Publications by authors named "David S Russell"

42 Publications

Cerebral Expression of Metabotropic Glutamate Receptor Subtype 5 in Idiopathic Autism Spectrum Disorder and Fragile X Syndrome: A Pilot Study.

Int J Mol Sci 2021 Mar 11;22(6). Epub 2021 Mar 11.

Department of Psychiatry and Behavioral Sciences-Child Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Multiple lines of evidence suggest that dysfunction of the metabotropic glutamate receptor subtype 5 (mGluR) plays a role in the pathogenesis of autism spectrum disorder (ASD). Yet animal and human investigations of mGluR expression provide conflicting findings about the nature of dysregulation of cerebral mGluR pathways in subtypes of ASD. The demonstration of reduced mGluR expression throughout the living brains of men with fragile X syndrome (FXS), the most common known single-gene cause of ASD, provides a clue to examine mGluR expression in ASD. We aimed to (A) compare and contrast mGluR expression in idiopathic autism spectrum disorder (IASD), FXS, and typical development (TD) and (B) show the value of positron emission tomography (PET) for the application of precision medicine for the diagnosis and treatment of individuals with IASD, FXS, and related conditions. Two teams of investigators independently administered 3-[F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([F]FPEB), a novel, specific mGluR PET ligand to quantitatively measure the density and the distribution of mGluRs in the brain regions, to participants of both sexes with IASD and TD and men with FXS. In contrast to participants with TD, mGluR expression was significantly increased in the cortical regions of participants with IASD and significantly reduced in all regions of men with FXS. These results suggest the feasibility of this protocol as a valuable tool to measure mGluR expression in clinical trials of individuals with IASD and FXS and related conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22062863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999711PMC
March 2021

Reduced Expression of Cerebral Metabotropic Glutamate Receptor Subtype 5 in Men with Fragile X Syndrome.

Brain Sci 2020 Nov 24;10(12). Epub 2020 Nov 24.

Department of Psychiatry and Behavioral Sciences-Child Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Glutamatergic receptor expression is mostly unknown in adults with fragile X syndrome (FXS). Favorable behavioral effects of negative allosteric modulators (NAMs) of the metabotropic glutamate receptor subtype 5 (mGluR) in knockout (KO) mouse models have not been confirmed in humans with FXS. Measurement of cerebral mGluR expression in humans with FXS exposed to NAMs might help in that effort. We used positron emission tomography (PET) to measure the mGluR density as a proxy of mGluR expression in cortical and subcortical brain regions to confirm target engagement of NAMs for mGluRs. The density and the distribution of mGluR were measured in two independent samples of men with FXS ( = 9) and typical development (TD) ( = 8). We showed the feasibility of this complex study including MRI and PET, meaning that this challenging protocol can be accomplished in men with FXS with an adequate preparation. Analysis of variance of estimated mGluR expression showed that mGluR expression was significantly reduced in cortical and subcortical regions of men with FXS in contrast to age-matched men with TD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/brainsci10120899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760509PMC
November 2020

Assessment of 18F-PI-2620 as a Biomarker in Progressive Supranuclear Palsy.

JAMA Neurol 2020 11;77(11):1408-1419

Department of Nuclear Medicine, University of Leipzig, Leipzig, Germany.

Importance: Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy. Region-specific tau aggregates establish the neuropathologic diagnosis of definite PSP post mortem. Future interventional trials against tau in PSP would strongly benefit from biomarkers that support diagnosis.

Objective: To investigate the potential of the novel tau radiotracer 18F-PI-2620 as a biomarker in patients with clinically diagnosed PSP.

Design, Setting, And Participants: In this cross-sectional study, participants underwent dynamic 18F-PI-2620 positron emission tomography (PET) from 0 to 60 minutes after injection at 5 different centers (3 in Germany, 1 in the US, and 1 in Australia). Patients with PSP (including those with Richardson syndrome [RS]) according to Movement Disorder Society PSP criteria were examined together with healthy controls and controls with disease. Four additionally referred individuals with PSP-RS and 2 with PSP-non-RS were excluded from final data analysis owing to incomplete dynamic PET scans. Data were collected from December 2016 to October 2019 and were analyzed from December 2018 to December 2019.

Main Outcomes And Measures: Postmortem autoradiography was performed in independent PSP-RS and healthy control samples. By in vivo PET imaging, 18F-PI-2620 distribution volume ratios were obtained in globus pallidus internus and externus, putamen, subthalamic nucleus, substantia nigra, dorsal midbrain, dentate nucleus, dorsolateral, and medial prefrontal cortex. PET data were compared between patients with PSP and control groups and were corrected for center, age, and sex.

Results: Of 60 patients with PSP, 40 (66.7%) had RS (22 men [55.0%]; mean [SD] age, 71 [6] years; mean [SD] PSP rating scale score, 38 [15]; score range, 13-71) and 20 (33.3%) had PSP-non-RS (11 men [55.0%]; mean [SD] age, 71 [9] years; mean [SD] PSP rating scale score, 24 [11]; score range, 11-41). Ten healthy controls (2 men; mean [SD] age, 67 [7] years) and 20 controls with disease (of 10 [50.0%] with Parkinson disease and multiple system atrophy, 7 were men; mean [SD] age, 61 [8] years; of 10 [50.0%] with Alzheimer disease, 5 were men; mean [SD] age, 69 [10] years). Postmortem autoradiography showed blockable 18F-PI-2620 binding in patients with PSP and no binding in healthy controls. The in vivo findings from the first large-scale observational study in PSP with 18F-PI-2620 indicated significant elevation of tracer binding in PSP target regions with strongest differences in PSP vs control groups in the globus pallidus internus (mean [SD] distribution volume ratios: PSP-RS, 1.21 [0.10]; PSP-non-RS, 1.12 [0.11]; healthy controls, 1.00 [0.08]; Parkinson disease/multiple system atrophy, 1.03 [0.05]; Alzheimer disease, 1.08 [0.06]). Sensitivity and specificity for detection of PSP-RS vs any control group were 85% and 77%, respectively, when using classification by at least 1 positive target region.

Conclusions And Relevance: This multicenter evaluation indicates a value of 18F-PI-2620 to differentiate suspected patients with PSP, potentially facilitating more reliable diagnosis of PSP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaneurol.2020.2526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341407PMC
November 2020

Clinical evaluation of [F] JNJ-64326067, a novel candidate PET tracer for the detection of tau pathology in Alzheimer's disease.

Eur J Nucl Med Mol Imaging 2020 12 13;47(13):3176-3185. Epub 2020 Jun 13.

Janssen Research & Development, La Jolla, CA, USA.

Purpose: The accumulation of misfolded tau is a common feature of several neurodegenerative disorders, with Alzheimer's disease (AD) being the most common. Earlier we identified JNJ-64326067, a novel isoquinoline derivative with high affinity and selectivity for tau aggregates from human AD brain. We report the dosimetry of [F] JNJ-64326067 and results of a proof-of-concept study comparing subjects with probable Alzheimer's disease to age-matched healthy controls.

Methods: [F] JNJ-64326067 PET scans were acquired for 90 min and then from 120 to 180 min in 5 participants with [F]-florbetapir PET amyloid positive probable AD (73 ± 9 years) and 5 [F]-florbetapir PET amyloid negative healthy controls (71 ± 7 years). Whole-body [F] JNJ-64326067 PET CT scans were acquired in six healthy subjects for 5.5 h in 3 scanning sessions. Brain PET scans were visually reviewed. Regional quantification included kinetic analysis of distribution volume ration (DVR) estimated by Logan graphical analysis over the entire scan and static analysis of SUVr in late frames. Both methods used ventral cerebellar cortex as a reference region.

Results: One of the healthy controls had focal areas of PET signal in occipital and parietal cortex underlying the site of a gunshot injury as an adolescent; the other four healthy subjects had no tau brain signal. Four of the 5 AD participants had visually apparent retention of [F] JNJ-64326067 in relevant cortical regions. One of the AD subjects was visually negative. Cortical signal in visually positive subjects approached steady state by 120 min. Temporal and frontal cortical SUVr/DVR values in visually positive AD subjects ranged from 1.21 to 3.09/1.2 to 2.18 and from 0.92 to 1.28/0.91 to 1.16 in healthy controls. Whole-body effective dose was estimated to be 0.0257 mSv/MBq for females and 0.0254 mSv/MBq for males.

Conclusions: [F] JNJ-64326067 could be useful for detection and quantitation of tau aggregates.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00259-020-04880-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680304PMC
December 2020

Early-phase [F]PI-2620 tau-PET imaging as a surrogate marker of neuronal injury.

Eur J Nucl Med Mol Imaging 2020 11 21;47(12):2911-2922. Epub 2020 Apr 21.

Department of Nuclear Medicine, University Hospital of Munich LMU Munich, Marchioninstraße 15, 81377, Munich, Germany.

Purpose: Second-generation tau radiotracers for use with positron emission tomography (PET) have been developed for visualization of tau deposits in vivo. For several β-amyloid and first-generation tau-PET radiotracers, it has been shown that early-phase images can be used as a surrogate of neuronal injury. Therefore, we investigated the performance of early acquisitions of the novel tau-PET radiotracer [F]PI-2620 as a potential substitute for [F]fluorodeoxyglucose ([F]FDG).

Methods: Twenty-six subjects were referred with suspected tauopathies or overlapping parkinsonian syndromes (Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, multi-system atrophy, Parkinson's disease, multi-system atrophy, Parkinson's disease, frontotemporal dementia) and received a dynamic [F]PI-2620 tau-PET (0-60 min p.i.) and static [F]FDG-PET (30-50 min p.i.). Regional standardized uptake value ratios of early-phase images (single frame SUVr) and the blood flow estimate (R) of [F]PI-2620-PET were correlated with corresponding quantification of [F]FDG-PET (global mean/cerebellar normalization). Reduced tracer uptake in cortical target regions was also interpreted visually using 3-dimensional stereotactic surface projections by three more and three less experienced readers. Spearman rank correlation coefficients were calculated between early-phase [F]PI-2620 tau-PET and [F]FDG-PET images for all cortical regions and frequencies of disagreement between images were compared for both more and less experienced readers.

Results: Highest agreement with [F]FDG-PET quantification was reached for [F]PI-2620-PET acquisition from 0.5 to 2.5 min p.i. for global mean (lowest R = 0.69) and cerebellar scaling (lowest R = 0.63). Correlation coefficients (summed 0.5-2.5 min SUVr & R) displayed strong agreement in all cortical target regions for global mean (R 0.76, R = 0.77) and cerebellar normalization (R 0.68, R = 0.68). Visual interpretation revealed high regional correlations between early-phase tau-PET and [F]FDG-PET. There were no relevant differences between more and less experienced readers.

Conclusion: Early-phase imaging of [F]PI-2620 can serve as a surrogate biomarker for neuronal injury. Dynamic imaging or a dual time-point protocol for tau-PET imaging could supersede additional [F]FDG-PET imaging by indexing both the distribution of tau and the extent of neuronal injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00259-020-04788-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567714PMC
November 2020

Sex differences by design and outcome in the Safety of Urate Elevation in PD (SURE-PD) trial.

Neurology 2019 10 4;93(14):e1328-e1338. Epub 2019 Sep 4.

From the Departments of Neurology (M.A.S., R.B., S.B., R.L., A.Y.H., G.B.) and Medicine (E.A.M.), Massachusetts General Hospital, Boston; University of Cincinnati (A.J.E.), OH; Rush University (C.G.G.), Chicago, IL; Michigan State University (J.L.G.), East Lansing; Struthers Parkinson's Center (S.A.P.), Minneapolis, MN; Boston University (M.H.S.-H.), MA; University of Rochester (A.R.), NY; University of Miami (J.M.H.), FL; Brigham and Women's Hospital (G.C.C.), Boston, MA; Yale University School of Medicine (D.S.R.), New Haven, CT; and Department of Nutrition (A.A.), Harvard School of Public Health, Boston, MA.

Objective: To investigate whether women and men with Parkinson disease (PD) differ in their biochemical and clinical responses to long-term treatment with inosine.

Methods: The Safety of Urate Elevation in Parkinson's Disease (SURE-PD) trial enrolled 75 people with early PD and baseline serum urate below 6 mg/dL and randomized them to 3 double-blinded treatment arms: oral placebo or inosine titrated to produce mild (6.1-7.0 mg/dL) or moderate (7.1-8.0 mg/dL) serum urate elevation for up to 2 years. Parkinsonism, serum urate, and plasma antioxidant capacity were measured at baseline and repeatedly on treatment; CSF urate was assessed once, at 3 months. Here in secondary analyses results are stratified by sex.

Results: Inosine produced an absolute increase in average serum urate from baseline that was 50% greater in women (3.0 mg/dL) than in men (2.0 mg/dL), consistent with expected lower baseline levels in women. Similarly, only among women was CSF urate significantly greater on mild or moderate inosine (+87% [ < 0.001] and +98% [ < 0.001], respectively) than on placebo (in contrast to men: +10% [ = 0.6] and +14% [ = 0.4], respectively). Women in the higher inosine dosing group showed a 7.0 Unified Parkinson's Disease Rating Scale (UPDRS) points/year lower rate of decline vs placebo ( = 0.01). In women, slower rates of UPDRS change were associated with greater increases in serum urate ( = -0.52; = 0.001), and with greater increases in plasma antioxidant capacity ( = -0.44; = 0.006). No significant associations were observed in men.

Conclusions: Inosine produced greater increases in serum and CSF urate in women compared to men in the SURE-PD trial, consistent with the study's design and with preliminary evidence for slower clinical decline in early PD among women treated with urate-elevating doses of inosine.

Clinicaltrialsgov Identifier: NCT00833690.

Classification Of Evidence: This study provides Class II evidence that inosine produced greater urate elevation in women than men and may slow PD progression in women.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000008194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814412PMC
October 2019

F-flortaucipir tau positron emission tomography distinguishes established progressive supranuclear palsy from controls and Parkinson disease: A multicenter study.

Ann Neurol 2017 Oct;82(4):622-634

Memory and Aging Center, University of California, San Francisco, San Francisco, CA.

Objective: F-flortaucipir (formerly F-AV1451 or F-T807) binds to neurofibrillary tangles in Alzheimer disease, but tissue studies assessing binding to tau aggregates in progressive supranuclear palsy (PSP) have yielded mixed results. We compared in vivo F-flortaucipir uptake in patients meeting clinical research criteria for PSP (n = 33) to normal controls (n = 46) and patients meeting criteria for Parkinson disease (PD; n = 26).

Methods: Participants underwent magnetic resonance imaging and positron emission tomography for amyloid-β ( C-PiB or F-florbetapir) and tau ( F-flortaucipir). F-flortaucipir standardized uptake value ratios were calculated (t = 80-100 minutes, cerebellum gray matter reference). Voxelwise and region-of-interest group comparisons were performed in template space, with receiver operating characteristic curve analyses to assess single-subject discrimination. Qualitative comparisons with postmortem tau are reported in 1 patient who died 9 months after F-flortaucipir.

Results: Clinical PSP patients showed bilaterally elevated F-flortaucipir uptake in globus pallidus, putamen, subthalamic nucleus, midbrain, and dentate nucleus relative to controls and PD patients (voxelwise p < 0.05 family wise error corrected). Globus pallidus binding best distinguished PSP patients from controls and PD (area under the curve [AUC] = 0.872 vs controls, AUC = 0.893 vs PD). PSP clinical severity did not correlate with F-flortaucipir in any region. A patient with clinical PSP and pathological diagnosis of corticobasal degeneration had severe tau pathology in PSP-related brain structures with good correspondence between in vivo F-flortaucipir and postmortem tau neuropathology.

Interpretation: F-flortaucipir uptake was elevated in PSP versus controls and PD patients in a pattern consistent with the expected distribution of tau pathology. Ann Neurol 2017;82:622-634.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.25060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5665658PMC
October 2017

A randomized trial of a low-dose Rasagiline and Pramipexole combination (P2B001) in early Parkinson's disease.

Mov Disord 2017 05 3;32(5):783-789. Epub 2017 Apr 3.

Clintrex LLC, Rye, New York, USA.

Background: Rasagiline and pramipexole act to improve striatal dopaminergic transmission in PD via distinct and potentially synergistic mechanisms. We performed a placebo-controlled study to determine whether 2 doses of a novel slow-release, low-dose combination of rasagiline and pramipexole (P2B001) are effective and have a good safety profile in patients with early untreated PD.

Methods: Previously untreated patients with early PD were randomized (1:1:1) to once-daily treatment with P2B001 (0.3 mg pramipexole/0.75 mg rasagiline), P2B001 (0.6 mg pramipexole/0.75 mg rasagiline) or placebo in a 12-week multicenter double-blind, placebo-controlled trial. The primary endpoint was the change from baseline to final visit in Total-UPDRS score versus placebo. Secondary measures included responder analyses of patients achieving ≥4 UPDRS point reduction, and changes in Parkinson Disease Quality of Life Scale-39 and UPDRS activities of daily living and motor scores.

Results: A total of 149 participants were randomized and 136 (91.3%) completed the study. Adjusted mean change from baseline to final visit versus placebo in Total-UPDRS score was -4.67 ± 1.28 points for the P2B001 0.6/0.75 mg group (P = .0004) and -3.84 ± 1.25 points for the 0.3/0.75 mg group (P = .003). Significant benefits were also observed for both doses in the responder analysis (P = .0002 and P = .0001), Parkinson Disease Quality of Life Scale-39 scores (P = .05 and P = .01), and the UPDRS motor (P = .02 and P = .006) and activities of daily living (P = .005 and P = .0004) subscores. Adverse events of P2B001 were comparable to placebo apart from transient nausea and somnolence, which were more common with P2B001 treatment.

Conclusions: P2B001 offers a promising treatment option for patients with early PD with good clinical efficacy and a low risk of adverse events. © 2017 International Parkinson and Movement Disorder Society.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mds.26941DOI Listing
May 2017

Clinical utility of DaTscan™ imaging in the evaluation of patients with parkinsonism: a US perspective.

Expert Rev Neurother 2017 03 23;17(3):219-225. Epub 2016 Nov 23.

g Institute for Neurodegenerative Disorders , New Haven , CT , USA.

Introduction: Single photon emission computed tomography (SPECT) with Ioflupane I123 injection (DaTscan™) was approved by the Food and Drug Administration in 2011 for striatal dopamine transporter visualization to assist in the evaluation of adult patients with suspected parkinsonian syndromes. While brain SPECT imaging using DaTscan is a covered service under Medicare policy, there is a lack of consensus on its role in routine clinical practice in the US. Areas covered: To address this issue, an expert group of US-based movement disorders neurologists convened to discuss the clinical utility of DaTscan in movement disorders practices within the US. The group identified and discussed routine clinical scenarios where imaging with DaTscan can provide useful information that may impact management and/or clarify clinical diagnoses. This paper summarizes a consensus reached by the expert group at this meeting. Expert commentary: The major utility of DaTscan imaging is the assistance it provides in distinguishing between nigrostriatal dopaminergic degeneration and non-nigrostriatal degeneration in patients displaying equivocal signs and symptoms of parkinsonism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14737175.2017.1256205DOI Listing
March 2017

Change in PDE10 across early Huntington disease assessed by [18F]MNI-659 and PET imaging.

Neurology 2016 Feb 22;86(8):748-54. Epub 2016 Jan 22.

From the Institute for Neurodegenerative Disorders and Molecular NeuroImaging, New Haven, CT.

Objective: To evaluate whether striatal [(18)F]MNI-659 PET imaging of phosphodiesterase 10A (PDE10) serves as a sensitive and reliable biomarker of striatal neurodegeneration in a longitudinal cohort of participants with early Huntington disease (HD).

Methods: A cohort of participants with HD, including both participants premanifest or manifest with motor signs, underwent clinical assessments, genetic determination, and 2 [(18)F]MNI-659 PET imaging sessions approximately 1 year apart. Eleven healthy control (HC) participants underwent clinical assessments and [(18)F]MNI-659 PET imaging once. Striatal binding potentials (BPnd) were estimated for brain regions of interest, specifically within the basal ganglia, and compared between baseline and follow-up imaging. Clinical measures of HD severity were assessed at each visit.

Results: Eight participants with HD (6 manifest; 2 premanifest) participated. Of those with manifest HD, all had relatively early stage disease (stage 1, n = 2; stage 2, n = 4) and a Unified Huntington's Disease Rating Scale total motor score <45. As expected, the HD cohort as a whole had a reduction in the basal ganglia BPnd to approximately 50% of that seen in HC. On follow-up scans, [(18)F]MNI-659 uptake declined in the putamen and caudate nucleus in all 8 participants. The mean annualized rates of decline in signal in the caudate, putamen, and globus pallidus and the putamen were 16.6%, 6.9%, and 5.8%, respectively. In HC, the annualized reduction in signal in striatal regions was less than 1%.

Conclusion: Longitudinal data in this small cohort of participants with early HD support [(18)F]MNI-659 PET imaging of PDE10 as a useful biomarker to track HD disease progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000002391DOI Listing
February 2016

Impact of Depression on Progression of Impairment and Disability in Early Parkinson's Disease.

Mov Disord Clin Pract 2015 Dec 14;2(4):371-378. Epub 2015 Jul 14.

Northwestern University, Chicago, Illinois, USA.

Background: Depression is one of the most common nonmotor symptoms associated with Parkinson's disease (PD), yet the impact of depression on progression of disease is unclear.

Objective: The aim of this study was to prospectively characterize the relationship between depressive symptoms and measures of disease progression in a large sample of patients with early, medically treated PD.

Methods: Baseline and longitudinal Beck Depression Inventory (BDI) scores from participants in the NINDS Exploratory Trials in PD Long Term Study 1 were correlated with changes in multiple measures of disease severity over 5 years. Multivariate analysis of predictors of change in BDI was performed.

Results: Of 1,741 participants, 746 completed 5-year assessments and were included. Mean age was 62.00 years (standard deviation [SD]: 9.22) and mean disease duration was 1.69 years (SD, 1.16). Mean BDI score was 6.24 (SD, 5.02) at baseline and 8.57 (SD, 6.60) at 5 years. Baseline BDI score was strongly associated with rate of change in all examined measures of disease severity. In multivariate analysis, BDI 5-year change was associated with change in UPDRS Part I (excluding depression item; < 0.01), 33-item Parkinson's Disease Questionnaire ( < 0.01), EuroQOL Five Dimensional Questionnaire ( = 0.02), and Total Functional Capacity ( < 0.01), but was not associated with motor or cognitive measures. This model explained 68.8% of the variance 5-year change of the BDI score.

Conclusions: Worse baseline BDI scores are associated with a decline in multiple measures of disease severity in PD. Worsening of BDI at 5 years was associated with worsening in UPDRS Part I and quality-of-life measures, but not with motor or cognitive measures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mdc3.12205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5381520PMC
December 2015

The phosphodiesterase 10 positron emission tomography tracer, [18F]MNI-659, as a novel biomarker for early Huntington disease.

JAMA Neurol 2014 Dec;71(12):1520-8

Institute for Neurodegenerative Disorders, New Haven, Connecticut2Molecular NeuroImaging, LLC, New Haven, Connecticut.

Importance: In Huntington disease (HD) striatal neuron loss precedes and predicts motor signs or symptoms. Current imaging biomarkers lack adequate sensitivity for assessing the early stages of HD. Developing an imaging biomarker for HD spanning the time of onset of motor signs remains a major unmet research need. Intracellular proteins whose expression is altered by the mutant huntingtin protein may be superior markers for early HD stages.

Objective: To evaluate whether [18F]MNI-659 (2-(2-(3-(4-(2-[18F]fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione), a novel phosphodiesterase 10 positron emission tomography (PET) ligand, is a sensitive marker for striatal changes in early HD.

Design, Setting, And Participants: A cohort of individuals with HD, including premanifest (pre-HD) or manifest with motor signs (mHD), underwent clinical assessments, genetic determination, [18F]MNI-659 PET imaging, and brain magnetic resonance imaging. Age-matched healthy volunteers (HVs) also received clinical assessments and PET and magnetic resonance imaging.

Main Outcomes And Measures: Binding potentials (BPnds) were estimated for brain regions of interest, specifically within the basal ganglia, and compared between participants with HD and the HVs and correlated with markers of HD severity and atrophy of basal ganglia nuclei.

Results: Eleven participants with HD (8 mHD and 3 pre-HD) and 9 HVs participated. Ten of 11 HD participants had known huntingtin CAG repeat length, allowing determination of a burden of pathology (BOP) score. One individual with HD declined CAG determination. All participants with mHD had relatively early-stage disease (4 with stage 1 and 4 with stage 2) and a Unified Huntington's Disease Rating Scale (UHDRS) total Motor subscale score of less than 50. The HD cohort had significantly lower striatal [18F]MNI-659 uptake than did the HV cohort (mean, -48.4%; P < .001). The HD cohort as a whole had a reduction in the basal ganglia BPnd to approximately 50% of the level in the HVs (mean, -47.6%; P < .001). The 3 pre-HD participants had intermediate basal ganglia BPnds. Striatal [18F]MNI-659 uptake correlated strongly with the severity of disease measured by the clinical scale (UHDRS Motor subscale; R = 0.903; P < .001), the molecular marker (BOP; R = 0.908; P < .001), and regional atrophy (R = 0.667; P < .05).

Conclusions And Relevance: As a promising striatal imaging biomarker, [18F]MNI-659 is potentially capable of assessing the extent of disease in early mHD. Furthermore, [18F]MNI-659 may identify early changes in medium spiny neurons and serve as a marker to predict conversion to mHD. Additional studies with larger, stratified cohorts of patients with HD and prospective studies of individuals with pre-HD are warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaneurol.2014.1954DOI Listing
December 2014

A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit.

Authors:
M Flint Beal David Oakes Ira Shoulson Claire Henchcliffe Wendy R Galpern Richard Haas Jorge L Juncos John G Nutt Tiffini Smith Voss Bernard Ravina Clifford M Shults Karen Helles Victoria Snively Mark F Lew Brian Griebner Arthur Watts Shan Gao Emmanuelle Pourcher Louisette Bond Katie Kompoliti Pinky Agarwal Cherissa Sia Mandar Jog Linda Cole Munira Sultana Roger Kurlan Irene Richard Cheryl Deeley Cheryl H Waters Angel Figueroa Ani Arkun Matthew Brodsky William G Ondo Christine B Hunter Joohi Jimenez-Shahed Alicia Palao Janis M Miyasaki Julie So James Tetrud Liza Reys Katharine Smith Carlos Singer Anita Blenke David S Russell Candace Cotto Joseph H Friedman Margaret Lannon Lin Zhang Edward Drasby Rajeev Kumar Thyagarajan Subramanian Donna Stuppy Ford David A Grimes Diane Cote Jennifer Conway Andrew D Siderowf Marian Leslie Evatt Barbara Sommerfeld Abraham N Lieberman Michael S Okun Ramon L Rodriguez Stacy Merritt Camille Louise Swartz W R Wayne Martin Pamela King Natividad Stover Stephanie Guthrie Ray L Watts Anwar Ahmed Hubert H Fernandez Adrienna Winters Zoltan Mari Ted M Dawson Becky Dunlop Andrew S Feigin Barbara Shannon Melissa Jill Nirenberg Mattson Ogg Samuel A Ellias Cathi-Ann Thomas Karen Frei Ivan Bodis-Wollner Sofya Glazman Thomas Mayer Robert A Hauser Rajesh Pahwa April Langhammer Ranjit Ranawaya Lorelei Derwent Kapil D Sethi Buff Farrow Rajan Prakash Irene Litvan Annette Robinson Alok Sahay Maureen Gartner Vanessa K Hinson Samuel Markind Melisa Pelikan Joel S Perlmutter Johanna Hartlein Eric Molho Sharon Evans Charles H Adler Amy Duffy Marlene Lind Lawrence Elmer Kathy Davis Julia Spears Stephanie Wilson Maureen A Leehey Neal Hermanowicz Shari Niswonger Holly A Shill Sanja Obradov Alex Rajput Marilyn Cowper Stephanie Lessig David Song Deborah Fontaine Cindy Zadikoff Karen Williams Karen A Blindauer Jo Bergholte Clara Schindler Propsom Mark A Stacy Joanne Field Dragos Mihaila Mark Chilton Ergun Y Uc Jeri Sieren David K Simon Lauren Kraics Althea Silver James T Boyd Robert W Hamill Christopher Ingvoldstad Jennifer Young Karen Thomas Sandra K Kostyk Joanne Wojcieszek Ronald F Pfeiffer Michel Panisset Monica Beland Stephen G Reich Michelle Cines Nancy Zappala Jean Rivest Richard Zweig L Pepper Lumina Colette Lynn Hilliard Stephen Grill Marye Kellermann Paul Tuite Susan Rolandelli Un Jung Kang Joan Young Jayaraman Rao Maureen M Cook Lawrence Severt Karyn Boyar

JAMA Neurol 2014 May;71(5):543-52

Department of Neurology, Beth Israel Medical Center, New York, New York.

Importance: Coenzyme Q10 (CoQ10), an antioxidant that supports mitochondrial function, has been shown in preclinical Parkinson disease (PD) models to reduce the loss of dopamine neurons, and was safe and well tolerated in early-phase human studies. A previous phase II study suggested possible clinical benefit.

Objective: To examine whether CoQ10 could slow disease progression in early PD.

Design, Setting, And Participants: A phase III randomized, placebo-controlled, double-blind clinical trial at 67 North American sites consisting of participants 30 years of age or older who received a diagnosis of PD within 5 years and who had the following inclusion criteria: the presence of a rest tremor, bradykinesia, and rigidity; a modified Hoehn and Yahr stage of 2.5 or less; and no anticipated need for dopaminergic therapy within 3 months. Exclusion criteria included the use of any PD medication within 60 days, the use of any symptomatic PD medication for more than 90 days, atypical or drug-induced parkinsonism, a Unified Parkinson's Disease Rating Scale (UPDRS) rest tremor score of 3 or greater for any limb, a Mini-Mental State Examination score of 25 or less, a history of stroke, the use of certain supplements, and substantial recent exposure to CoQ10. Of 696 participants screened, 78 were found to be ineligible, and 18 declined participation.

Interventions: The remaining 600 participants were randomly assigned to receive placebo, 1200 mg/d of CoQ10, or 2400 mg/d of CoQ10; all participants received 1200 IU/d of vitamin E.

Main Outcomes And Measures: Participants were observed for 16 months or until a disability requiring dopaminergic treatment. The prospectively defined primary outcome measure was the change in total UPDRS score (Parts I-III) from baseline to final visit. The study was powered to detect a 3-point difference between an active treatment and placebo.

Results: The baseline characteristics of the participants were well balanced, the mean age was 62.5 years, 66% of participants were male, and the mean baseline total UPDRS score was 22.7. A total of 267 participants required treatment (94 received placebo, 87 received 1200 mg/d of CoQ10, and 86 received 2400 mg/d of CoQ10), and 65 participants (29 who received placebo, 19 who received 1200 mg/d of CoQ10, and 17 who received 2400 mg/d of CoQ10) withdrew prematurely. Treatments were well tolerated with no safety concerns. The study was terminated after a prespecified futility criterion was reached. At study termination, both active treatment groups showed slight adverse trends relative to placebo. Adjusted mean changes (worsening) in total UPDRS scores from baseline to final visit were 6.9 points (placebo), 7.5 points (1200 mg/d of CoQ10; P = .49 relative to placebo), and 8.0 points (2400 mg/d of CoQ10; P = .21 relative to placebo).

Conclusions And Relevance: Coenzyme Q10 was safe and well tolerated in this population, but showed no evidence of clinical benefit.

Trial Registration: clinicaltrials.gov Identifier: NCT00740714.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaneurol.2014.131DOI Listing
May 2014

Teaching video neuroimages: spasmodic dysphonia preceding idiopathic parkinsonism.

Neurology 2014 Feb;82(6):e55

From the Department of Medicine, Yale-New Haven Medical Center (F.H.-S.), Yale School of Medicine (D.S.R., M.J.H.), and Institute for Neurodegenerative Disorders (D.S.R.), New Haven, CT; and the Harvard Neurology Residency Program (M.M.), Brigham and Women's Hospital & Massachusetts General Hospital, Harvard School of Medicine, Boston.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000000110DOI Listing
February 2014

Clinical comparison of 99mTc exametazime and 123I Ioflupane SPECT in patients with chronic mild traumatic brain injury.

PLoS One 2014 24;9(1):e87009. Epub 2014 Jan 24.

Myrna Brind Center of Integrative Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.

Background: This study evaluated the clinical interpretations of single photon emission computed tomography (SPECT) using a cerebral blood flow and a dopamine transporter tracer in patients with chronic mild traumatic brain injury (TBI). The goal was to determine how these two different scan might be used and compared to each other in this patient population.

Methods And Findings: Twenty-five patients with persistent symptoms after a mild TBI underwent SPECT with both (99m)Tc exametazime to measure cerebral blood flow (CBF) and (123)I ioflupane to measure dopamine transporter (DAT) binding. The scans were interpreted by two expert readers blinded to any case information and were assessed for abnormal findings in comparison to 10 controls for each type of scan. Qualitative CBF scores for each cortical and subcortical region along with DAT binding scores for the striatum were compared to each other across subjects and to controls. In addition, symptoms were compared to brain scan findings. TBI patients had an average of 6 brain regions with abnormal perfusion compared to controls who had an average of 2 abnormal regions (p<0.001). Patient with headaches had lower CBF in the right frontal lobe, and higher CBF in the left parietal lobe compared to patients without headaches. Lower CBF in the right temporal lobe correlated with poorer reported physical health. Higher DAT binding was associated with more depressive symptoms and overall poorer reported mental health. There was no clear association between CBF and DAT binding in these patients.

Conclusions: Overall, both scans detected abnormalities in brain function, but appear to reflect different types of physiological processes associated with chronic mild TBI symptoms. Both types of scans might have distinct uses in the evaluation of chronic TBI patients depending on the clinical scenario.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0087009PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3901727PMC
February 2015

Inosine to increase serum and cerebrospinal fluid urate in Parkinson disease: a randomized clinical trial.

JAMA Neurol 2014 Feb;71(2):141-50

Clinical Coordination Center, University of Rochester, Rochester, New York.

Importance: Convergent biological, epidemiological, and clinical data identified urate elevation as a candidate strategy for slowing disability progression in Parkinson disease (PD).

Objective: To determine the safety, tolerability, and urate-elevating capability of the urate precursor inosine in early PD and to assess its suitability and potential design features for a disease-modification trial.

Design, Setting, And Participants: The Safety of Urate Elevation in PD (SURE-PD) study, a randomized, double-blind, placebo-controlled, dose-ranging trial of inosine, enrolled participants from 2009 to 2011 and followed them for up to 25 months at outpatient visits to 17 credentialed clinical study sites of the Parkinson Study Group across the United States. Seventy-five consenting adults (mean age, 62 years; 55% women) with early PD not yet requiring symptomatic treatment and a serum urate concentration less than 6 mg/dL (the approximate population median) were enrolled.

Interventions: Participants were randomized to 1 of 3 treatment arms: placebo or inosine titrated to produce mild (6.1-7.0 mg/dL) or moderate (7.1-8.0 mg/dL) serum urate elevation using 500-mg capsules taken orally up to 2 capsules 3 times per day. They were followed for up to 24 months (median, 18 months) while receiving the study drug plus 1 washout month.

Main Outcomes And Measures: The prespecified primary outcomes were absence of unacceptable serious adverse events (safety), continued treatment without adverse event requiring dose reduction (tolerability), and elevation of urate assessed serially in serum and once (at 3 months) in cerebrospinal fluid. RESULTS Serious adverse events (17), including infrequent cardiovascular events, occurred at the same or lower rates in the inosine groups relative to placebo. No participant developed gout and 3 receiving inosine developed symptomatic urolithiasis. Treatment was tolerated by 95% of participants at 6 months, and no participant withdrew because of an adverse event. Serum urate rose by 2.3 and 3.0 mg/dL in the 2 inosine groups (P < .001 for each) vs placebo, and cerebrospinal fluid urate level was greater in both inosine groups (P = .006 and <.001, respectively). Secondary analyses demonstrated nonfutility of inosine treatment for slowing disability.

Conclusions And Relevance: Inosine was generally safe, tolerable, and effective in raising serum and cerebrospinal fluid urate levels in early PD. The findings support advancing to more definitive development of inosine as a potential disease-modifying therapy for PD.

Trial Registration: clinicaltrials.gov Identifier: NCT00833690.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaneurol.2013.5528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3940333PMC
February 2014

Kinetic modeling, test-retest, and dosimetry of 123I-MNI-420 in humans.

J Nucl Med 2013 Oct 22;54(10):1760-7. Epub 2013 Aug 22.

Molecular NeuroImaging, LLC, New Haven, Connecticut; and.

Unlabelled: In vivo imaging of adenosine 2A receptors (A2A) in the brain has attracted significant interest from the scientific community, because studies have shown that dysregulation of these receptors is implicated in a variety of neurodegenerative and psychiatric disorders, including Parkinson and Huntington diseases. This work aimed to describe the kinetic properties, test-retest results, and dosimetry estimates of (123)I-MNI-420, a SPECT radiotracer for the in vivo imaging of A2A in the brain.

Methods: Nine healthy human subjects were enrolled in this study; 7 completed (123)I-MNI-420 brain SPECT studies, and 2 participated in whole-body planar imaging evaluating (123)I-MNI-420 biodistribution and dosimetry. For 3 of the brain SPECT studies, arterial blood was collected for invasive modeling. Noninvasive models were also explored, including Logan graphical analysis and simplified reference tissue models. Test-retest reliability was assessed in 4 subjects. To evaluate radiotracer biodistribution and dosimetry, serial whole-body images were acquired immediately after injection and at selected time points after injection. Urine samples were collected over a period of 21 h to calculate urinary excretion.

Results: (123)I-MNI-420 rapidly entered the human brain and displayed uptake consistent with known A2A densities. At pseudoequilibrium (reached at 90 min after radiotracer injection), stable target-to-cerebellum ratios of around 1.4-2.0 were determined. Binding potentials around 0.8-1.2 were estimated using different kinetic models and the cerebellum as the reference region. Average test-retest variability in the striatum was 4.8%, 3.5%, and 6.5% for the simplified reference tissue model, Logan graphical analysis, and standardized uptake value ratio methods, respectively. The estimated radiation effective dose determined from whole-body studies was 0.036 mSv/MBq.

Conclusion: The data indicate that (123)I-MNI-420 is a useful SPECT radiotracer for imaging A2A in the brain and has radiation doses that would allow for multiple scans in the same research subject each year. The availability of (123)I-MNI-420 offers the possibility of investigating A2A activity in specific conditions and evaluating drug occupancy for A2A candidate therapeutics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2967/jnumed.113.119933DOI Listing
October 2013

Persistent fifth aortic arch: echocardiographic diagnosis of a persistent fifth aortic arch.

Echocardiography 2011 Feb 17;28(2):E44-5. Epub 2010 Nov 17.

The Herma Heart Center, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1540-8175.2010.01324.xDOI Listing
February 2011

Peripheral insulin-like growth factor-I produces antidepressant-like behavior and contributes to the effect of exercise.

Behav Brain Res 2009 Mar 14;198(2):366-71. Epub 2008 Nov 14.

Division of Molecular Psychiatry, Abraham Ribicoff Research Facilities, Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508, USA.

Growth factors in the brain are important to depression and it's treatment and we assessed the ability of peripherally administered insulin-like growth factor-I (IGF-I) to influence behavior related to depression. We found that mice that received chronic IGF-I treatment showed antidepressant-like behavior in forced-swim and novelty-induced hypophagia (NIH) tests and increased sucrose consumption after chronic mild unpredictable stress exposure. Additionally, peripheral anti-IGF-I administration blocked exercise-induced antidepressant effects in the forced-swim test (FST). These results support the functional relevance of neurotrophic mechanisms to depression and extend this idea to include neurotrophic factors in the periphery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbr.2008.11.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2729431PMC
March 2009

Voluntary exercise produces antidepressant and anxiolytic behavioral effects in mice.

Brain Res 2008 Mar 3;1199:148-58. Epub 2008 Jan 3.

Division of Molecular Psychiatry, Abraham Ribicoff Research Facilities, Department of Psychiatry and Pharmacology, Yale University School of Medicine, New Haven, CT 06508, USA.

Reports of beneficial effects of exercise on psychological health in humans are increasingly supported by basic research studies. Exercise is hypothesized to regulate antidepressant-related mechanisms and we therefore characterized the effects of chronic exercise in mouse behavioral paradigms relevant to antidepressant actions. Mice given free access to running wheels showed antidepressant-like behavior in learned helplessness, forced-swim (FST) and tail suspension paradigms. These responses were similar to responses of antidepressant drug-treated animals. When tested under conditions where locomotor activity was not altered, exercising mice also showed reduced anxiety compared to sedentary control mice. In situ hybridization analysis showed that BDNF mRNA was increased in specific subfields of hippocampus after wheel running. We chose one paradigm, the FST, in which to investigate a functional role for brain-derived neurotrophic factor (BDNF) in the behavioral response to exercise. We tested mice heterozygous for a deletion of the BDNF gene in the FST after wheel-running. Exercising wild-type mice showed the expected antidepressant-like behavioral response in the FST but exercise was ineffective in improving FST performance in heterozygous BDNF knockout mice. A possible functional contribution of a BDNF signaling pathway to FST performance in exercising mice was investigated using the specific MEK inhibitor PD184161 to block the MAPK signaling pathway. Subchronic administration of PD184161 to exercising mice blocked the antidepressant-like behavioral response seen in vehicle-treated exercising mice in the FST. In summary, chronic wheel-running exercise in mice results in antidepressant-like behavioral changes that may involve a BDNF related mechanism similar to that hypothesized for antidepressant drug treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.brainres.2007.12.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2330082PMC
March 2008

Antidepressant actions of the exercise-regulated gene VGF.

Nat Med 2007 Dec 2;13(12):1476-82. Epub 2007 Dec 2.

Department of Psychiatry, Yale University, 34 Park Street, New Haven, Connecticut 06508 USA.

Exercise has many health benefits, including antidepressant actions in depressed human subjects, but the mechanisms underlying these effects have not been elucidated. We used a custom microarray to identify a previously undescribed profile of exercise-regulated genes in the mouse hippocampus, a brain region implicated in mood and antidepressant response. Pathway analysis of the regulated genes shows that exercise upregulates a neurotrophic factor signaling cascade that has been implicated in the actions of antidepressants. One of the most highly regulated target genes of exercise and of the growth factor pathway is the gene encoding the VGF nerve growth factor, a peptide precursor previously shown to influence synaptic plasticity and metabolism. We show that administration of a synthetic VGF-derived peptide produces a robust antidepressant response in mice and, conversely, that mutation of VGF in mice produces the opposite effects. The results suggest a new role for VGF and identify VGF signaling as a potential therapeutic target for antidepressant drug development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nm1669DOI Listing
December 2007

Repeated unpredictable stress and antidepressants differentially regulate expression of the bcl-2 family of apoptotic genes in rat cortical, hippocampal, and limbic brain structures.

Neuropsychopharmacology 2008 Jun 15;33(7):1545-58. Epub 2007 Aug 15.

Department of Psychiatry, Menninger Department of Psychiatry, Baylor College of Medicine and Michael E DeBakey Veterans Affairs, Houston, TX, USA.

Apoptosis has been proposed as a contributing cellular mechanism to the structural alterations that have been observed in stress-related mood disorders. Antidepressants, on the other hand, are hypothesized to exert trophic and/or neuroprotective actions. The present study examined the regulation of the major antiapoptotic (Bcl-2, Bcl-xl) and proapoptotic (Bax) genes by repeated unpredictable stress (an animal model of depression) and antidepressant treatments (ADT). In adult rats, exposure to unpredictable stress reduced Bcl-2 mRNA levels in the central nucleus of the amygdala (CeA), cingulate (Cg), and frontal (Fr) cortices. Bcl-xl mRNA was significantly decreased in hippocampal subfields. In contrast, chronic administration of clinically effective antidepressants from four different classes, ie fluoxetine, reboxetine, tranylcypromine, and electroconvulsive seizures (ECS) upregulated Bcl-2 mRNA expression in the Cg, Fr, and CeA. Reboxetine, tranylcypromine, and ECS selectively increased Bcl-xl, but not Bcl-2 mRNA expression in the hippocampus. Chemical ADT but not ECS, robustly enhanced Bcl-2 expression in the medial amygdaloid nucleus and ventromedial hypothalamus. Fluoxetine did not influence Bcl-xl expression in the hippocampus, but it was the only ADT that decreased Bax expression in this region. In the CeA, again in direct contrast to the stress effects, exposure to all classes of ADTs significantly increased Bcl-2 mRNA. The selective regulation of Bcl-xl and Bax in hippocampal subfields and of Bcl-2 in the Cg cortex, amygdala, and hypothalamus suggests that these cellular adaptations contribute to the long-term neural plastic adaptations to stress and ADTs in cortical, hypothalamic, and limbic brain structures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/sj.npp.1301527DOI Listing
June 2008

Regulation of neuronal PLCgamma by chronic morphine.

Brain Res 2007 Jul 4;1156:9-20. Epub 2007 May 4.

Interdepartmental Neuroscience Program, Yale University School of Medicine, and Connecticut Mental Health Center, New Haven, CT 06508, USA.

Alterations in neurotrophic signaling pathways may contribute to the changes in the mesolimbic dopamine system induced by chronic morphine exposure. In a rat model of morphine dependence, we previously identified increased levels of phospholipase C gamma-1 (PLCgamma1) immunoreactivity specifically within the ventral tegmental area (VTA) following chronic morphine treatment. Using an antibody specific for the tyrosine-phosphorylated, activated form of PLCgamma1, we now show that chronic morphine also significantly upregulates PLCgamma1 activity in the VTA, as well as in the nucleus accumbens and hippocampus, regions which are also implicated in the reinforcing properties of morphine. In contrast, no increase in PLCgamma1 activity was found in the substantia nigra or dorsal striatum. HSV-mediated overexpression of PLCgamma1 in PC12 cells induced ERK activation via a mechanism dependent, in part, on both MAP-ERK kinase (MEK) and protein kinase C. PLCgamma1 overexpression in the VTA similarly induced ERK activation in the VTA in vivo. As chronic morphine treatment has been shown to increase ERK activity within the VTA, the current results suggest that increased PLCgamma1 activity may be an upstream mediator of this effect.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.brainres.2007.04.059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2020853PMC
July 2007

The second century-- frustrations or challenges?

Authors:
David S Russell

J Okla State Med Assoc 2007 Mar;100(3):74

View Article and Find Full Text PDF

Download full-text PDF

Source
March 2007

The second century--advocating for our colleagues.

Authors:
David S Russell

J Okla State Med Assoc 2006 Nov;99(11):534

View Article and Find Full Text PDF

Download full-text PDF

Source
November 2006

IRS2-Akt pathway in midbrain dopamine neurons regulates behavioral and cellular responses to opiates.

Nat Neurosci 2007 Jan 3;10(1):93-9. Epub 2006 Dec 3.

Department of Psychiatry and Center for Basic Neuroscience, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9070, USA.

Chronic morphine administration (via subcutaneous pellet) decreases the size of dopamine neurons in the ventral tegmental area (VTA), a key reward region in the brain, yet the molecular basis and functional consequences of this effect are unknown. In this study, we used viral-mediated gene transfer in rat to show that chronic morphine-induced downregulation of the insulin receptor substrate 2 (IRS2)-thymoma viral proto-oncogene (Akt) signaling pathway in the VTA mediates the decrease in dopamine cell size seen after morphine exposure and that this downregulation diminishes morphine reward, as measured by conditioned place preference. We further show that the reduction in size of VTA dopamine neurons persists up to 2 weeks after morphine withdrawal, which parallels the tolerance to morphine's rewarding effects caused by previous chronic morphine exposure. These findings directly implicate the IRS2-Akt signaling pathway as a critical regulator of dopamine cell morphology and opiate reward.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nn1812DOI Listing
January 2007

The second century--political involvement.

Authors:
David S Russell

J Okla State Med Assoc 2006 Sep;99(9):466

View Article and Find Full Text PDF

Download full-text PDF

Source
September 2006

Benign tremulous parkinsonism.

Authors:
David S Russell

Arch Neurol 2006 Sep;63(9):1346

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/archneur.63.9.1346-aDOI Listing
September 2006

Protecting motor neurons from toxic insult by antagonism of adenosine A2a and Trk receptors.

J Neurosci 2006 Sep;26(36):9250-63

Department of Neurology, Children's Hospital of Philadelphia, Joseph Stokes Jr. Research Institute, Philadelphia, Pennsylvania 19104, USA.

The death of motor neurons in amyotrophic lateral sclerosis (ALS) is thought to result from the interaction of a variety of factors including excitotoxicity, accumulation of toxic proteins, and abnormal axonal transport. Previously, we found that the susceptibility of motor neurons to excitotoxic insults can be limited by inhibiting signals evoked by brain-derived neurotrophic factor (BDNF) activation of the receptor tyrosine kinase B (TrkB). Here we show that this can be achieved by direct kinase inhibition or by blockade of a transactivation pathway that uses adenosine A2a receptors and src-family kinases (SFKs). Downstream signaling cascades (such as mitogen-activated protein kinase and phosphatidylinositol-3 kinase) are inhibited by these blockers. In addition to protecting motor neurons from excitotoxic insult, these agents also prevent toxicity that follows from the expression of mutant proteins (G85R superoxide dismutase 1; G59S p150(glued)) that cause familial motor neuron disease. TrkB, adenosine A2a receptors, and SFKs associate into complexes in lipid raft and nonlipid raft membranes and the signaling from lipids rafts may be particularly important because their disruption by cholesterol depletion blocks the ability of BDNF to render motor neurons vulnerable to insult. The neuroprotective versatility of Trk antagonism suggests that it may have broad utility in the treatment of ALS patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/JNEUROSCI.1856-06.2006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6674510PMC
September 2006

A role for MAP kinase signaling in behavioral models of depression and antidepressant treatment.

Biol Psychiatry 2007 Mar 30;61(5):661-70. Epub 2006 Aug 30.

Laboratory of Molecular Psychiatry, Center for Genes and Behavior, Departments of Psychiatry and Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA.

Background: Brain-derived neurotrophic factor (BDNF) is upregulated in the hippocampus by antidepressant treatments, and centrally administered BDNF can produce antidepressant-like effects in rodent behavioral models of depression. BDNF-regulated signaling pathways are thus potential targets for investigation of antidepressant mechanisms.

Methods: We examined the effects of inhibition of MAPK kinase (MEK) in mouse behavioral models for depression including interactions with effects of antidepressant drugs. We also assessed the behavioral consequences of a heterozygous gene deletion for BDNF combined with MEK inhibition or stress.

Results: Acute administration of the MEK inhibitor PD184161 produced depressive-like behavior. PD184161 blocked the antidepressant-like effects of desipramine and sertraline in the forced swim test and blocked the effects of desipramine in the tail suspension test. Heterozygous deletion of BDNF alone did not influence behavior in the forced swim test but resulted in a depressive phenotype when combined with a low-dose MEK inhibitor or stress exposure.

Conclusions: We demonstrate that acute blockade of MAPK signaling produces a depressive-like phenotype and blocks behavioral actions of antidepressants. We also demonstrate in BDNF heterozygous knockout mice an example of a how a defined genetic alteration can confer vulnerability to a pharmacologic or environmental challenge resulting in a depressive behavioral phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopsych.2006.05.047DOI Listing
March 2007