No abstract

Kallikrein 6 (K6) is a member of the kallikrein gene family that comprises 15 structurally and functionally related serine proteases. In prior studies we showed that, while this trypsin-like enzyme is preferentially expressed in neurons and oligodendroglia of the adult central nervous system (CNS), it is up-regulated at sites of injury due to expression by infiltrating immune and resident CNS cells. Given this background we hypothesized that K6 is a key contributor to the pathophysiology of traumatic spinal cord injury (SCI), influencing neural repair and regeneration. Examination of K6 expression following contusion injury to the adult rat cord, and in cases of human traumatic SCI, indicated significant elevations at acute and chronic time points, not only at the injury site but also in cord segments above and below. Elevations in K6 were particularly prominent in macrophages, microglia and reactive astrocytes. To determine potential effects of elevated K6 on the regeneration environment, the ability of neurons to adhere to and extend processes on substrata which had been exposed to recombinant K6 was examined. Limited (1 h) or excess (24 h) K6-mediated proteolytic digestion of a growth-facilitatory substrate, laminin, significantly decreased neurite outgrowth. By contrast, similar hydrolysis of a growth-inhibitory substrate, aggrecan, significantly increased neurite extension and cell adherence. These data support the hypothesis that K6 enzymatic cascades mediate events secondary to spinal cord trauma, including dynamic modification of the capacity for axon outgrowth.

Mitochondrial dysfunction has long been implicated in the pathogenesis of Parkinson’s disease (PD). PD brain tissues show evidence for mitochondrial respiratory chain Complex I deficiency. Pharmacological inhibitors of Complex I, such as rotenone, cause experimental parkinsonism. The cytoprotective protein DJ-1, whose deletion is sufficient to cause genetic PD, is also known to have mitochondria-stabilizing properties. We have previously shown that DJ-1 is over-expressed in PD astrocytes, and that DJ-1 deficiency impairs the capacity of astrocytes to protect co-cultured neurons against rotenone. Since DJ-1 modulated, astrocyte-mediated neuroprotection against rotenone may depend upon proper astrocytic mitochondrial functioning, we hypothesized that DJ-1 deficiency would impair astrocyte mitochondrial motility, fission/fusion dynamics, membrane potential maintenance, and respiration, both at baseline and as an enhancement of rotenone-induced mitochondrial dysfunction. In astrocyte-enriched cultures, we observed that DJ-1 knock-down reduced mitochondrial motility primarily in the cellular processes of both untreated and rotenone treated cells. In these same cultures, DJ-1 knock-down did not appreciably affect mitochondrial fission, fusion, or respiration, but did enhance rotenone-induced reductions in the mitochondrial membrane potential. In neuron–astrocyte co-cultures, astrocytic DJ-1 knock-down reduced astrocyte process mitochondrial motility in untreated cells, but this effect was not maintained in the presence of rotenone. In the same co-cultures, astrocytic DJ-1 knock-down significantly reduced mitochondrial fusion in the astrocyte cell bodies, but not the processes, under the same conditions of rotenone treatment in which DJ-1 deficiency is known to impair astrocyte-mediated neuroprotection. Our studies therefore demonstrated the following new findings: (i) DJ-1 deficiency can impair astrocyte mitochondrial physiology at multiple levels, (ii) astrocyte mitochondrial dynamics vary with sub-cellular region, and (iii) the physical presence of neurons can affect astrocyte mitochondrial behavior.

Activated microglia are an important feature of many neurological diseases and can be imaged in vivo using 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK11195), a ligand that binds the peripheral benzodiazepine receptor (PBR). N-(2,5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl) acetamide (DAA1106) is a new PBR-specific ligand that has been reported to bind to PBR with higher affinity compared with PK11195. We hypothesized that this high-affinity binding of DAA1106 to PBR will enable better delineation of microglia in vivo using positron emission tomography. [(3)H]DAA1106 showed higher binding affinity compared with [(3)H](R)-PK11195 in brain tissue derived from normal rats and the rats injected intrastriatally with 6-hydroxydopamine or lipopolysaccharide at the site of the lesion. Immunohistochemistry combined with autoradiography in brain tissues as well as correlation analyses showed that increased [(3)H]DAA1106 binding corresponded mainly to activated microglia. Finally, ex vivo autoradiography and positron emission tomography imaging in vivo showed greater retention of [(11)C]DAA1106 compared with [(11)C](R)-PK11195 in animals injected with either lipopolysaccaride or 6-hydroxydopamine at the site of lesion. These results indicate that DAA1106 binds with higher affinity to microglia in rat models of neuroinflammation when compared with PK11195, suggesting that [(11)C]DAA1106 may represent a significant improvement over [(11)C](R)-PK11195 for in vivo imaging of activated microglia in human neuroinflammatory disorders.

Background : PD psychosis is often associated with cognitive impairment, including dementia, and involves dopaminergic, serotonergic, and cholinergic mechanisms. Objective : To evaluate the differential effect of the antipsychotic pimavanserin, a selective serotonin 2A receptor inverse agonist, in PD psychosis patients with versus without cognitive impairment and in those receiving versus not receiving cognitive‐enhancing medications. Methods : Data from the pivotal randomized clinical trial of pimavanserin for PD psychosis were stratified by (1) screening MMSE score as cognitively impaired (21‐24) versus unimpaired (≥25) and (2) concomitant use versus nonuse of cognitive‐enhancing medications. The primary outcome measure was change in the PD‐adapted Scale for the Assessment of Positive Symptoms. Results : Mean (pimavanserin vs. placebo) change from baseline was larger in the cognitively impaired (n = 50; –6.62 vs. –0.91; P = 0.002) versus the cognitively unimpaired (n = 135; –5.50 vs. –3.23; p = 0.046) group. The comparable change was –6.04 versus –2.18 ( P = 0.012) and –5.66 versus –3.15 ( P = 0.041) in patients treated (n = 69) and not treated (n = 116) with concomitant cognitive‐enhancing medication. Pimavanserin was similarly tolerated across all cognitive groups with no additional safety concerns identified. Overall adverse event rates were comparable across the concomitant cognitive‐enhancing medication groups; however, rates of serious adverse events and discontinuations attributed to adverse events were increased in patients taking cholinesterase inhibitors. Conclusions : The antipsychotic effect of pimavanserin is robust in PD patients with cognitive impairment and may be enhanced by concomitant cognitive‐enhancing medication use. Future prospective studies are needed to confirm these preliminary findings. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

had > 2 opioid prescriptions, we identified beneficiaries with high-dose use (> 120 daily morphine milligram equivalents for ≥ 90 consecutive days) and multiple providers (≥ 4 prescribers and ≥ 4 pharmacies) each year; and concurrent benzodiazepine use (≥ 30 cumulative days) from 2013-2015 when Part D began coverage for benzodiazepines. We obtained adjusted annual rates of high-risk measures across 306 hospital referral regions (HRRs) using multivariable logistic regression and examined the association between these measures and overdose risk(claimbased) in the subsequent year using Cox proportional regression, adjusting for sociodemographic, health status, and access-to-care factors. ReSultS: Adjusted annual rates of high-dose use (~9%), having multiple providers(~5%), and concurrent benzodiazepine use (~34%) remained stable over five years. In 2015, the ratio of 75th-to-25th percentile rates of high-risk measures across HRRs were 1.80 for high-dose use, 1.87 for having multiple providers, and 1.33 for concurrent benzodiazepine use. The top 3 HRRs with the highest rate of: high-dose use were Sarasota, FL(17.2%), Sun City, AZ(17.2%) and Clearwater, FL(16.9%); multiple providers were Slidell, LA(14.0%), Muskegon, MI(12.5%), and Bryan, TX(12.0%); and concurrent benzodiazepine use were Dearborn, MI(58.0%), Miami, FL(55.4%), and Spartanburg, SC(55.1%). These measures were associated with subsequent overdose risk for high-dose (hazard ratio [HR]= 2.19, 95%CI= 1.86-2.57); multiple providers (HR= 1.58,; and concurrent benzodiazepine use (HR= 1.82, 95%CI= 1.58-2.10). ConCluSionS: High-risk opioid use measures were associated with overdose risk among disabled Medicare beneficiaries. Areas and individuals with prevalent high-risk opioid use may benefit from targeted interventions (e.g.,lock-in programs) to prevent overdose. MH4

Activated microglia are an important feature of several neurological diseases. We propose that activated microglia can be imaged using Positron Emission Tomography (PET) by taking advantage of elevated levels of peripheral benzodiazepine receptors (PBR) on activated microglia. We tested the hypothesis that DAA1106, a novel high‐affinity ligand to PBR, will specifically label activated microglia in vivo using PET. [3H]DAA1106 showed significantly higher binding in brain tissues in rats injected intrastriataly with either 6‐hydroxydopamine (6‐OHDA) or lipopolysaccaride (LPS) at the site of lesion. Immunohistochemistry combined with autoradiography in lesioned rats as well as cell cultures showed increased [3H]DAA1106 binding corresponding to activated microglia. PET imaging in vivo showed greater retention [11C]DAA1106 at the site of lesion in animals injected with either LPS or 6‐OHDA. Finally, DAA1106 showed higher affinity binding when compared to the well‐characterized PBR PET ligand PK11195 in both brain tissues and in vivo. These results indicate that DAA1106 binds with high affinity to microglia in neuroinflammatory disorders.

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