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1.  What Can Biomarkers Tell Us About Cognition in Parkinson's Disease? 
Cognitive decline is common in Parkinson's disease (PD), even in the early motor stage, and this non-motor feature impacts quality of life and prognosis tremendously. In this article, we discuss marker candidates for cognitive decline in PD from different angles, including functional and structural imaging techniques, biological fluid markers in cerebrospinal fluid, and blood genetic predictors, as well as gait as a surrogate marker of cognitive decline. Specifically, imaging-based markers of cognitive impairment in PD include cortical atrophy, reduced cortical metabolism, loss of cortical cholinergic and frontal dopaminergic function, as well as an increased cortical amyloid load. Reduced β-amyloid(1-42) in cerebrospinal fluid and lower plasma levels of epidermal growth factor are predictors for cognitive decline in PD. In addition, genetic variation in the apolipoprotein E (APOE), catechol-O-methyltransferase (COMT), microtubule-associated protein tau (MAPT), and glucocerebrosidase (GBA) genes may confer risk for cognitive impairment in PD; and gait disturbance may also indicate an increased risk for dementia. Other marker candidates have been proposed and are discussed. All of the current studies are hampered by gaps in our knowledge about the molecular causes of cognitive decline, which will have to be considered in future biomarker studies.
PMCID: PMC4384332  PMID: 24757111
Parkinson's disease; dementia; imaging; cerebrospinal fluid; blood; genetics; biomarker; gait
2.  Full-Sun observations for identifying the source of the slow solar wind 
Nature Communications  2015;6:5947.
Fast (>700 km s−1) and slow (~400 km s−1) winds stream from the Sun, permeate the heliosphere and influence the near-Earth environment. While the fast wind is known to emanate primarily from polar coronal holes, the source of the slow wind remains unknown. Here we identify possible sites of origin using a slow solar wind source map of the entire Sun, which we construct from specially designed, full-disk observations from the Hinode satellite, and a magnetic field model. Our map provides a full-Sun observation that combines three key ingredients for identifying the sources: velocity, plasma composition and magnetic topology and shows them as solar wind composition plasma outflowing on open magnetic field lines. The area coverage of the identified sources is large enough that the sum of their mass contributions can explain a significant fraction of the mass loss rate of the solar wind.
Both fast and slow solar winds emanate from our Sun, although the source of the slow component remains elusive. Towards identifying this, Brooks et al. present full-Sun spectral images from Hinode, combined with magnetic modelling, to produce a solar wind source map.
PMCID: PMC4354106  PMID: 25562705
3.  Probabilistic classification learning with corrective feedback is associated with in vivo striatal dopamine release in the ventral striatum, while learning without feedback is not 
Human Brain Mapping  2014;35(10):5106-5115.
The basal ganglia (BG) mediate certain types of procedural learning, such as probabilistic classification learning on the ‘weather prediction task’ (WPT). Patients with Parkinson's disease (PD), who have BG dysfunction, are impaired at WPT-learning, but it remains unclear what component of the WPT is important for learning to occur. We tested the hypothesis that learning through processing of corrective feedback is the essential component and is associated with release of striatal dopamine. We employed two WPT paradigms, either involving learning via processing of corrective feedback (FB) or in a paired associate manner (PA). To test the prediction that learning on the FB but not PA paradigm would be associated with dopamine release in the striatum, we used serial 11C-raclopride (RAC) positron emission tomography (PET), to investigate striatal dopamine release during FB and PA WPT-learning in healthy individuals. Two groups, FB, (n = 7) and PA (n = 8), underwent RAC PET twice, once while performing the WPT and once during a control task. Based on a region-of-interest approach, striatal RAC-binding potentials reduced by 13–17% in the right ventral striatum when performing the FB compared to control task, indicating release of synaptic dopamine. In contrast, right ventral striatal RAC binding non-significantly increased by 9% during the PA task. While differences between the FB and PA versions of the WPT in effort and decision-making is also relevant, we conclude striatal dopamine is released during FB-based WPT-learning, implicating the striatum and its dopamine connections in mediating learning with FB.
PMCID: PMC4285817  PMID: 24777947
basal ganglia; 11C-raclopride positron emission tomography; non-motor skill learning; probabilistic learning; procedural learning; weather prediction task
4.  Early Detection of Dengue Virus by Use of Reverse Transcription-Recombinase Polymerase Amplification 
Journal of Clinical Microbiology  2015;53(3):830-837.
A method for the rapid diagnosis of early dengue virus (DENV) infection is highly needed. Here, a prototype reverse transcription-recombinase polymerase amplification (RT-RPA) assay was developed. The assay detected DENV RNA in <20 min without the need for thermocycling amplification. The assay enabled the detection of as few as 10 copies of DENV RNA. The designed RT-RPA primers and exo probe detected the DENV genome of at least 12 genotypes of DENV circulating globally without cross-reacting with other arboviruses. We assessed the diagnostic performance of the RT-RPA assay for the detection of DENV RNA in 203 serum samples of patients with clinically suspected dengue. The sera were simultaneously tested for DENV using a reverse transcription-loop-mediated isothermal amplification (RT-LAMP) assay, quantitative RT-PCR (qRT-PCR), and IgM- and IgG-capture enzyme-linked immunosorbent assays (ELISA). Acute DENV infection was confirmed in 130 samples and 61 of the samples (46.9%) were classified as viremic with qRT-PCR. The RT-RPA assay showed good concordance (κ of ≥0.723) with the RT-LAMP and qRT-PCR assays in detecting the dengue viremic samples. When used in combination with ELISA, both the RT-RPA and RT-LAMP assays increased the detection of acute DENV infection to ≥95.7% (≥45/47) in samples obtained within 5 days of illness. The results from the study suggest that the RT-RPA assay is the most rapid molecular diagnostic tool available for the detection of DENV. Hence, it is possible to use the RT-RPA assay in a laboratory to complement routine serology testing for dengue.
PMCID: PMC4390637  PMID: 25568438
5.  Decoding the complexity of type I interferon to treat persistent viral infections 
Trends in microbiology  2013;21(12):10.1016/j.tim.2013.10.003.
Type I interferons (IFN-I) are a broad family of cytokines that are central to the innate immune response. These proteins have long been appreciated for the critical roles they play in restraining viral infections and shaping antiviral immune responses. However, in recent years there has been increased awareness of the immunosuppressive actions of these proteins as well. While there are many current therapeutic applications to manipulate IFN-I pathways we have limited understanding of the mechanisms by which these therapies are actually functioning. In this review we highlight the diversity and temporal impact of IFN-I signaling, discuss the current therapeutic uses of IFN-I, and explore the strategy of blocking IFN-I to alleviate immune dysfunction in persistent virus infections.
PMCID: PMC3864553  PMID: 24216022
type I interferon; persistent; virus; LCMV; immunosuppression; therapy; immune activation; HIV
6.  Reference region automatic extraction in dynamic [11C]PIB 
The positron emission tomography (PET) radiotracer [11C]Pittsburgh Compound B (PIB) is a marker of amyloid plaque deposition in brain, and binding potential is usually quantified using the cerebellum as a reference where the specific binding is negligible. The use of the cerebellum as a reference, however, has been questioned by the reported cerebellar [11C]PIB retention in familial Alzheimer's disease (AD) subjects. In this work, we developed a supervised clustering procedure for the automatic extraction of a reference region in [11C]PIB studies. Supervised clustering models each gray matter voxel as the linear combination of three predefined kinetic classes, normal and lesion gray matter, and blood pool, and extract reference voxels in which the contribution of the normal gray matter class is high. In the validation with idiopathic AD subjects, supervised clustering extracted reference voxels mostly in the cerebellum that indicated little specific [11C]PIB binding, and total distribution volumes of the extracted region were lower than those of the cerebellum. Next, the methodology was applied to the familial AD cohort where the cerebellar amyloid load had been demonstrated previously, resulting in higher binding potential compared with that obtained with the cerebellar reference. The supervised clustering method is a useful tool for the accurate quantification of [11C]PIB studies.
PMCID: PMC3824180  PMID: 23921900
[11C]PIB; PET; reference region; supervised clustering
7.  Test–retest reproducibility of cannabinoid-receptor type 1 availability quantified with the PET ligand [11C]MePPEP 
Neuroimage  2014;97:151-162.
Endocannabinoids are involved in normal cognition, and dysfunction in cannabinoid-receptor-mediated neurotransmission has been suggested in a variety of neurological and psychiatric pathologies. The type 1 cannabinoid receptor (CB1) is widely expressed in the human central nervous system. The objective of this study was to quantify the test–retest reproducibility of measures of the PET ligand [11C]MePPEP in order to assess the stability of CB1-receptor quantification in humans in vivo.
Fifteen healthy subjects (eight females; median age 32 years, range 25 to 65 years) had a 90-minute PET scan on two occasions after injection of a median dose of [11C]MePPEP of 364 MBq. Metabolite-corrected arterial plasma input functions were obtained for all scans. Eight ROIs, reflecting different levels of receptor densities/concentrations, were defined automatically: hippocampus, anterior cingulate gyrus, inferior frontal gyrus, caudate nucleus, globus pallidus, nucleus accumbens, thalamus, and pons. We used seven quantification methods: reversible compartmental models with one and two tissue classes, two and four rate constants, and a variable blood volume term (2kbv; 4kbv); model-free (spectral) analyses with and without regularisation, including one with voxel-wise quantification; the simplified reference tissue model (SRTM) with pons as a pseudo-reference region; and modified standard uptake values (mSUVs) calculated for the period of ~ 30–60 min after injection. Percentage test–retest change and between-subject variability were both assessed, and test–retest reliability was quantified by the intraclass correlation coefficient (ICC). The ratio of binding estimates pallidum:pons served as an indicator of a method's ability to reflect binding heterogeneity.
Neither the SRTM nor the 4kbv model produced reliable measures, with ICCs around zero. Very good (> 0.75) or excellent (> 0.80) ICCs were obtained with the other methods. The most reliable were spectral analysis parametric maps (average across regions ± standard deviation 0.83 ± 0.03), rank shaping regularised spectral analysis (0.82 ± 0.05), and the 2kbv model (0.82 ± 0.09), but mSUVs were also reliable for most regions (0.79 ± 0.13). Mean test–retest changes among the five well-performing methods ranged from 12 ± 10% for mSUVs to 16% for 2kbv. Intersubject variability was high, with mean between-subject coefficients of variation ranging from 32 ± 13% for mSUVs to 45% for 2kbv. The highest pallidum:pons ratios of binding estimates were achieved by mSUV (4.2), spectral analysis-derived parametric maps (3.6), and 2kbv (3.6).
Quantification of CB1 receptor availability using [11C]MePPEP shows good to excellent reproducibility with several kinetic models and model-free analyses, whether applied on a region-of-interest or voxelwise basis. Simple mSUV measures were also reliable for most regions, but do not allow fully quantitative interpretation. [11C]MePPEP PET is well placed as a tool to investigate CB1-receptor mediated neurotransmission in health and disease.
Graphical abstract
Cannabinoid receptor concentrations assessed with [11C]MePPEP-PET. Top, reliability (ICCs ± SDs) of different quantification strategies: blue, compartmental models; red, spectral analysis variants; green, SRTM; yellow, modified SUVs. Bottom, parametric VT map.
•[11C]MePPEP is a PET tracer for cannabinoid receptors (CB1R).•Extensive evaluation of [11C]MePPEP data quantification strategies in large sample•We highlight successful methods to quantify CB1R in regions of interest.•Highly reliable parametric maps (ICC 0.83 ± 0.03) allow whole-brain surveys.•Modified standard uptake values also reliable, without arterial input functions
PMCID: PMC4283194  PMID: 24736184
CB1; Positron Emission Tomography; Reliability; Intra-class correlation coefficient
8.  Rapid Detection of Mycobacterium tuberculosis by Recombinase Polymerase Amplification 
PLoS ONE  2014;9(8):e103091.
Improved access to effective tests for diagnosing tuberculosis (TB) has been designated a public health priority by the World Health Organisation. In high burden TB countries nucleic acid based TB tests have been restricted to centralised laboratories and specialised research settings. Requirements such as a constant electrical supply, air conditioning and skilled, computer literate operators prevent implementation of such tests in many settings. Isothermal DNA amplification technologies permit the use of simpler, less energy intensive detection platforms more suited to low resource settings that allow the accurate diagnosis of a disease within a short timeframe. Recombinase Polymerase Amplification (RPA) is a rapid, low temperature isothermal DNA amplification reaction. We report here RPA-based detection of Mycobacterium tuberculosis complex (MTC) DNA in <20 minutes at 39°C. Assays for two MTC specific targets were investigated, IS6110 and IS1081. When testing purified MTC genomic DNA, limits of detection of 6.25 fg (IS6110) and 20 fg (IS1081)were consistently achieved. When testing a convenience sample of pulmonary specimens from suspected TB patients, RPA demonstrated superior accuracy to indirect fluorescence microscopy. Compared to culture, sensitivities for the IS1081 RPA and microscopy were 91.4% (95%CI: 85, 97.9) and 86.1% (95%CI: 78.1, 94.1) respectively (n = 71). Specificities were 100% and 88.6% (95% CI: 80.8, 96.1) respectively. For the IS6110 RPA and microscopy sensitivities of 87.5% (95%CI: 81.7, 93.2) and 70.8% (95%CI: 62.9, 78.7) were obtained (n = 90). Specificities were 95.4 (95% CI: 92.3,98.1) and 88% (95% CI: 83.6, 92.4) respectively. The superior specificity of RPA for detecting tuberculosis was due to the reduced ability of fluorescence microscopy to distinguish Mtb complex from other acid fast bacteria. The rapid nature of the RPA assay and its low energy requirement compared to other amplification technologies suggest RPA-based TB assays could be of use for integration into a point-of-care test for use in resource constrained settings.
PMCID: PMC4138011  PMID: 25118698
9.  Aromatase promoter I.f is regulated by progesterone receptor in mouse hypothalamic neuronal cell lines 
Aromatase catalyzes the conversion of C19 steroids to estrogens. Aromatase and progesterone, both of which function at different steps of steroidogenesis, are crucial for the sexually dimorphic development of the fetal brain and the regulation of gonadotropin secretion and sexual interest in adults. The aromatase gene (Cyp19a1) is selectively expressed in distinct neurons of the mouse hypothalamus through a distal brain-specific promoter, I.f, located ~40 kb upstream of the coding region. However, the regulation of aromatase expression in the brain is not well understood. In this study, we investigated a short feedback effect of progesterone analogues on aromatase mRNA expression and enzyme activity in estrogen receptor α (Esr1)-positive or -negative mouse embryonic hypothalamic neuronal cell lines that express aromatase via promoter I.f. In a hypothalamic neuronal cell line that highly expresses aromatase, progesterone receptor (Pgr), and Esr1, a progesterone agonist, R5020, inhibited aromatase mRNA level and enzyme activity. The inhibitory effect of R5020 was reversed by its antagonist, RU486. Deletion mutants of promoter I.f suggested that inhibition of aromatase expression by progesterone is conferred by the nt −1000/ −500 region, and R5020 enhanced binding of Pgr to the nt −800/ −600 region of promoter I.f. Small interfering RNA knockdown of Pgr eliminated progesterone-dependent inhibition of aromatase mRNA and enzyme activity. Taken together, progesterone enhances recruitment of Pgr to specific regions of the promoter I.f of Cyp19a1 and regulates aromatase expression in hypothalamic neurons.
PMCID: PMC4130222  PMID: 21628418
10.  Genetic impact on cognition and brain function in newly diagnosed Parkinson’s disease: ICICLE-PD study 
Brain  2014;137(10):2743-2758.
See Dujardin (doi:10.1093/brain/awu218) for a scientific commentary on this article. Nombela et al. present data from the ICICLE-PD study of cognition in newly diagnosed Parkinson’s disease. Consistent with the ‘Dual Syndrome’ hypothesis, impairments in executive function reflect a frontal dopaminergic syndrome modulated by COMT genotype, while visuospatial and memory deficits reflect disruption of temporo-parietal systems modulated by MAPT and APOE.
Parkinson’s disease is associated with multiple cognitive impairments and increased risk of dementia, but the extent of these deficits varies widely among patients. The ICICLE-PD study was established to define the characteristics and prevalence of cognitive change soon after diagnosis, in a representative cohort of patients, using a multimodal approach. Specifically, we tested the ‘Dual Syndrome’ hypothesis for cognitive impairment in Parkinson’s disease, which distinguishes an executive syndrome (affecting the frontostriatal regions due to dopaminergic deficits) from a posterior cortical syndrome (affecting visuospatial, mnemonic and semantic functions related to Lewy body pathology and secondary cholinergic loss). An incident Parkinson’s disease cohort (n = 168, median 8 months from diagnosis to participation) and matched control group (n = 85) were recruited to a neuroimaging study at two sites in the UK. All participants underwent clinical, neuropsychological and functional magnetic resonance imaging assessments. The three neuroimaging tasks (Tower of London, Spatial Rotations and Memory Encoding Tasks) were designed to probe executive, visuospatial and memory encoding domains, respectively. Patients were also genotyped for three polymorphisms associated with cognitive change in Parkinson’s disease and related disorders: (i) rs4680 for COMT Val158Met polymorphism; (ii) rs9468 for MAPT H1 versus H2 haplotype; and (iii) rs429358 for APOE-ε2, 3, 4. We identified performance deficits in all three cognitive domains, which were associated with regionally specific changes in cortical activation. Task-specific regional activations in Parkinson’s disease were linked with genetic variation: the rs4680 polymorphism modulated the effect of levodopa therapy on planning-related activations in the frontoparietal network; the MAPT haplotype modulated parietal activations associated with spatial rotations; and APOE allelic variation influenced the magnitude of activation associated with memory encoding. This study demonstrates that neurocognitive deficits are common even in recently diagnosed patients with Parkinson’s disease, and that the associated regional brain activations are influenced by genotype. These data further support the dual syndrome hypothesis of cognitive change in Parkinson’s disease. Longitudinal data will confirm the extent to which these early neurocognitive changes, and their genetic factors, influence the long-term risk of dementia in Parkinson’s disease. The combination of genetics and functional neuroimaging provides a potentially useful method for stratification and identification of candidate markers, in future clinical trials against cognitive decline in Parkinson’s disease.
PMCID: PMC4163033  PMID: 25080285
Parkinson’s disease; cognition; functional MRI; genetics
11.  Parkinson’s Disease – the Debate on the Clinical Phenomenology, Aetiology, Pathology and Pathogenesis 
The definition of Parkinson’s disease (PD) is changing with the expansion of clinical phenomenology and improved understanding of environmental and genetic influences that impact on the pathogenesis of the disease at the cellular and molecular level. This had led to debate and discussion with as yet, no general acceptance of the direction that change should take either at the level of diagnosis or of what should and should not be sheltered under an umbrella of PD. This article is one contribution to this on-going discussion. There are two different themes running through the article - widening the definition of PD/LBD/synucleinopathies and the heterogeneity that exists within PD itself from a clinical, pathological and genetic per-spective. The conclusion reached is that in the future, further diagnostic categories will need to be recognized. These are likely to include - Parkinson’s syndrome, Parkinson’s syndrome likely to be Lewy body PD, clinical PD (defined by QSBB criteria), Lewy body disease (PD, LBD, REM SBD) and synucleinopathies (including LBD, MSA).
PMCID: PMC4078250  PMID: 23938306
Parkinson’s disease; phenomenology; aetiology; pathology; pathogenesis; synucleinopathies
12.  Amyloid-related imaging abnormalities (ARIA) in Alzheimer’s disease patients treated with bapineuzumab: A retrospective analysis 
Lancet neurology  2012;11(3):241-249.
Amyloid-related imaging abnormalities (ARIA) have been reported in Alzheimer’s disease (AD) patients treated with bapineuzumab, a humanized monoclonal antibody to amyloid-β. ARIA includes MRI signal abnormalities suggestive of vasogenic edema and sulcal effusions (ARIA-E) and hemosiderin deposits (ARIA-H). A better understanding of the incidence and risk factors for ARIA may further the development of amyloid-modifying treatments for AD.
Two neuroradiologists independently reviewed (kappa=0.76) and then reached consensus reads on over 2500 FLAIR-MRIs from 262 participants in three phase 2 studies of bapineuzumab. Subjects (n=210) were included in risk analyses if they had no evidence of ARIA-E on pre-treatment MRI, received bapineuzumab, and had at least one post-treatment MRI.
36/210 (17%) subjects developed ARIA-E during treatment; 28 of these 36 (78%) did not report associated symptoms. Adverse events reported in 8 symptomatic patients included headache, confusion, neuropsychiatric and gastrointestinal symptoms. 15/36 of the ARIA-E cases (42%) were detected only on central review. 13/15 received additional infusions while ARIA-E was present, without any associated symptoms reported. ARIA-E incidence increased with bapineuzumab dose (Hazard Ratio [HR] 2.24 per mg/kg increase in dose; p<0·001) and with APOE ε4 allele number (HR 2.55 per allele; p<0·001).
ARIA appears to represent a spectrum of imaging findings with variable clinical correlates, with some cases remaining asymptomatic even when treated through ARIA-E. The increased risk of ARIA with APOE ε4 and bapineuzumab dose, and the time course in relation to dosing, is consistent with alterations in vascular amyloid burden.
PMCID: PMC4063417  PMID: 22305802
13.  Networking at the level of host immunity: immune cell interactions during persistent viral infections 
Cell host & microbe  2013;13(6):652-664.
Persistent viral infections are the result of a series of connected events that culminate in diminished immunity and the inability to eliminate infection. By building our understanding of how distinct components of the immune system function both individually and collectively in productive vs. abortive responses, new potential therapeutic targets can be developed to overcome immune dysfunction and thus fight persistent infections. Using lymphocytic choriomeningitis virus (LCMV) as a model of a persistent virus infection and drawing parallels to persistent human viral infections such as human immunodeficiency virus (HIV) and hepatitis C virus (HCV), we describe the cellular relationships and interactions that determine the outcome of initial infection and highlight immune targets for therapeutic intervention to prevent or treat persistent infections. Ultimately, these findings will further our understanding of the immunologic basis of persistent viral infection and likely lead to strategies to treat human viral infections.
PMCID: PMC3713852  PMID: 23768490
14.  Microglia, Amyloid, and Glucose Metabolism in Parkinson's Disease with and without Dementia 
Neuropsychopharmacology  2013;38(6):938-949.
[11C](R)PK11195-PET measures upregulation of translocator protein, which is associated with microglial activation, [11C]PIB-PET is a marker of amyloid, while [18F]FDG-PET measures cerebral glucose metabolism (rCMRGlc). We hypothesize that microglial activation is an early event in the Parkinson's disease (PD) spectrum and is independent of the amyloid pathology. The aim of this study is to evaluate in vivo the relationship between microglial activation, amyloid deposition, and glucose metabolism in Parkinson's disease dementia (PDD) and PD subjects without dementia. Here, we evaluated 11 PDD subjects, 8 PD subjects without dementia, and 24 control subjects. Subjects underwent T1 and T2 MRI, [11C](R)PK11195, [18F]FDG, and [11C]PIB PET scans. Parametric maps of [11C](R)PK11195 binding potential, rCMRGlc, and [11C]PIB uptake were interrogated using region of interest and SPM (statistical parametric mapping) analysis. The PDD patients showed a significant increase of microglial activation in anterior and posterior cingulate, striatum, frontal, temporal, parietal, and occipital cortical regions compared with the controls. The PD subjects also showed a statistically significant increase in microglial activation in temporal, parietal, and occipital regions. [11C]PIB uptake was marginally increased in PDD and PD. There was a significant reduction in glucose metabolism in PDD and PD. We have also demonstrated pixel-by-pixel correlation between mini-mental state examination (MMSE) score and microglial activation, and MMSE score and rCMRGlc. In conclusion, we have demonstrated that cortical microglial activation and reduced glucose metabolism can be detected early on in this disease spectrum. Significant microglial activation may be a factor in driving the disease process in PDD. Given this, agents that affect microglial activation could have an influence on disease progression.
PMCID: PMC3629382  PMID: 23303049
Amyloid; Cognition; glucose metabolism; Imaging; Clinical or Preclinical; Microglia; Movement Disorders; Neurology; Parkinson's disease; Parkinson's disease dementia; PK11195; amyloid; microglia; Parkinson's disease; Parkinson's disease dementia; glucose metabolism
15.  Blockade of Chronic Type I Interferon Signaling to Control Persistent LCMV Infection 
Science (New York, N.Y.)  2013;340(6129):202-207.
Type I interferons (IFN-I) are critical for antiviral immunity; however, chronic IFN-I signaling is associated with hyperimmune activation and disease progression in persistent infections. We demonstrated in mice that blockade of IFN-I signaling diminished chronic immune activation and immune suppression, restored lymphoid tissue architecture, and increased immune parameters associated with control of virus replication, ultimately facilitating clearance of the persistent infection. The accelerated control of persistent infection induced by blocking IFN-I signaling required CD4 T cells and was associated with enhanced IFN-γ production. Thus, we demonstrated that interfering with chronic IFN-I signaling during persistent infection redirects the immune environment to enable control of infection.
PMCID: PMC3704950  PMID: 23580528
16.  Benefits of putaminal GDNF infusion in Parkinson disease are maintained after GDNF cessation 
Neurology  2013;81(13):1176-1178.
We previously reported clinical improvement, increase in putamen [18F]-dopa uptake on PET imaging, and neuropathologic evidence of sprouting of dopaminergic fibers following chronic intraputaminal delivery of glial cell line–derived neurotrophic factor (GDNF) in idiopathic Parkinson disease (PD).1–3 We now provide clinical and PET evidence of persistent efficacy lasting for at least 3 years following cessation of GDNF infusion in a patient with PD. This is a single-case observational study, providing Class IV evidence.
PMCID: PMC3795600  PMID: 23946313
17.  Genome-Wide DNA Methylation Analysis Predicts an Epigenetic Switch for GATA Factor Expression in Endometriosis 
PLoS Genetics  2014;10(3):e1004158.
Endometriosis is a gynecological disease defined by the extrauterine growth of endometrial-like cells that cause chronic pain and infertility. The disease is limited to primates that exhibit spontaneous decidualization, and diseased cells are characterized by significant defects in the steroid-dependent genetic pathways that typify this process. Altered DNA methylation may underlie these defects, but few regions with differential methylation have been implicated in the disease. We mapped genome-wide differences in DNA methylation between healthy human endometrial and endometriotic stromal cells and correlated this with gene expression using an interaction analysis strategy. We identified 42,248 differentially methylated CpGs in endometriosis compared to healthy cells. These extensive differences were not unidirectional, but were focused intragenically and at sites distal to classic CpG islands where methylation status was typically negatively correlated with gene expression. Significant differences in methylation were mapped to 403 genes, which included a disproportionally large number of transcription factors. Furthermore, many of these genes are implicated in the pathology of endometriosis and decidualization. Our results tremendously improve the scope and resolution of differential methylation affecting the HOX gene clusters, nuclear receptor genes, and intriguingly the GATA family of transcription factors. Functional analysis of the GATA family revealed that GATA2 regulates key genes necessary for the hormone-driven differentiation of healthy stromal cells, but is hypermethylated and repressed in endometriotic cells. GATA6, which is hypomethylated and abundant in endometriotic cells, potently blocked hormone sensitivity, repressed GATA2, and induced markers of endometriosis when expressed in healthy endometrial cells. The unique epigenetic fingerprint in endometriosis suggests DNA methylation is an integral component of the disease, and identifies a novel role for the GATA family as key regulators of uterine physiology–aberrant DNA methylation in endometriotic cells correlates with a shift in GATA isoform expression that facilitates progesterone resistance and disease progression.
Author Summary
Women develop endometriosis when endometrial tissue with altered sensitivity to ovarian hormones grows outside the uterus. The persistent survival of these cells results in chronic pelvic pain and infertility. Although the origin of the disease remains a mystery, it only occurs in women and menstruating primates, suggesting that the unique evolution behind primate uterine development and menstruation are linked to the disease. Epigenetic defects affecting the uterine physiological response to ovarian hormones are also involved in endometriosis, and several genes implicated in disease progression are differentially methylated. Here we compared DNA methylation with gene expression in endometriosis using large-scale arrays. By comparing healthy and diseased cells treated with or without hormones to mimic part of the menstrual cycle, we uncovered many differentially methylated genes with defective expression in endometriosis that also regulate the hormone-dependent aspects of menstruation. In addition to expanding our understanding of how methylation affects endometriosis many fold, this also led us to propose an epigenetic switch that permits GATA6 expression in endometriosis instead of GATA2, and this switch promotes the aberrant expression of many of the genes seen in endometriosis. Our work provides novel unifying insight into the cause and development of endometriosis.
PMCID: PMC3945170  PMID: 24603652
18.  Serotonergic mechanisms responsible for levodopa-induced dyskinesias in Parkinson’s disease patients 
The Journal of Clinical Investigation  2014;124(3):1340-1349.
Levodopa-induced dyskinesias (LIDs) are the most common and disabling adverse motor effect of therapy in Parkinson’s disease (PD) patients. In this study, we investigated serotonergic mechanisms in LIDs development in PD patients using 11C-DASB PET to evaluate serotonin terminal function and 11C-raclopride PET to evaluate dopamine release. PD patients with LIDs showed relative preservation of serotonergic terminals throughout their disease. Identical levodopa doses induced markedly higher striatal synaptic dopamine concentrations in PD patients with LIDs compared with PD patients with stable responses to levodopa. Oral administration of the serotonin receptor type 1A agonist buspirone prior to levodopa reduced levodopa-evoked striatal synaptic dopamine increases and attenuated LIDs. PD patients with LIDs that exhibited greater decreases in synaptic dopamine after buspirone pretreatment had higher levels of serotonergic terminal functional integrity. Buspirone-associated modulation of dopamine levels was greater in PD patients with mild LIDs compared with those with more severe LIDs. These findings indicate that striatal serotonergic terminals contribute to LIDs pathophysiology via aberrant processing of exogenous levodopa and release of dopamine as false neurotransmitter in the denervated striatum of PD patients with LIDs. Our results also support the development of selective serotonin receptor type 1A agonists for use as antidyskinetic agents in PD.
PMCID: PMC3934188  PMID: 24531549
19.  Imaging markers for Alzheimer disease 
Neurology  2013;81(5):487-500.
Revised diagnostic criteria for Alzheimer disease (AD) acknowledge a key role of imaging biomarkers for early diagnosis. Diagnostic accuracy depends on which marker (i.e., amyloid imaging, 18F-fluorodeoxyglucose [FDG]-PET, SPECT, MRI) as well as how it is measured (“metric”: visual, manual, semiautomated, or automated segmentation/computation). We evaluated diagnostic accuracy of marker vs metric in separating AD from healthy and prognostic accuracy to predict progression in mild cognitive impairment. The outcome measure was positive (negative) likelihood ratio, LR+ (LR−), defined as the ratio between the probability of positive (negative) test outcome in patients and the probability of positive (negative) test outcome in healthy controls. Diagnostic LR+ of markers was between 4.4 and 9.4 and LR− between 0.25 and 0.08, whereas prognostic LR+ and LR− were between 1.7 and 7.5, and 0.50 and 0.11, respectively. Within metrics, LRs varied up to 100-fold: LR+ from approximately 1 to 100; LR− from approximately 1.00 to 0.01. Markers accounted for 11% and 18% of diagnostic and prognostic variance of LR+ and 16% and 24% of LR−. Across all markers, metrics accounted for an equal or larger amount of variance than markers: 13% and 62% of diagnostic and prognostic variance of LR+, and 29% and 18% of LR−. Within markers, the largest proportion of diagnostic LR+ and LR− variability was within 18F-FDG-PET and MRI metrics, respectively. Diagnostic and prognostic accuracy of imaging AD biomarkers is at least as dependent on how the biomarker is measured as on the biomarker itself. Standard operating procedures are key to biomarker use in the clinical routine and drug trials.
PMCID: PMC3776529  PMID: 23897875
20.  Characterizing mild cognitive impairment in incident Parkinson disease 
Neurology  2014;82(4):308-316.
To describe the frequency of mild cognitive impairment (MCI) in Parkinson disease (PD) in a cohort of newly diagnosed incident PD cases and the associations with a panel of biomarkers.
Between June 2009 and December 2011, 219 subjects with PD and 99 age-matched controls participated in clinical and neuropsychological assessments as part of a longitudinal observational study. Consenting individuals underwent structural MRI, lumbar puncture, and genotyping for common variants of COMT, MAPT, SNCA, BuChE, EGF, and APOE. PD-MCI was defined with reference to the new Movement Disorder Society criteria.
The frequency of PD-MCI was 42.5% using level 2 criteria at 1.5 SDs below normative values. Memory impairment was the most common domain affected, with 15.1% impaired at 1.5 SDs. Depression scores were significantly higher in those with PD-MCI than the cognitively normal PD group. A significant correlation was found between visual Pattern Recognition Memory and cerebrospinal β-amyloid 1–42 levels (β standardized coefficient = 0.350; p = 0.008) after controlling for age and education in a linear regression model, with lower β-amyloid 1–42 and 1–40 levels observed in those with PD-MCI. Voxel-based morphometry did not reveal any areas of significant gray matter loss in participants with PD-MCI compared with controls, and no specific genotype was associated with PD-MCI at the 1.5-SD threshold.
In a large cohort of newly diagnosed PD participants, PD-MCI is common and significantly correlates with lower cerebrospinal β-amyloid 1–42 and 1–40 levels. Future longitudinal studies should enable us to determine those measures predictive of cognitive decline.
PMCID: PMC3929202  PMID: 24363137
21.  Inflammation makes T cells sensitive 
Immunity  2013;38(1):5-7.
Inflammatory cytokines shape CD8+[J1] T cell responses. In this issue of Immunity Richer et al. and Raue et al. demonstrate that inflammatory cytokines dynamically fine-tune antigen sensitivity of CD8+ T cells to potently detect and better eliminate infected cells.
PMCID: PMC3619688  PMID: 23352218
22.  Caveolin-1 Orchestrates TCR Synaptic Polarity, Signal Specificity, and Function in CD8 T Cells 
Journal of immunology (Baltimore, Md. : 1950)  2011;187(6):10.4049/jimmunol.1101447.
TCR engagement triggers the polarized recruitment of membrane, actin, and transducer assemblies within the T cell–APC contact that amplify and specify signaling cascades and Teffector activity. We report that caveolin-1, a scaffold that regulates polarity and signaling in nonlymphoid cells, is required for optimal TCR-induced actin polymerization, synaptic membrane raft polarity, and function in CD8, but not CD4, T cells. In CD8+ T cells, caveolin-1 ablation selectively impaired TCR-induced NFAT-dependent NFATc1 and cytokine gene expression, whereas caveolin-1 re-expression promoted NFATc1 gene expression. Alternatively, caveolin-1 ablation did not affect TCR-induced NF-κB–dependent Iκbα expression. Cav-1−/− mice did not efficiently promote CD8 immunity to lymphocytic choriomeningitis virus, nor did cav-1−/− OT-1+ CD8+ T cells efficiently respond to Listeria mono-cytogenes-OVA after transfer into wild-type hosts. Therefore, caveolin-1 is a T cell-intrinsic orchestrator of TCR-mediated membrane polarity and signal specificity selectively employed by CD8 T cells to customize TCR responsiveness.
PMCID: PMC3881976  PMID: 21849673
23.  Ventral striatal dopamine synthesis capacity is associated with individual differences in behavioral disinhibition 
Pathological gambling, alongside addictive and antisocial disorders, forms part of a broad psychopathological spectrum of externalizing disorders, which share an underlying genetic vulnerability. The shared externalizing propensity is a highly heritable, continuously varying trait. Disinhibitory personality traits such as impulsivity and novelty seeking (NS) function as indicators of this broad shared externalizing tendency, which may reflect, at the neurobiological level, variation in the reactivity of dopaminergic (DAergic) brain reward systems centered on the ventral striatum (VS). Here, we examined whether individual differences in ventral striatal dopamine (DA) synthesis capacity were associated with individual variation in disinhibitory personality traits. Twelve healthy male volunteers underwent 6-[18F]Fluoro-L-DOPA (FDOPA) positron emission tomography (PET) scanning to measure striatal DA synthesis capacity, and completed a measure of disinhibited personality (NS). We found that levels of ventral, but not dorsal, striatal DA synthesis capacity were significantly correlated with inter-individual variation in disinhibitory personality traits, particularly a propensity for financial extravagance and irresponsibility. Our results are consistent with preclinical models of behavioral disinhibition and addiction proneness, and provide novel insights into the neurobiology of personality based vulnerability to pathological gambling and other externalizing disorders.
PMCID: PMC3954060  PMID: 24672449
addiction; dopamine; externalizing; impulsivity; positron emission tomography; pathological gambling; reward; ventral striatum
24.  Serotonergic loss in motor circuitries correlates with severity of action-postural tremor in PD 
Neurology  2013;80(20):1850-1855.
The underlying pathophysiology of tremor in Parkinson disease (PD) is unclear; however, it is known that tremor does not appear to be as responsive to dopaminergic medication as bradykinesia or rigidity. It is suggested that serotonergic dysfunction could have a role in tremor development.
Using 11C-DASB PET, a marker of serotonin transporter binding, and clinical observations, we have investigated function of serotonergic terminals in 12 patients with tremor-predominant and 12 with akinetic-rigid PD. Findings were compared with those of 12 healthy controls.
Reductions of 11C-DASB in caudate, putamen, and raphe nuclei significantly correlated with tremor severity on posture and action, but not with resting tremor. The tremor-predominant group also showed reductions of 11C-DASB in other regions involved in motor circuitry, including the thalamus and Brodmann areas 4 and 10.
Our findings support a role for serotonergic dysfunction in motor circuitries in the generation of postural tremor in PD.
PMCID: PMC3908354  PMID: 23596065
25.  The sterol regulatory element binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity 
Nature immunology  2013;14(5):489-499.
Newly activated CD8+ T cells reprogram their metabolism to meet the extraordinary biosynthetic demands of clonal expansion; however, the signals mediating metabolic reprogramming remain poorly defined. Herein, we demonstrate an essential role for sterol regulatory element binding proteins (SREBPs) in the acquisition of effector cell metabolism. Without SREBP signaling, CD8+ T cells are unable to blast, resulting in markedly attenuated clonal expansion during viral infection. Mechanistic studies indicate that SREBPs are essential to meet the heightened lipid requirements of membrane synthesis during blastogenesis. SREBPs are dispensable for homeostatic proliferation, indicating a context-specific requirement for SREBPs in effector responses. These studies provide insights into the molecular signals underlying metabolic reprogramming of CD8+ T cells during the transition from quiescence to activation.
PMCID: PMC3652626  PMID: 23563690
SREBP; LCMV; lipids; CD8+ T cell; metabolism; proliferation

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