the meta-analytical software Neurosynth. Brain-behavior covariance patterns between cognitive functions and nodal strength were estimated using Partial Least Squares. Extracted latent variable (LV) scores were matched with the performances in the three cognitive domains (memory, visuospatial, and executive) and striatal dopamine transporter binding ratios (SBR) using linear modeling. Finally, influence of nigrostriatal dopaminergic deficiency on the modularity of the "cognitive network" was analyzed. For the range of deficits studied, better executive performance was associated with increased dorsal fronto-parietal cortical processing and inhibited subcortical and primary sensory involvement. This profile was also characterized by a relative preservation of nigrostriatal dopaminergic function. The profile associated with better memory performance correlated with increased prefronto-limbic processing, and was not associated with presynaptic striatal dopamine uptake. SBR ratios were negatively correlated with modularity of the "cognitive network," suggesting integrative effects of the preserved nigrostriatal dopamine system on this circuitry.