Improving Access to Yoga for Chronic Pain in a Spanish-Speaking Community: A Quality Improvement Initiative.

BACKGROUND: The recent increase in opioid misuse and overdose among the Hispanic population signifies the need for an initiative to increase efforts in pain management in the Hispanic population. Yoga is an evidence-based therapeutic intervention that is effective for several pain-associated disorders. However, in the United States, it is primarily taught in English and not always accessible. This quality improvement (QI) project aimed to assess the outcome of implementing a yoga program on pain and quality of life in the Hispanic population. METHODS: Twenty Spanish-speaking community center members participated in a linguistically-tailored yoga program over the course of 10 weeks that included educational, demonstration, and practice videos. Outcome measures of the QI program included changes in pain interference, physical function, opioid medication use, the overall impression of change in pain, satisfaction with the program, and the likelihood of continuation of yoga practice. RESULTS: Data collected from participants (n = 16) after the 10-week period indicated that nearly 60% experienced an improvement in their overall impression of change in pain; their reported likelihood of continuation of yoga practice at home or another location were 6.8 and 7.4, respectively, on a 10-point scale. While pain interference was unaffected, there was an improvement in markers of physical function, including a two-fold improvement in general activity without limitations. The mean average intensity of pain decreased by 33%. CONCLUSION: The use of a linguistically-tailored yoga program improved self-reported overall pain, physical function, average intensity of pain, and initiated an interest in participants in utilizing yoga practice for self-management of pain. This QI project provides results that can be used for further implementation initiatives at other sites and consideration of use in diverse populations.

Implementation of a Clinic-Based Yoga Program for Chronic Pain.

PURPOSE: Although many integrative therapies exist, studies increasingly demonstrate yoga can help change the negative neuroplastic effects experienced by people living with chronic pain. Despite encouraging findings, a gap exists in accessible yoga programs designed to meet the individual needs of those experiencing limitations from chronic pain. This study evaluated a yoga program designed for people living with chronic pain delivered in a health care setting. Although yoga began as a spiritual practice thousands of years ago, it is now widely practiced for its physical and mental well-being aspects achieved through movement and breathing techniques. DESIGN: This was a piolt study that did not include a control group. METHODS: Twenty-one people with chronic pain participated in an in-person group yoga program for 8 weeks that included an educational program and yoga practice. A prepost design was used to measure effectiveness of the program on pain interference (Brief Pain Inventory), physical function, opioid medication use, overall impression of change in pain, satisfaction with the program, and likelihood of continuation of yoga practice. RESULTS: Data collected from participants demonstrated a decrease in pain interference as measured by the Brief Pain Inventory subscale between pre- and postintervention (5.6 ± 2.2 to 4.0 ± 2.3). In addition, the proportion of respondents with a pain interference rating of severe decreased by 15.4% (38.1% to 22.7%) between the pre- and postintervention time point. On follow-up from a survey 3 months after the completion of the study, more than 25% (N = 5) of participants were still practicing yoga daily. CONCLUSIONS: Despite yoga being practiced for thousands of years, studies evaluating the neural effects of yoga show possible reversal of persistent patterns leading to chronic pain, leading to new interest in an ancient practice. This study helps fill the gap in research findings addressing the benefits of yoga programs designed to meet the needs of people living in chronic pain and provides an accessible option. This program provides pain management nurses an innovative nonpharmacological intervention to consider for people living with chronic pain. CLINICAL IMPLICATIONS: Evidence supporting the use of yoga in the treatment of chronic pain is growing, yet it remains an underutilized approach in a comprehensive treatment plan. Yoga can not only improve self-agency, but also reduces social isolation. Pain management nurses can play an important role in promoting the application of yoga for chronic pain and advocating for yoga programs that are focused on accessibility for people living with pain.

Midsagittal corpus callosal thickness and cognitive impairment in Parkinson's disease.

People diagnosed with Parkinson's disease (PD) can experience significant neuropsychiatric symptoms, including cognitive impairment and dementia, the neuroanatomical substrates of which are not fully characterised. Symptoms associated with cognitive impairment and dementia in PD may relate to direct structural changes to the corpus callosum via primary white matter pathology or as a secondary outcome due to the degeneration of cortical regions. Using magnetic resonance imaging, the corpus callosum can be investigated at the midsagittal plane, where it converges to a contiguous mass and is not intertwined with other tracts. The objective of this project was thus twofold: First, we investigated possible changes in the thickness of the midsagittal callosum and cortex in patients with PD with varying levels of cognitive impairment; and secondly, we investigated the relationship between the thickness of the midsagittal corpus callosum and the thickness of the cortex. Study participants included cognitively unimpaired PD participants (n = 35), PD participants with mild cognitive impairment (n = 22), PD participants with dementia (n = 17) and healthy controls (n = 27). We found thinning of the callosum in PD-related dementia compared with PD-related mild cognitive impairment and cognitively unimpaired PD participants. Regression analyses found thickness of the left medial orbitofrontal cortex to be positively correlated with thickness of the anterior callosum in PD-related mild cognitive impairment. This study suggests that a midsagittal thickness model can uncover changes to the corpus callosum in PD-related dementia, which occur in line with changes to the cortex in this advanced disease stage.

The Neuroinflammatory Acute Phase Response in Parkinsonian-Related Disorders.

BACKGROUND: Neuroinflammation is implicated in the pathophysiology of Parkinson's disease (PD) and related conditions, yet prior clinical biomarker data report mixed findings. OBJECTIVES: The aim was to measure a panel of neuroinflammatory acute phase response (APR) proteins in the cerebrospinal fluid (CSF) of participants with PD and related disorders. METHODS: Eleven APR proteins were measured in the CSF of 867 participants from the BioFINDER cohort who were healthy (612) or had a diagnosis of PD (155), multiple system atrophy (MSA) (26), progressive supranuclear palsy (PSP) (22), dementia with Lewy bodies (DLB) (23), or Parkinson's disease with dementia (PDD) (29). RESULTS: CSF APR proteins were mostly unchanged in PD, with only haptoglobin and α1-antitrypsin significantly elevated compared to controls. These proteins were variably increased in the other disorders. Certain protein components yielded unique signatures according to diagnosis: ferritin and transthyretin were selectively elevated in MSA and discriminated these patients from all others. Haptoglobin was selectively increased in PSP, discriminating this disease from MSA when used in combination with ferritin and transthyretin. This panel of proteins did not correlate well with severity of motor impairment in any disease category, but several (particularly ceruloplasmin and ferritin) were associated with memory performance (Mini-Mental State Examination) in patients with DLB and PDD. CONCLUSIONS: These findings provide new insights into inflammatory changes in PD and related disorders while also introducing biomarkers of potential clinical diagnostic utility. © 2022 International Parkinson and Movement Disorder Society.

Plasma Phospho-Tau Identifies Alzheimer's Co-Pathology in Patients with Lewy Body Disease.

BACKGROUND: Alzheimer's disease co-pathology is common in dementia with Lewy bodies and Parkinson's disease with dementia (Lewy body disease) and can reliably be detected with positron emission tomography (PET) or cerebrospinal fluid (CSF) biomarkers. Recently developed blood biomarkers are more accessible and less expensive alternatives. OBJECTIVE: To investigate if plasma phospho-tau217 and phospho-tau181 can detect Alzheimer's pathology in Lewy body disease with dementia. METHODS: In this cross-sectional study we investigated plasma phospho-tau217 and phospho-tau181 in 35 patients with Lewy body disease with dementia. Patients underwent tau-PET imaging (18 F-RO948). RESULTS: Plasma phospho-tau217 correlated with plasma phospho-tau181, CSF phospho-tau217 (rs = 0.68, P < 0.001), and negatively with CSF ß-amyloid42/40 (rs = -0.52, P = 0.001). Plasma phospho-tau217 and phospho-tau181 correlated with tau-PET signal in the temporal cortex (rs > 0.56, P < 0.001) and predicted abnormal tau-PET status and ß-amyloid status (area under the curve > 0.78 and > 0.81, respectively). CONCLUSION: Plasma phospho-tau might be a useful marker for Alzheimer's co-pathology in Lewy body disease with dementia. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Longitudinal degeneration of the basal forebrain predicts subsequent dementia in Parkinson's disease.

OBJECTIVES: Cholinergic dysfunction plays a prominent role in cognitive impairment in Parkinson's disease (PD). The aim of this study was to assess the relationship of baseline and longitudinal basal forebrain atrophy with cognitive decline and dementia in PD. METHODS: We included 106 non-demented PD patients, 19 PD dementia (PDD) patients and 42 controls with longitudinal structural MRI and cognitive testing. After 4.2 ± 1.8 years, 20 non-demented PD patients were diagnosed with dementia (PD-dementia converters), whereas the rest of PD patients remained non-demented (stable-PD). We compared MRI volumes of the medial septum/diagonal band (Ch1/Ch2) and nucleus basalis of Meynert (Ch4) between groups. Cox regression analyses were applied to test whether Ch1/Ch2 or Ch4 atrophy could predict future dementia and linear mixed models assessed their association with cognitive decline. RESULTS: Compared to controls, we found reduced Ch4 baseline volumes in PD-dementia converters (p = .003) and those who already had PDD (p < .001) but not in stable-PD. Over time, there was a greater loss in Ch1/Ch2 volumes in PD-dementia converters and PDD compared to the other groups (p = .004). Baseline and longitudinal Ch4 volumes were associated with cognition (p < .002) and longitudinal Ch4 atrophy predicted future dementia (p = .009). CONCLUSIONS: Atrophy of Ch4 precedes and predicts future dementia in PD and is followed by changes in Ch1/Ch2, reflecting a posterior-anterior pattern of basal forebrain atrophy. This pattern could be used to track the spread of cholinergic degeneration and identify patients at risk of developing dementia.

Cerebrospinal fluid levels of neurogranin in Parkinsonian disorders.

BACKGROUND: CSF concentration of neurogranin has been suggested as a biomarker for synapse dysfunction. OBJECTIVES: To investigate CSF neurogranin in parkinsonian disorders compared to controls and Alzheimer's disease and the possible correlations between neurogranin and cognitive and motor impairment. METHODS: We included 157 patients with PD, 29 with PD with dementia, 11 with dementia with Lewy bodies, 26 with MSA, 21 with PSP, 6 with corticobasal syndrome, 47 controls, and 124 with Alzheimer's disease. CSF neurogranin was measured using two enzyme-linked immunosorbent assays; from EUROIMMUN and the University of Gothenburg. RESULTS: We found a strong correlation between CSF neurogranin-EI and CSF neurogranin-University of Gothenburg (Rs = 0.890; P < 0.001). Neurogranin was decreased in PD, PD with dementia, MSA, and PSP compared to controls and Alzheimer's disease. Neurogranin did not correlate with motor or cognitive impairment, longitudinal decline, or progression to dementia in PD. CONCLUSIONS: CSF neurogranin is decreased in parkinsonian disorders compared to controls, emphasizing the importance of synaptic dysfunction in these disorders. © 2019 International Parkinson and Movement Disorder Society.

Diffusion Tensor MRI to Distinguish Progressive Supranuclear Palsy from α-Synucleinopathies.

Background The differential diagnosis of progressive supranuclear palsy (PSP) and Lewy body disorders, which include Parkinson disease and dementia with Lewy bodies, is often challenging due to the overlapping symptoms. Purpose To develop a diagnostic tool based on diffusion tensor imaging (DTI) to distinguish between PSP and Lewy body disorders at the individual-subject level. Materials and Methods In this retrospective study, skeletonized DTI metrics were extracted from two independent data sets: the discovery cohort from the Swedish BioFINDER study and the validation cohort from the Penn Frontotemporal Degeneration Center (data collected between 2010 and 2018). Based on previous neuroimaging studies and neuropathologic evidence, a combination of regions hypothesized to be sensitive to pathologic features of PSP were identified (ie, the superior cerebellar peduncle and frontal white matter) and fractional anisotropy (FA) was used to compute an FA score for each individual. Classification performances were assessed by using logistic regression and receiver operating characteristic analysis. Results In the discovery cohort, 16 patients with PSP (mean age ± standard deviation, 73 years ± 5; eight women, eight men), 34 patients with Lewy body disorders (mean age, 71 years ± 6; 14 women, 20 men), and 44 healthy control participants (mean age, 66 years ± 8; 26 women, 18 men) were evaluated. The FA score distinguished between clinical PSP and Lewy body disorders with an area under the curve of 0.97 ± 0.04, a specificity of 91% (31 of 34), and a sensitivity of 94% (15 of 16). In the validation cohort, 34 patients with PSP (69 years ± 7; 22 women, 12 men), 25 patients with Lewy body disorders (70 years ± 7; nine women, 16 men), and 32 healthy control participants (64 years ± 7; 22 women, 10 men) were evaluated. The accuracy of the FA score was confirmed (area under the curve, 0.96 ± 0.04; specificity, 96% [24 of 25]; and sensitivity, 85% [29 of 34]). Conclusion These cross-validated findings lay the foundation for a clinical test to distinguish progressive supranuclear palsy from Lewy body disorders. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Shah in this issue.

Feasibility Trial of a 10-Week Adaptive.

BACKGROUND: This study assessed the feasibility of implementing a yoga intervention adapted for participants diagnosed with chronic pain in a large Midwest neuroscience pain clinic. Although conducted using a small convenience sample, this was a novel program in that it was led by an advanced practice nurse certified in pain management and to teach yoga. She was therefore uniquely qualified to tailor the yoga practice to suit individual needs of study participants. DESIGN: The intervention consisted of a weekly 1-hour class for 10 weeks. Feasibility measures included patient recruitment, program adherence, patient satisfaction, global impression of change, and likelihood of continuing yoga practice. In addition, it was hypothesized that the program would positively affect participants' pain interference, physical function, pain intensity, pain behavior, mood, sleep, and pain medication usage. METHODS: Survey measurements were conducted 10 weeks before class start, immediately before the first class, and immediately after the last class. CONCLUSIONS: Although there is a strong body of research supporting the benefits of yoga for chronic pain conditions, our experience highlights some of the challenges of implementing an adaptive yoga program. Our study found that recruitment of patient through physician referral was highly feasible; however, retention rates for participants were very low. Program adherence is a barrier for research on yoga in chronic pain, as well as for clinical practice. A slight reduction in pain interference and physical function over time and trend toward improvement in all exploratory outcomes was identified. None of these trends were statistically significant, likely because of small sample size.

Alteration of putaminal fractional anisotropy in Parkinson's disease: a longitudinal diffusion kurtosis imaging study.

PURPOSE: In Parkinson's disease (PD), pathological microstructural changes occur that may be detected using diffusion magnetic resonance imaging (dMRI). However, there are few longitudinal studies that explore the effect of disease progression on diffusion indices. METHODS: We prospectively included 76 patients with PD and 38 healthy controls (HC), all of whom underwent diffusion kurtosis imaging (DKI) as part of the prospective Swedish BioFINDER study at baseline and 2 years later. Annualized rates of change in DKI parameters, including fractional anisotropy (FA), mean diffusivity (MD), and mean kurtosis (MK), were estimated in the gray matter (GM) by placing regions of interest (ROIs) in the basal ganglia and the thalamus, and in the white matter (WM) by tract-based spatial statistics (TBSS) analysis. RESULTS: When adjusting for potential confounding factors (age, gender, baseline-follow-up interval, and software upgrade of MRI scanner), only a decrease in FA in the putamen of PD patients (ß = - 0.248, P < .01) over 2 years was significantly different from the changes observed in HC over the same time period. This 2-year decrease in FA in the putamen in PD correlated with higher L-dopa equivalent dose at baseline (Spearman's rho = .399, P < .0001). CONCLUSION: The study indicates that in PD microstructural changes in the putamen occur selectively over a 2-year period and can be detected with DKI.

IL-17A enhances IL-13 activity by enhancing IL-13-induced signal transducer and activator of transcription 6 activation.

BACKGROUND: Increased IL-17A production has been associated with more severe asthma; however, the mechanisms whereby IL-17A can contribute to IL-13-driven pathology in asthmatic patients remain unclear. OBJECTIVE: We sought to gain mechanistic insight into how IL-17A can influence IL-13-driven responses. METHODS: The effect of IL-17A on IL-13-induced airway hyperresponsiveness, gene expression, mucus hypersecretion, and airway inflammation was assessed by using in vivo models of IL-13-induced lung pathology and in vitro culture of murine fibroblast cell lines and primary fibroblasts and human epithelial cell lines or primary human epithelial cells exposed to IL-13, IL-17A, or both. RESULTS: Compared with mice given intratracheal IL-13 alone, those exposed to IL-13 and IL-17A had augmented airway hyperresponsiveness, mucus production, airway inflammation, and IL-13-induced gene expression. In vitro, IL-17A enhanced IL-13-induced gene expression in asthma-relevant murine and human cells. In contrast to the exacerbating influence of IL-17A on IL-13-induced responses, coexposure to IL-13 inhibited IL-17A-driven antimicrobial gene expression in vivo and in vitro. Mechanistically, in both primary human and murine cells, the IL-17A-driven increase in IL-13-induced gene expression was associated with enhanced IL-13-driven signal transducer and activator of transcription 6 activation. CONCLUSIONS: Our data suggest that IL-17A contributes to asthma pathophysiology by increasing the capacity of IL-13 to activate intracellular signaling pathways, such as signal transducer and activator of transcription 6. These data represent the first mechanistic explanation of how IL-17A can directly contribute to the pathogenesis of IL-13-driven pathology.

Thiazolothiazole Fluorophores Exhibiting Strong Fluorescence and Viologen-Like Reversible Electrochromism.

The synthesis, electrochemical, and photophysical characterization of N,N'-dialkylated and N,N'-dibenzylated dipyridinium thiazolo[5,4-d]thiazole derivatives are reported. The thiazolothiazole viologens exhibit strong blue fluorescence with high quantum yields between 0.8-0.96. The dioctyl, dimethyl, and dibenzyl derivatives also show distinctive and reversible yellow to dark blue electrochromism at low reduction potentials. The fused bicyclic thiazolo[5,4-d]thiazole heterocycle allows the alkylated pyridinium groups to remain planar, strongly affecting their electrochemical properties. The singlet quantum yield is greatly enhanced with quaternarization of the peripheral 4-pyridyl groups (ΦF increases from 0.22 to 0.96) while long-lived fluorescence lifetimes were observed between 1.8-2.4 ns. The thiazolothiazole viologens have been characterized using cyclic voltammetry, UV-visible absorbance and fluorescence spectroscopy, spectroelectrochemistry, and time-resolved photoluminescence. The electrochromic properties observed in solution, in addition to their strong fluorescent emission properties, which can be suppressed upon 2 e- reduction, make these materials attractive for multifunctional optoelectronic, electron transfer sensing, and other photochemical applications.

Detection of ESKAPE Bacterial Pathogens at the Point of Care Using Isothermal DNA-Based Assays in a Portable Degas-Actuated Microfluidic Diagnostic Assay Platform.

An estimated 1.5 billion microbial infections occur globally each year and result in ∼4.6 million deaths. A technology gap associated with commercially available diagnostic tests in remote and underdeveloped regions prevents timely pathogen identification for effective antibiotic chemotherapies for infected patients. The result is a trial-and-error approach that is limited in effectiveness, increases risk for patients while contributing to antimicrobial drug resistance, and reduces the lifetime of antibiotics. This paper addresses this important diagnostic technology gap by describing a low-cost, portable, rapid, and easy-to-use microfluidic cartridge-based system for detecting the ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) bacterial pathogens that are most commonly associated with antibiotic resistance. The point-of-care molecular diagnostic system consists of a vacuum-degassed microfluidic cartridge preloaded with lyophilized recombinase polymerase amplification (RPA) assays and a small portable battery-powered electronic incubator/reader. The isothermal RPA assays detect the targeted ESKAPE pathogens with high sensitivity (e.g., a limit of detection of ∼10 nucleic acid molecules) that is comparable to that of current PCR-based assays, and they offer advantages in power consumption, engineering, and robustness, which are three critical elements required for the point-of-care setting. IMPORTANCE: This paper describes a portable system for rapidly identifying bacteria in resource-limited environments; we highlight the capabilities of the technology by detecting different pathogens within the ESKAPE collection, which cause nosocomial infections. The system is designed around isothermal DNA-based assays housed within an autonomous plastic cartridge that are designed with the end user in mind, who may have limited technological training. Displaying excellent sensitivity and specificity, the assay systems that we demonstrate may enable future diagnoses of bacterial infection to guide the development of effective chemotherapies and may have a role in areas beyond health where rapid detection is valuable, including in industrial processing and manufacturing, food security, agriculture, and water quality testing.

Longitudinal Measurements of Cerebrospinal Fluid Biomarkers in Parkinson's Disease.

OBJECTIVE: The purpose of this study was to investigate whether cerebrospinal fluid (CSF) levels of tau, phosphorylated tau, ß-amyloid42 , α-synuclein, neurofilament light, and YKL-40 change over time and if changes correlate with motor progression and/or cognitive decline in patients with PD and controls. METHODS: We included 63 patients with PD (nondemented) and 21 neurologically healthy controls from the prospective and longitudinal Swedish BioFINDER study, all of whom had clinical assessments and lumbar punctures at baseline and after 2 years. RESULTS: CSF tau levels correlated strongly with α-synuclein. The levels of CSF α-synuclein, tau, phosphorylated tau, neurofilament light, and YKL-40, but not ß-amyloid42 , increased in CSF over 2 years in PD. No changes were seen in the control group. Studying patients with a short disease duration ( ≤ 5 years) and patients with a long disease duration ( > 5 years) separately, α-synuclein and tau only increased in the PD group with long disease duration. In the PD group, an increase in phosphorylated tau over 2 years correlated with faster motor progression and faster cognitive decline. An increase in YKL-40 over 2 years correlated with faster cognitive decline. CONCLUSION: CSF biomarkers reflecting Lewy body pathology and neurodegeneration (α-synuclein), neuronal degeneration (tau, phosphorylated tau, and neurofilament light), and inflammation (YKL-40) increase significantly over 2 years in PD. CSF levels of α-synuclein and tau correlate and remain stable in the early symptomatic phase of PD but increase in the later phase. We hypothesize that CSF α-synuclein levels might increase as a result of more intense neurodegeneration in PD with long disease duration. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Cyclic non-opioid dynorphin A analogues for the bradykinin receptors.

Nerve injury and inflammation cause up-regulation of an endogenous opioid ligand, dynorphin A (Dyn A), in the spinal cord resulting in hyperalgesia via the interaction with bradykinin receptors (BRs). This is a non-opioid neuroexcitatory effect that cannot be blocked by opioid antagonists. Our systematic structure-activity relationships study on Dyn A identified lead ligands 1 and 4, along with the key structural feature (i.e. amphipathicity) for the BRs. However, the ligands showed very low metabolic stability in plasma (t1/2 <1h) and therefore, in order to improve their metabolic stabilities with retained biological activities, various modifications were performed. Cyclization of ligand 4 afforded a cyclic Dyn A analogue 5 that retained the same range of binding affinity as the linear ligand with improved metabolic stability (t1/2 >5h) and therefore possesses the potential as a pharmacophoric scaffold to be utilized for drug development.

Modification of amphipathic non-opioid dynorphin A analogues for rat brain bradykinin receptors.

It has been shown that under chronic pain or nerve injury conditions, up-regulated dynorphin A (Dyn A) interacts with bradykinin receptors (BRs) to cause hyperalgesia in the spinal cord. Thus BRs antagonist can modulate hyperalgesia by blocking Dyn A's interaction with the BRs in the central nervous system. In our earlier structure-activity relationship (SAR) study, [des-Arg(7)]-Dyn A-(4-11) 13 was discovered as a minimum pharmacophore for rat brain BRs with its antagonist activity (anti-hyperalgesic effect) in in vivo tests using naïve or injured animals. We have pursued further modification on the [des-Arg(7)]-Dyn A analogues and identified a key insight into the pharmacophore of the rat brain BRs: amphipathicity.

Disease-specific structural changes in thalamus and dentatorubrothalamic tract in progressive supranuclear palsy.

INTRODUCTION: The aim of this study is to identify disease-specific changes of the thalamus, basal ganglia, pons, and midbrain in patients with progressive supranuclear palsy (PSP), Parkinson's disease (PD), and multiple system atrophy with predominant parkinsonism (MSA-P) using diffusion tensor imaging and volumetric analysis. METHODS: MRI diffusion and volumetric data were acquired in a derivation of 30 controls and 8 patients with PSP and a validation cohort comprised of controls (n = 21) and patients with PSP (n = 27), PD (n = 10), and MSA-P (n = 11). Analysis was performed using regions of interest (ROI), tract-based spatial statistic (TBSS), and tractography and results compared between diagnostic groups. RESULTS: In the derivation cohort, we observed increased mean diffusivity (MD) in the thalamus, superior cerebellar peduncle, and the midbrain in PSP compared to controls. Furthermore, volumetric analysis showed reduced thalamic volumes in PSP. In the validation cohort, the observations of increased MD were replicated by ROI-based analysis and in the thalamus by TBSS-based analysis. Such differences were not found for patients with PD in any of the cohorts. Tractography of the dentatorubrothalamic tract (DRTT) showed increased MD in PSP patients from both cohorts compared to controls and in the validation cohort in PSP compared to PD and MSA patients. Increased MD in the thalamus and along the DRTT correlated with disease stage and motor function in PSP. CONCLUSION: Patients with PSP, but not PD or MSA-P, exhibit signs of structural abnormalities in the thalamus and in the DRTT. These changes are associated with disease stage and impaired motor function.

Discovery of amphipathic dynorphin A analogues to inhibit the neuroexcitatory effects of dynorphin A through bradykinin receptors in the spinal cord.

We hypothesized that under chronic pain conditions, up-regulated dynorphin A (Dyn A) interacts with bradykinin receptors (BRs) in the spinal cord to promote hyperalgesia through an excitatory effect, which is opposite to the well-known inhibitory effect of opioid receptors. Considering the structural dissimilarity between Dyn A and endogenous BR ligands, bradykinin (BK) and kallidin (KD), this interaction could not be predicted, but it allowed us to discover a potential neuroexcitatory target. Well-known BR ligands, BK, [des-Arg(10), Leu(9)]-kallidin (DALKD), and HOE140 showed different binding profiles at rat brain BRs than that previously reported. These results suggest that neuronal BRs in the rat central nervous system (CNS) may be pharmacologically distinct from those previously defined in non-neuronal tissues. Systematic structure-activity relationship (SAR) study at the rat brain BRs was performed, and as a result, a new key structural feature of Dyn A for BR recognition was identified: amphipathicity. NMR studies of two lead ligands, Dyn A-(4-11) 7 and [des-Arg(7)]-Dyn A-(4-11) 14, which showed the same high binding affinity, confirmed that the Arg residue in position 7, which is known to be crucial for Dyn A's biological activity, is not necessary, and that a type I ß-turn structure at the C-terminal part of both ligands plays an important role in retaining good binding affinities at the BRs. Our lead ligand 14 blocked Dyn A-(2-13) 10-induced hyperalgesic effects and motor impairment in in vivo assays using naïve rats. In a model of peripheral neuropathy, intrathecal (i.th.) administration of ligand 14 reversed thermal hyperalgesia and mechanical hypersensitivity in a dose-dependent manner in nerve-injured rats. Thus, ligand 14 may inhibit abnormal pain states by blocking the neuroexcitatory effects of enhanced levels of Dyn A, which are likely to be mediated by BRs in the spinal cord.

Structure-activity relationships of non-opioid [des-Arg(7)]-dynorphin A analogues for bradykinin receptors.

In our earlier studies, bradykinin receptors (BRs) were identified as a potential target for the neuroexcitatory effects of dynorphin A (Dyn A) in the central nervous system (CNS), and [des-Arg(7)]-Dyn A-(4-11) (6) was discovered as a lead ligand to modulate Dyn A-(2-13) induced neuroexcitatory effects in the CNS as an antagonist. In an effort to gain insights into key structural features of the Dyn A for the BRs, we pursued further structure-activity relationships (SAR) study on the [des-Arg(7)]-Dyn A analogs and confirmed that all of the [des-Arg(7)]-Dyn A analogues showed good binding affinities at the BRs.