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Background: Parkinson’s disease (PD) is characterized by brain metabolic networks, specifically associated with motor and cognitive manifestations. Few studies have investigated network changes in cerebral hemispheres ipsilateral and contralateral to the clinically more affected body side. Objective: We examined hemispheric network abnormalities and their relationship to striatal dopaminergic deficits in PD patients at different stages. Methods: 45 PD patients underwent dual-tracer positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) and 18F-fluorodopa (FDOPA) in a high-resolution PET scanner. In all patients, we computed expression levels for the PD-related motor/cognition metabolic patterns (PDRP/PDCP) as well as putamen/caudate FDOPA uptake values in both hemispheres. Resulting hemispheric measures in the PD group were compared with corresponding healthy control values and assessed across disease stages. Results: Hemispheric PDRP and PDCP expression was significantly elevated contralateral and ipsilateral to the more affected body side in patients with unilateral symptoms (H&Y 1: p

Background Alterations in the GBA gene (NM_000157.3) are the most important genetic risk factor for Parkinson's disease (PD). Biallelic GBA mutations cause the lysosomal storage disorder Gaucher's disease. The GBA variants p.E365K and p.T408M are associated with PD but not with Gaucher's disease. The pathophysiological role of these variants needs to be further explored. Objective This study analyzed clinical, neuropsychological, metabolic, and neuroimaging phenotypes of patients with PD carrying the GBA variants p.E365K and p.T408M. Methods GBA was sequenced in 56 patients with mid-stage PD. Carriers of GBA variants were compared with noncarriers regarding clinical history and symptoms, neuropsychological features, metabolomics, and multimodal neuroimaging. Blood plasma gas chromatography coupled to mass spectrometry, 6-[18 F]fluoro-L-Dopa positron emission tomography (PET), [18 F]fluorodeoxyglucose PET, and resting-state functional magnetic resonance imaging were performed. Results Sequence analysis detected 13 heterozygous GBA variant carriers (7 with p.E365K, 6 with p.T408M). One patient carried a GBA mutation (p.N409S) and was excluded. Clinical history and symptoms were not significantly different between groups. Global cognitive performance was lower in variant carriers. Metabolomic group differences were suggestive of more severe PD-related alterations in carriers versus noncarriers. Both PET scans showed signs of a more advanced disease; [18 F]fluorodeoxyglucose PET and functional magnetic resonance imaging showed similarities with Lewy body dementia and PD dementia in carriers. Conclusions This is the first study to comprehensively assess (neuro-)biological phenotypes of GBA variants in PD. Metabolomics and neuroimaging detected more significant group differences than clinical and behavioral evaluation. These alterations could be promising to monitor effects of disease-modifying treatments targeting glucocerebrosidase metabolism. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

We conducted a double-blinded phase I clinical trial to establish whether nicotinamide adenine dinucleotide (NAD) replenishment therapy, via oral intake of nicotinamide riboside (NR), is safe, augments cerebral NAD levels, and impacts cerebral metabolism in Parkinson’s disease (PD). Thirty newly diagnosed, treatment-naive patients received 1,000 mg NR or placebo for 30 days. NR treatment was well tolerated and led to a significant, but variable, increase in cerebral NAD levels—measured by 31phosphorous magnetic resonance spectroscopy—and related metabolites in the cerebrospinal fluid. NR recipients showing increased brain NAD levels exhibited altered cerebral metabolism, measured by 18fluoro-deoxyglucose positron emission tomography, and this was associated with mild clinical improvement. NR augmented the NAD metabolome and induced transcriptional upregulation of processes related to mitochondrial, lysosomal, and proteasomal function in blood cells and/or skeletal muscle. Furthermore, NR decreased the levels of inflammatory cytokines in serum and cerebrospinal fluid. Our findings nominate NR as a potential neuroprotective therapy for PD, warranting further investigation in larger trials. publishedVersion

BACKGROUND AND PURPOSE The diagnosis and monitoring of semantic variant primary progressive aphasia (sv-PPA) are clinically challenging. We aimed to establish a distinctive metabolic pattern in sv-PPA for diagnosis and severity evaluation. METHODS Fifteen sv-PPA patients and 15 controls were enrolled to identify sv-PPA-related pattern (sv-PPARP) by principal component analysis of 18 F-fluorodeoxyglucose positron emission tomography. Eighteen Alzheimer disease dementia (AD) and 14 behavioral variant frontotemporal dementia (bv-FTD) patients were enrolled to test the discriminatory power. Correspondingly, regional metabolic activities extracted from the voxelwise analysis were evaluated for the discriminatory power. RESULTS The sv-PPARP was characterized as decreased metabolic activity mainly in the bilateral temporal lobe (left predominance), middle orbitofrontal gyrus, left hippocampus/parahippocampus gyrus, fusiform gyrus, insula, inferior orbitofrontal gyrus, and striatum, with increased activity in the bilateral lingual gyrus, cuneus, calcarine gyrus, and right precentral and postcentral gyrus. The pattern expression had significant discriminatory power (area under the curve [AUC] = 0.98, sensitivity = 100%, specificity = 94.4%) in distinguishing sv-PPA from AD, and the asymmetry index offered complementary discriminatory power (AUC = 0.91, sensitivity = 86.7%, specificity = 92.9%) in distinguishing sv-PPA from bv-FTD. In sv-PPA patients, the pattern expression correlated with Boston Naming Test scores at baseline and showed significant increase in the subset of patients with follow-up. The voxelwise analysis showed similar topography, and the regional metabolic activities had equivalent or better discriminatory power and clinical correlations with Boston Naming Test scores. The ability to reflect disease progression in longitudinal follow-up seemed to be inferior to the pattern expression. CONCLUSIONS The sv-PPARP might serve as an objective biomarker for diagnosis and progression evaluation.

Recent studies on a rodent model of Parkinson's disease (PD) have raised the possibility of increased blood-brain barrier (BBB) permeability, demonstrated by histology, autoradiography, and positron emission tomography (PET). However, in human PD patients, in vivo evidence of increased BBB permeability is lacking. We examined the hypothesis that levodopa treatment increases BBB permeability in human subjects with PD, particularly in those with levodopa-induced dyskinesia (LID).We used rubidium-82 (Rubidium influx into brain tissue was undetectable in PD patients with or without LID, scanned on and off drug. No significant differences in regional V

ObjectiveTo determine whether the Alzheimer disease (AD) dementia conversion-related pattern (ADCRP) on [18F]FDG PET can serve as a valid predictor for the development of AD dementia, the individual expression of the ADCRP (subject score) and its prognostic value were examined in patients with mild cognitive impairment (MCI) and biologically defined AD.MethodsA total of 269 patients with available [18F]FDG PET, [18F]AV-45 PET, phosphorylated and total tau in CSF, and neurofilament light chain in plasma were included. Following the AT(N) classification scheme, where AD is defined biologically by in vivo biomarkers of β-amyloid (Aβ) deposition (“A”) and pathologic tau (“T”), patients were categorized to the A−T−, A+T−, A+T+ (AD), and A−T+ groups.ResultsThe mean subject score of the ADCRP was significantly higher in the A+T+ group compared to each of the other group (all p < 0.05) but was similar among the latter (all p > 0.1). Within the A+T+ group, the subject score of ADCRP was a significant predictor of conversion to dementia (hazard ratio, 2.02 per z score increase; p < 0.001), with higher predictive value than of alternative biomarkers of neurodegeneration (total tau and neurofilament light chain). Stratification of A+T+ patients by the subject score of ADCRP yielded well-separated groups of high, medium, and low conversion risks.ConclusionsThe ADCRP is a valuable biomarker of neurodegeneration in patients with MCI and biologically defined AD. It shows great potential for stratifying the risk and estimating the time to conversion to dementia in patients with MCI and underlying AD (A+T+).Classification of EvidenceThis study provides Class I evidence that [18F]FDG PET predicts the development of AD dementia in individuals with MCI and underlying AD as defined by the AT(N) framework.

Purpose Multiple system atrophy (MSA) is an atypical parkinsonian syndrome and often difficult to discriminate clinically from progressive supranuclear palsy (PSP) and Parkinson's disease (PD) in early stages. Although a characteristic metabolic brain network has been reported for MSA, it is unknown whether this network can provide a clinically useful biomarker in different centers. This study was aimed to identify and cross-validate MSA-related brain network and assess its ability for differential diagnosis and clinical correlations in Chinese and American patient cohorts. Methods We included 18F-FDG PET scans retrospectively from 128 clinically diagnosed parkinsonian patients (34 MSA, 34 PSP and 60 PD) and 40 normal subjects in China and in the USA. Using PET images from 20 moderate-stage MSA patients of parkinsonian subtype and 20 normal subjects in both centers, we reproduced MSA-related pattern (MSAPRP) of spatial covariance and estimated its reliability. MSAPRP scores were evaluated in assessing differential diagnosis among moderate- and early-stage MSA, PSP or PD patients and clinical correlations with disease severity. Regional metabolic differences were detected using statistical parameter mapping analysis. MSA-related network and regional topographies of metabolic abnormality were cross-validated between the Chinese and American cohorts. Results We generated a highly reliable MSAPRP characterized by decreased loading in inferior frontal cortex, striatum and cerebellum, and increased loading in sensorimotor, parietal and occipital cortices. MSAPRP scores discriminated between normal, MSA, PSP and PD subjects and correlated with standardized ratings of clinical stages and motor symptoms in MSA. High similarities in MSAPRPs, network scores and corresponding maps of metabolic abnormality were observed between two different cohorts. Conclusion We have demonstrated reproducible metabolic topographies associated with MSA at both network and regional levels in two independent patient cohorts. Moreover, MSAPRP scores are sensitive for evaluating disease discrimination and clinical correlates. This study supports differential diagnosis of MSA regardless of different patient populations, PET scanners and imaging protocols.

The value of 18F-FDG PET for predicting conversion from mild cognitive impairment (MCI) to Alzheimer dementia (AD) is currently under debate. We used a principal components analysis (PCA) to identify a metabolic AD conversion-related pattern (ADCRP) and investigated the prognostic value of the resulting pattern expression score (PES). Methods: 18F-FDG PET scans of 544 MCI patients were obtained from the Alzheimer Disease Neuroimaging Initiative database and analyzed. We implemented voxel-based PCA and standard Statistical Parametric Mapping analysis (as a reference) to disclose cerebral metabolic patterns associated with conversion from MCI to AD. By Cox proportional hazards regression, we examined the prognostic value of candidate predictors. Also, we constructed prognostic models with clinical, imaging, and clinical and imaging variables in combination. Results: PCA revealed an ADCRP that involved regions with relative decreases in metabolism (temporoparietal, frontal, posterior cingulate, and precuneus cortices) and relative increases in metabolism (sensorimotor and occipital cortices, cerebellum, and left putamen). Among the predictor variables age, sex, Functional Activities Questionnaire, Mini-Mental State Examination, apolipoprotein E, PES, and normalized 18F-FDG uptake (regions with significant hypo- and hypermetabolism in patients with conversion vs. those without conversion), PES was the best independent predictor of conversion (hazard ratio, 1.77, per z score increase; 95% CI, 1.24-2.52; P < 0.001). Moreover, adding PES to the model including the clinical variables significantly increased its prognostic value. Conclusion: The ADCRP expression score was a valid predictor of conversion. A combination of clinical variables and PES yielded a higher accuracy than each single tool in predicting conversion from MCI to AD, underlining the incremental utility of 18F-FDG PET.

PURPOSE Neuroimaging indicators of Parkinson disease have been developed and applied in clinical practices. Dopaminergic imaging reflects nigrostriatal dopaminergic dysfunction, and metabolic network imaging offers disease-related metabolic changes at a system level. We aimed to elucidate the association between Parkinsonian symptoms and neuroimaging, and interactions between different imaging techniques. METHODS We conducted a dual-tracer PET study for the combined assessments of dopaminergic binding (C-CFT) and glucose metabolism (F-FDG) in 103 participants with Parkinson disease (65 male and 38 female subjects). The detailed clinical rating scores were systematically collected in all members. The interactions among dopaminergic bindings, metabolic changes, and clinical manifestations were evaluated at voxel, regional, and network levels. RESULTS Striatal DAT binding correlated with akinesia-rigidity (P < 0.001) but not with tremor; the metabolic PET imaging, nonspecific to the dopaminergic dysfunction, disclosed a set of brain regions correlating with the cardinal symptoms, including tremor. In addition, the unilateral symptom correlated with the contralateral nigrostriatal dopamine loss, but with bilateral metabolic changes, suggesting their differences in the application of disease-related mechanistic studies. Further imaging-imaging correlation study revealed that dopaminergic dysfunction correlated with widely distributed metabolic changes in Parkinson disease, and the modest correlations supported the findings on the clinical-imaging correlation. CONCLUSIONS In this dual-tracer PET study, we demonstrated the robust interactions among dopaminergic dysfunction, metabolic brain changes and clinical manifestations at voxel, regional, and network levels. Our findings might promote the understanding in the proper application of dopaminergic and metabolic PET imaging in Parkinson disease and offer more evidence in support of Parkinsonian pathophysiological mechanisms.

Progressive supranuclear palsy (PSP) is a rare movement disorder and often difficult to distinguish clinically from Parkinson’s disease (PD) and multiple system atrophy (MSA) in early phases. In this study, we report reproducible disease-related topographies of brain network and regional glucose metabolism associated with PSP in clinically-confirmed independent cohorts of PSP, MSA and PD patients and healthy controls in the USA and China. Using (18)F-FDG PET images from PSP and healthy subjects, we applied spatial covariance analysis with bootstrapping to identify a PSP-related pattern (PSPRP) and estimate its reliability, and evaluated the ability of network scores for differential diagnosis. We also detected regional metabolic differences using statistical parametric mapping analysis. We produced a highly reliable PSPRP characterized by relative metabolic decreases in the middle prefrontal cortex/cingulate, ventrolateral prefrontal cortex, striatum, thalamus and midbrain, covarying with relative metabolic increases in the hippocampus, insula and parieto-temporal regions. PSPRP network scores correlated positively with PSP duration and accurately discriminated between healthy, PSP, MSA and PD groups in two separate cohorts of parkinsonian patients at both early and advanced stages. Moreover, PSP patients shared many overlapping areas with abnormal metabolism in the same cortical and subcortical regions as in the PSPRP. With rigorous cross-validation, this study demonstrated highly comparable and reproducible PSP-related metabolic topographies at network and regional levels across different patient populations and PET scanners. Metabolic brain network activity may serve as a reliable and objective marker of PSP, although cross-validation applying recent diagnostic criteria and classification is warranted.

Purpose: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. In China, chronic hepatitis B virus (HBV) infection remains the major risk factor for HCC. In this study, we performed a genome-wide association study (GWAS) among Chinese populations to identify novel genetic loci contributing to susceptibility to HBV-related HCC. Experimental Design: GWAS scan is performed in a collection of 205 HBV-related HCC trios (each trio includes an affected proband and his/her both parents), and 355 chronic HBV carriers with HCC (cases) and 360 chronic HBV carriers without HCC (controls), followed by two rounds of replication studies totally consisting of 3,796 cases and 2,544 controls. Results: We identified a novel association signal within the CDK14 gene at 7q21.13 (index rs10272859, OR = 1.28, P = 9.46 × 10−10). Furthermore, we observed that the at-risk rs10272859[G] allele was significantly associated with higher mRNA expression levels of CDK14 in liver tissues. Chromosome conformation capture assays in liver cells confirmed that a physical interaction exists between the promoter region of CDK14 and the risk-associated SNPs in strong linkage disequilibrium with the index rs10272859 at 7q21.13. This index rs10272859 also showed significant association with the survival of HCC patients. Conclusions: Our findings highlight a novel locus at 7q21.13 conferring both susceptibility and prognosis to HBV-related HCC, and suggest the CDK14 gene to be the functional target of the 7q21.13 locus. Clin Cancer Res; 24(4); 906–15. ©2017 AACR.

To evaluate the reproducibility of the expression of Parkinson's Disease Related Pattern (PDRP) across multiple sets of 18F-FDG-PET brain images reconstructed with different reconstruction algorithms.18F-FDG-PET brain imaging was performed in two independent cohorts of Parkinson's disease (PD) patients and normal controls (NC). Slovenian cohort (20 PD patients, 20 NC) was scanned with Siemens Biograph mCT camera and reconstructed using FBP, FBP+TOF, OSEM, OSEM+TOF, OSEM+PSF and OSEM+PSF+TOF. American Cohort (20 PD patients, 7 NC) was scanned with GE Advance camera and reconstructed using 3DRP, FORE-FBP and FORE-Iterative. Expressions of two previously-validated PDRP patterns (PDRP-Slovenia and PDRP-USA) were calculated. We compared the ability of PDRP to discriminate PD patients from NC, differences and correlation between the corresponding subject scores and ROC analysis results across the different reconstruction algorithms.The expression of PDRP-Slovenia and PDRP-USA networks was significantly elevated in PD patients compared to NC (p0.0001), regardless of reconstruction algorithms. PDRP expression strongly correlated between all studied algorithms and the reference algorithm (r⩾0.993, p0.0001). Average differences in the PDRP expression among different algorithms varied within 0.73 and 0.08 of the reference value for PDRP-Slovenia and PDRP-USA, respectively. ROC analysis confirmed high similarity in sensitivity, specificity and AUC among all studied reconstruction algorithms.These results show that the expression of PDRP is reproducible across a variety of reconstruction algorithms of 18F-FDG-PET brain images. PDRP is capable of providing a robust metabolic biomarker of PD for multicenter 18F-FDG-PET images acquired in the context of differential diagnosis or clinical trials.

To compare the efficacy and safety between drug-eluting bead (DEB) transarterial chemoembolization (TACE) with CalliSpheres® microspheres (CSM) and conventional TACE (cTACE) in hepatocellular carcinoma (HCC) patients, and to explore the predictive factors for treatment response and survival.89 HCC patients receiving DEB-TACE with CSM or cTACE were consecutively recruited in this cohort study. Treatment response was assessed at month 1 (M1)/M3/M6. Progression free survival (PFS) and overall survival (OS) were calculated. Liver function indexes were measured at M1 and adverse events occurred during operation and hospitalization were recorded.Higher complete response (CR) rate and objective response rate (ORR) at M1/M3 in DEB-TACE group were found compared to cTACE group, and no difference of PFS and OS was noted between the two groups. Multivariate analysis of ORR, DFS and OS disclosed that multifocal disease, ALT≥1upper limit of normal (ULN) and ALP≥1ULN independently predicted lower ORR, while bilobar tumor location and abnormal CA19.9 level were independent predictive factors for unfavorable PFS. As for liver function, there was no difference of all liver function indexes changes (M1-M0) between the two groups. Moreover, DEB-TACE group displayed more frequent pain during treatment, and more frequent pain and fever during hospitalization compared to cTACE group.The short-term CR and ORR of DEB-TACE treatment with CSM are better, while OS, DFS and safety were equivalent compared to cTACE in treating HCC patients.

The present study examined the predictive values of amyloid PET, (18)F-FDG PET, and nonimaging predictors (alone and in combination) for development of Alzheimer dementia (AD) in a large population of patients with mild cognitive impairment (MCI). Methods: The study included 319 patients with MCI from the Alzheimer Disease Neuroimaging Initiative database. In a derivation dataset (n = 159), the following Cox proportional-hazards models were constructed, each adjusted for age and sex: amyloid PET using (18)F-florbetapir (pattern expression score of an amyloid-β AD conversion–related pattern, constructed by principle-components analysis); (18)F-FDG PET (pattern expression score of a previously defined (18)F-FDG–based AD conversion–related pattern, constructed by principle-components analysis); nonimaging (functional activities questionnaire, apolipoprotein E, and mini-mental state examination score); (18)F-FDG PET + amyloid PET; amyloid PET + nonimaging; (18)F-FDG PET + nonimaging; and amyloid PET + (18)F-FDG PET + nonimaging. In a second step, the results of Cox regressions were applied to a validation dataset (n = 160) to stratify subjects according to the predicted conversion risk. Results: On the basis of the independent validation dataset, the (18)F-FDG PET model yielded a significantly higher predictive value than the amyloid PET model. However, both were inferior to the nonimaging model and were significantly improved by the addition of nonimaging variables. The best prediction accuracy was reached by combining (18)F-FDG PET, amyloid PET, and nonimaging variables. The combined model yielded 5-y free-of-conversion rates of 100%, 64%, and 24% for the low-, medium- and high-risk groups, respectively. Conclusion: (18)F-FDG PET, amyloid PET, and nonimaging variables represent complementary predictors of conversion from MCI to AD. Especially in combination, they enable an accurate stratification of patients according to their conversion risks, which is of great interest for patient care and clinical trials.

Summary Background Transarterial chemoembolization (TACE) is widely applied in hepatocellular carcinoma (HCC) patients who are not suitable for surgical treatment. We aimed to investigate the treatment outcomes and comprehensive prognostic factors of CalliSpheres® microspheres (CSM) drug-eluting bead TACE (DEB-TACE) treatment and conventional TACE (cTACE) treatment in HCC patients. Methods Three hundred and thirty-five HCC patients received DEB-TACE or cTACE treatment were consecutively enrolled in multi-center, retrospective cohort study. Treatment response was conducted at M1, M3 or M6 after treatment. Progression free survival (PFS) and overall survival (OS) were recorded. Thirty-seven baseline factors including demographic characteristics, clinical features, biochemical indexes and previous treatment histories were selected. Results In total patients, history of drink and largest nodule size ≥ 7 cm independently predicted worse ORR, DEB-TACE predicted better OS, while largest nodule size ≥ 7 cm, increased Child-Pugh stage, ALB abnormal, ALP abnormal or AFP abnormal predicted worse survival. For DEB-TACE group, previous cTACE and ANC abnormal independently predicted worse ORR, and hepatic vein invasion, increased Child-Pugh stage or AFP abnormal independently predicted poor survival. For cTACE group, largest nodule size ≥ 7 cm independently predicted poor ORR, and multifocal disease as well as ALB abnormal predicted poor OS. Conclusions History of drink, largest nodule size ≥ 7 cm, DEB-TACE, increased Child-Pugh stage, abnormal ALB, ALP or AFP are potential prognostic factors in total patients, previous cTACE and ANC abnormal, hepatic vein invasion, increased Child-Pugh stage or AFP abnormal are potential prognostic factors in DEB-TA group, and largest nodule size ≥ 7 cm, multifocal disease and ALB abnormal are potential prognostic factors in cTACE group.

Abnormal covariance pattern of regional metabolism associated with Parkinson disease (PD) is modulated by dopaminergic pharmacotherapy. Using high-resolution 18F-FDG PET and network analysis, we previously derived and validated a parkinsonism-related metabolic pattern (PRP) in nonhuman primate models of PD. It is currently not known whether this network is modulated by experimental therapeutics. In this study, we examined changes in network activity by striatal implantation of human levodopa-producing retinal pigment epithelial (hRPE) cells in parkinsonian macaques and evaluated the reproducibility of network activity in a small test–retest study. Methods:18F-FDG PET scans were acquired in 8 healthy macaques and 8 macaques with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)–induced bilateral nigrostriatal dopaminergic lesions after unilateral putaminal implantation of hRPE cells or sham surgery. PRP activity was measured prospectively in all animals and in a subset of test–retest animals using a network quantification approach. Network activity and regional metabolic values were compared on a hemispheric basis between animal groups and treatment conditions. Results: All individual macaques showed clinical improvement after hRPE cell implantation compared with the sham surgery. PRP activity was elevated in the untreated MPTP hemispheres relative to those of the normal controls (P

Gene therapy is emerging as a promising approach for treating neurological disorders, including Parkinson's disease (PD). A phase 2 clinical trial showed that delivering glutamic acid decarboxylase (GAD) into the subthalamic nucleus (STN) of patients with PD had therapeutic effects. To determine the mechanism underlying this response, we analyzed metabolic imaging data from patients who received gene therapy and those randomized to sham surgery, all of whom had been scanned preoperatively and at 6 and 12 months after surgery. Those who received GAD gene therapy developed a unique treatment-dependent polysynaptic brain circuit that we termed as the GAD-related pattern (GADRP), which reflected the formation of new polysynaptic functional pathways linking the STN to motor cortical regions. Patients in both the treatment group and the sham group expressed the previously reported placebo network (the sham surgery-related pattern or SSRP) when blinded to the treatment received. However, only the appearance of the GADRP correlated with clinical improvement in the gene therapy-treated subjects. Treatment-induced brain circuits can thus be useful in clinical trials for isolating true treatment responses and providing insight into their underlying biological mechanisms.

The purpose of this study was to evaluate the effects of different image reconstruction algorithms on topographic characteristics and diagnostic performance of the Parkinson's disease related pattern (PDRP).FDG-PET brain scans of 20 Parkinson's disease (PD) patients and 20 normal controls (NC) were reconstructed with six different algorithms in order to derive six versions of PDRP. Additional scans of 20 PD, 25 atypical parkinsonism (AP) patients and 20 NC subjects were used for validation. PDRP versions were compared by assessing differences in topographies, individual subject scores and correlations with patient's clinical ratings. Discrimination of PD from NC and AP subjects was evaluated across cohorts.The region weights of the six PDRPs highly correlated (R ≥ 0.991; p 0.0001). All PDRPs' expressions were significantly elevated in PD relative to NC and AP subjects (p 0.0001) and correlated with clinical ratings (R ≥ 0.47; p 0.05). Subject scores of the six PDRPs highly correlated within each of individual healthy and parkinsonian groups (R ≥ 0.972, p 0.0001) and were consistent across the algorithms when using the same reconstruction methods in PDRP derivation and validation. However, when derivation and validation reconstruction algorithms differed, subject scores were notably lower compared to the reference PDRP, in all subject groups.PDRP proves to be highly reproducible across FDG-PET image reconstruction algorithms in topography, ability to differentiate PD from NC and AP subjects and clinical correlation. When calculating PDRP scores in scans that have different reconstruction algorithms and imaging systems from those used for PDRP derivation, a calibration with NC subjects is advisable.

The delineation of resting state networks (RSNs) in the human brain relies on the analysis of temporal fluctuations in functional MRI signal, representing a small fraction of total neuronal activity. Here, we used metabolic PET, which maps nonfluctuating signals related to total activity, to identify and validate reproducible RSN topographies in healthy and disease populations. In healthy subjects, the dominant (first component) metabolic RSN was topographically similar to the default mode network (DMN). In contrast, in Parkinson's disease (PD), this RSN was subordinated to an independent disease-related pattern. Network functionality was assessed by quantifying metabolic RSN expression in cerebral blood flow PET scans acquired at rest and during task performance. Consistent task-related deactivation of the "DMN-like" dominant metabolic RSN was observed in healthy subjects and early PD patients; in contrast, the subordinate RSNs were activated during task performance. Network deactivation was reduced in advanced PD; this abnormality was partially corrected by dopaminergic therapy. Time-course comparisons of DMN loss in longitudinal resting metabolic scans from PD and Alzheimer's disease subjects illustrated that significant reductions appeared later for PD, in parallel with the development of cognitive dysfunction. In contrast, in Alzheimer's disease significant reductions in network expression were already present at diagnosis, progressing over time. Metabolic imaging can directly provide useful information regarding the resting organization of the brain in health and disease.

In a rodent model of Parkinson’s disease (PD), levodopa-induced involuntary movements have been linked to striatal angiogenesis — a process that is difficult to document in living human subjects. Angiogenesis can be accompanied by localized increases in cerebral blood flow (CBF) responses to hypercapnia. We therefore explored the possibility that, in the absence of levodopa, local hypercapnic CBF responses are abnormally increased in PD patients with levodopa-induced dyskinesias (LID) but not in their nondyskinetic (NLID) counterparts. We used H215O PET to scan 24 unmedicated PD subjects (12 LID and 12 NLID) and 12 matched healthy subjects in the rest state under normocapnic and hypercapnic conditions. Hypercapnic CBF responses were compared to corresponding levodopa responses from the same subjects. Group differences in hypercapnic vasoreactivity were significant only in the posterior putamen, with greater CBF responses in LID subjects compared with the other subjects. Hypercapnic and levodopa-mediated CBF responses measured in this region exhibited distinct associations with disease severity: the former correlated with off-state motor disability ratings but not symptom duration, whereas the latter correlated with symptom duration but not motor disability. These are the first in vivo human findings linking LID to microvascular changes in the basal ganglia.

The aim of the current study was to investigate the molecular mechanisms underlying hepatitis C virus (HCV)-induced hepatocellular carcinoma (HCC) using the expression profiles of HCV-infected Huh7 cells at different time points. The differentially expressed genes (DEGs) were identified with the Samr package in R software once the data were normalized. Functional and pathway enrichment analysis of the identified DEGs was also performed. Subsequently, MCODE in Cytoscape software was applied to conduct module analysis of the constructed co-expression networks. A total of 1,100 DEGs were identified between the HCV-infected and control samples at 12, 18, 24 and 48 h post-infection. DEGs at 24 and 48 h were involved in the same signaling pathways and biological processes, including sterol biosynthetic processes and tRNA amino-acylation. There were 22 time series genes which were clustered into 3 expression patterns, and the demarcation point of the 2 expression patterns that 401 overlapping DEGs at 24 and 48 h clustered into was 24 h post-infection. tRNA synthesis-related biological processes emerged at 24 and 48 h. Replication and assembly of HCV in HCV-infected Huh7 cells occurred mainly at 24 h post-infection. In view of this, the screened time series genes have the potential to become candidate target molecules for monitoring, diagnosing and treating HCV-induced HCC.

Neuroimaging of cerebral glucose metabolism and blood flow is ideally suited to assay widely-distributed brain circuits as a result of local molecular events and behavioral modulation in the central nervous system. With the progress in novel analytical methodology, this endeavor has succeeded in unraveling the mechanisms underlying a wide spectrum of neurodegenerative diseases. In particular, statistical brain mapping studies have made significant strides in describing the pathophysiology of Parkinson’s disease (PD) and related disorders by providing signature biomarkers to determine the systemic abnormalities in brain function and evaluate disease progression, therapeutic responses, and clinical correlates in patients. In this article, we review the relevant clinical applications in patients in relation to healthy volunteers with a focus on the generation of unique spatial covariance patterns associated with the motor and cognitive symptoms underlying PD. These characteristic biomarkers can be potentially used not only to improve patient recruitment but also to predict outcomes in clinical trials.

Patient responses to placebo and sham effects are a major obstacle to the development of therapies for brain disorders, including Parkinson's disease (PD). Here, we used functional brain imaging and network analysis to study the circuitry underlying placebo effects in PD subjects randomized to sham surgery as part of a double-blind gene therapy trial. Metabolic imaging was performed prior to randomization, then again at 6 and 12 months after sham surgery. In this cohort, the sham response was associated with the expression of a distinct cerebello-limbic circuit. The expression of this network increased consistently in patients blinded to treatment and correlated with independent clinical ratings. Once patients were unblinded, network expression declined toward baseline levels. Analogous network alterations were not seen with open-label levodopa treatment or during disease progression. Furthermore, sham outcomes in blinded patients correlated with baseline network expression, suggesting the potential use of this quantitative measure to identify "sham-susceptible" subjects before randomization. Indeed, Monte Carlo simulations revealed that a priori exclusion of such individuals substantially lowers the number of randomized participants needed to demonstrate treatment efficacy. Individualized subject selection based on a predetermined network criterion may therefore limit the need for sham interventions in future clinical trials.

Evidence exists for late-life depression (LLD) as both a prodrome of and risk factor for Alzheimer’s disease (AD). The underlying neurobiological mechanisms are poorly understood. Impaired peripheral glucose metabolism may explain the association between depression and AD given the connection between type 2 diabetes mellitus with both depression and AD. Positron emission tomography (PET) measures of cerebral glucose metabolism are sensitive to detecting changes in neural circuitry in LLD and AD. Fasting serum glucose (FSG) in non-diabetic young (YC; n=20) and elderly controls (EC; n=12) and LLD patients (n=16) was correlated with PET scans of cerebral glucose metabolism on a voxel-wise basis. The negative correlations were more extensive in EC versus YC and in LLD patients versus EC. Increased FSG correlated with decreased cerebral glucose metabolism in LLD patients to a greater extent than in EC in heteromodal association cortices involved in mood symptoms and cognitive deficits observed in LLD and dementia. Negative correlations in YC were observed in sensory and motor regions. Understanding the neurobiological consequences of diabetes and associated conditions will have substantial public health significance given that this is a modifiable risk factor for which prevention strategies could have an important impact on lowering dementia risk.

To determine whether the Parkinson disease-related covariance pattern (PDRP) expression is abnormally increased in idiopathic REM sleep behavior disorder (RBD) and whether increased baseline activity is associated with greater individual risk of subsequent phenoconversion.For this cohort study, we recruited 2 groups of RBD and control subjects. Cohort 1 comprised 10 subjects with RBD (63.5 ± 9.4 years old) and 10 healthy volunteers (62.7 ± 8.6 years old) who underwent resting-state metabolic brain imaging with (18)F-fluorodeoxyglucose PET. Cohort 2 comprised 17 subjects with RBD (68.9 ± 4.8 years old) and 17 healthy volunteers (66.6 ± 6.0 years old) who underwent resting brain perfusion imaging with ethylcysteinate dimer SPECT. The latter group was followed clinically for 4.6 ± 2.5 years by investigators blinded to the imaging results. PDRP expression was measured in both RBD groups and compared with corresponding control values.PDRP expression was elevated in both groups of subjects with RBD (cohort 1: p0.04; cohort 2: p0.005). Of the 17 subjects with long-term follow-up, 8 were diagnosed with Parkinson disease or dementia with Lewy bodies; the others did not phenoconvert. For individual subjects with RBD, final phenoconversion status was predicted using a logistical regression model based on PDRP expression and subject age at the time of imaging (r(2) = 0.64, p0.0001).Latent network abnormalities in subjects with idiopathic RBD are associated with a greater likelihood of subsequent phenoconversion to a progressive neurodegenerative syndrome.

We used a network approach to assess systems-level abnormalities in motor activation in humans with Parkinson's disease (PD). This was done by measuring the expression of the normal movement-related activation pattern (NMRP), a previously validated activation network deployed by healthy subjects during motor performance. In this study, NMRP expression was prospectively quantified in15O-water PET scans from a PD patient cohort comprised of a longitudinal early-stage group (n= 12) scanned at baseline and at two or three follow-up visits two years apart, and a moderately advanced group scanned on and off treatment with either subthalamic nucleus deep brain stimulation (n= 14) or intravenous levodopa infusion (n= 14). For each subject and condition, we measured NMRP expression during both movement and rest. Resting expression of the abnormal PD-related metabolic covariance pattern was likewise determined in the same subjects. NMRP expression was abnormally elevated (p< 0.001) in PD patients scanned in the nonmovement rest state. By contrast, network activity measured during movement did not differ from normal (p= 0.34). In the longitudinal cohort, abnormal increases in resting NMRP expression were evident at the earliest clinical stages (p< 0.05), which progressed significantly over time (p= 0.003). Analogous network changes were present at baseline in the treatment cohort (p= 0.001). These abnormalities improved with subthalamic nucleus stimulation (p< 0.005) but not levodopa (p= 0.25). In both cohorts, the changes in NMRP expression that were observed did not correlate with concurrent PD-related metabolic covariance pattern measurements (p> 0.22). Thus, the resting state in PD is characterized by changes in the activity of normal as well as pathological brain networks.

The therapeutic benefits of bilateral capsulotomy for the treatment of refractory obsessive compulsive disorder (OCD) are probably attributed to interruption of the cortico-striato-thalamo-cortical circuitry. We evaluated resting brain metabolism and treatment response in OCD patients using positron emission tomography (PET) imaging. [18F]-fluoro-deoxy-glucose PET was performed in eight OCD patients precapsulotomy and postcapsulotomy. We determined metabolic differences between preoperative images in patients and those in eight age-matched healthy volunteers, and postoperative changes and clinical correlations in the patients. The OCD patients showed widespread metabolic increases in normalized glucose metabolism in the bilateral orbitofrontal cortex and inferior frontal gyrus, cingulate gyrus, and bilateral pons/cerebellum, and metabolic decreases bilaterally in the precentral and lingual gyri. Bilateral capsulotomy resulted in significant metabolic decreases bilaterally in the prefrontal cortical regions, especially in the dorsal anterior cingulate cortex (ACC) and in the medial dorsal thalamus and caudate nucleus. In contrast, metabolism increased bilaterally in the precentral and lingual gyri. Clinical improvement in patients correlated with metabolic changes in the bilateral dorsal ACC and in the right middle occipital gyrus after capsulotomy. This study underscores the importance of the internal capsule in modulating ventral prefrontal and dorsal anterior cingulate neuronal activity in the neurosurgical management of OCD patients.

Changes in regional brain activity can be observed following global normalization procedures to reduce variability in the data. In particular, spurious regional differences may appear when scans from patients with low global activity are compared to those from healthy subjects. It has thus been suggested that the consistent increases in subcortical activity that characterize the abnormal Parkinson’s disease-related metabolic covariance pattern (PDRP) are artifacts of global normalization, and that similar topographies can be identified in scans from healthy subjects with varying global activity. To address this issue, we examined the effects of experimental reductions in global metabolic activity on PDRP expression. Ten healthy subjects underwent 18F-fluorodeoxyglucose PET in wakefulness and following sleep induction. In all subjects, the global metabolic rate (GMR) declined with sleep (mean −34%, range: −17 to −56%), exceeding the test-retest differences of the measure (p

The ability of cell-penetrating peptides (CPPs) to deliver a range of membrane-impermeable molecules into living cells makes them attractive potential vehicles for therapeutics. However, in vivo, the efficiency of CPP delivery to the cytosol remains unsatisfactory owing to endosomal entrapment and/or systemic toxicity, which severely restrict their bioavailability and efficacy in in vivo applications. In this study, we developed a series of novel chimeras consisting of various numbers of d- and l-arginine residues and investigated their cellular uptake behaviors and systemic toxicities. We demonstrated that the intracellular distribution, uptake efficiency, and systemic toxicity of these oligoarginines were all significantly affected by the number of d-arginine residues in the peptide sequence. We also found that a hybrid peptide, (rR)(3)R(2), possessed low systemic toxicity, high uptake efficiency, and, remarkably, achieved efficient cytosolic delivery not only in cultured cells but also in living tissue cells in mice after intravenous injection, implying that this heterogeneous motif might have promising applications in the delivery of cargoes of small sizes directed to cytosolic targets in vivo. Our studies into the uptake mechanism of (rR)(3)R(2) indicate that its cellular uptake was not affected by pharmacological or physical inhibitors of endocytosis but by the elimination of the membrane potential, suggesting that (rR)(3)R(2) does not enter the cells via endocytosis but rather through direct membrane translocation driven by the membrane potential. The results here might provide useful guidelines for the design and application of CPPs in drug delivery.

Cognitive dysfunction is common in Parkinson disease (PD), even early in its clinical course. This disease manifestation has been associated with impaired verbal learning performance as well as abnormal expression of a specific PD-related cognitive spatial covariance pattern (PDCP). It is not known, however, how this metabolic network relates to the cognitive response to dopaminergic therapy on the individual patient level.We assessed treatment-mediated changes in verbal learning and PDCP expression in 17 patients with PD without dementia who underwent cognitive testing and metabolic imaging in the unmedicated and levodopa-treated conditions. We also determined whether analogous changes were present in 12 other patients with PD without dementia who were evaluated before and during the treatment of cognitive symptoms with placebo.Levodopa-mediated changes in verbal learning correlated with concurrent changes in PDCP expression (r = -0.60, p0.01). The subset of patients with meaningful cognitive improvement on levodopa (n = 8) exhibited concurrent reductions in PDCP expression (p0.01) with treatment; network modulation was not evident in the remaining subjects. Notably, the levodopa cognitive response correlated with baseline PDCP levels (r = 0.70, p = 0.002). By contrast, placebo did not affect PDCP expression, even in the subjects (n = 7) with improved verbal learning during treatment.These findings suggest that cognitive dysfunction in PD may respond to treatment depending upon the degree of baseline PDCP expression. Quantification of treatment-mediated network changes can provide objective information concerning the efficacy of new agents directed at the cognitive manifestations of this disease.

Objectives Given the challenges in the clinical management of geriatric depression, research over the past decade has focused on developing early neurobiological markers of antidepressant treatment response. This study tested the hypothesis that lower baseline glucose metabolism and greater acute cerebral metabolic responses to a single, intravenous (IV) dose of the selective serotonin reuptake inhibitor (SSRI) citalopram would be associated with greater improvement of depressive symptoms after 12 weeks of citalopram treatment in geriatric depression. Methods Sixteen geriatric depressed patients underwent two scans to measure cerebral glucose metabolism after administration of either a saline placebo or citalopram infusion (40 mg, IV). Then, the patients were treated with the oral citalopram medication for 12 weeks. Results Greater improvement of depressive symptoms was associated with lower baseline metabolism in anterior cingulate, superior, middle, and inferior frontal gyri (bilaterally), inferior parietal lobule (bilaterally), precuneus (right), insula (left), parahippocampal gyrus (right), caudate (bilaterally), and putamen (left) regions. Greater improvement of depressive symptoms was associated with greater reductions in metabolism after acute citalopram administration in similar brain regions, including additional posterior cortical regions. Conclusions Lower baseline cerebral metabolism and greater decreases with acute citalopram administration are associated with better antidepressant response to chronic citalopram treatment. These data are consistent with previous studies of total sleep deprivation and suggest that dynamic, early adaptive changes or normalization of cerebral metabolism may represent early neurobiological markers of chronic SSRI treatment response in geriatric depression.

The circuit changes that mediate parkinsonian tremor, while likely differing from those underlying akinesia and rigidity, are not precisely known. In this study, to identify a specific metabolic brain network associated with this disease manifestation, we used FDG PET to scan nine tremor dominant Parkinson's disease (PD) patients at baseline and during ventral intermediate (Vim) thalamic nucleus deep brain stimulation (DBS). Ordinal trends canonical variates analysis (OrT/CVA) was performed on the within-subject scan data to detect a significant spatial covariance pattern with consistent changes in subject expression during stimulation-mediated tremor suppression. The metabolic pattern was characterized by covarying increases in the activity of the cerebellum/dentate nucleus and primary motor cortex, and, to a less degree, the caudate/putamen. Vim stimulation resulted in consistent reductions in pattern expression (p

Parkinson's disease (PD) is associated with elevated expression of a specific disease-related spatial covariance pattern (PDRP) in radiotracer scans of cerebral blood flow and metabolism. In this study, we scanned nine early-stage patients with PD and nine healthy controls using continuous arterial spin labeling (CASL) perfusion magnetic resonance imaging (pMRI). Parkinson's disease-related metabolic pattern expression in CASL pMRI scans was compared with the corresponding 18F-fluorodeoxyglucose positron emission tomography values. The PDRP expression was abnormally elevated ( P

Two multidisciplinary teams of investigators have reported results from double-blind, placebo-controlled trials of human embryonic dopaminergic tissue transplantation for advanced Parkinson’s disease (PD). In the first study, 39 PD patients were randomized to either bilateral tissue implantation in the putamen or sham surgery without immunosuppressive therapy and followed for 1 y with blinded clinical and 18F-fluorodopa (18F-FDOPA) PET evaluations (1). We found that transplantation significantly improved standardized motor ratings, although substantial clinical benefit was limited to younger (age ≤ 60 y) subjects. Nonetheless, putamen uptake of 18F-FDOPA, an index of graft viability, increased significantly in the transplanted cohort, regardless of age (2). In the second double-blind study, 34 PD patients underwent bilateral fetal dopaminergic cell transplantation in the putamen, with 1–4 donors per side, or placebo surgery along with pre- and postoperative immunosuppressive therapy over 6 mo (3). That study showed clinical benefit in less severely affected subjects and significant increases in putamen 18F-FDOPA uptake in all the transplant recipients at the 2-y follow-up. The results of these blinded studies agreed with reports from small open-label cohorts of PD patients showing persisting increases in 18F-FDOPA uptake at the site of implantation (4–6), histopathologic evidence of engraftment (7,8), and associations between 18F-FDOPA PET indices of graft viability and clinical outcome (9,10). To date, reports of the long-term outcome of fetal cell transplantation for advanced PD have been limited to small groups of subjects (4,6). Both double-blind clinical trials also reported the development of graft-induced dyskinesia (GID) in some of the transplant recipients when these recipients were assessed after dopaminergic medications had been stopped (1,3). It remains to be determined whether the clinical response to transplantation is offset by the troubling side effect of GID. In the present study, we report long-term clinical and 18F-FDOPA PET findings from our blinded transplantation trial (1,2). After the 1-y blinded phase of that study, 14 of the 20 placebo-operated patients went on to receive bilateral putamen grafts, resulting in a total of 33 transplanted patients. We assessed postoperative changes in motor ratings and striatal 18F-FDOPA uptake in these subjects at 1 and 2 y after implantation. Of these subjects, 15 were followed for an additional 2 y. In addition to correlating the clinical and PET changes over time, we determined whether these indices were influenced by subject age or sex. We also assessed the impact on the data of the 5 transplant recipients in whom GID developed (11). Last, we correlated clinical outcome with preoperative 18F-FDOPA PET to identify predictive imaging features (12) that might be used for patient selection in future trials of cell-based interventions for PD and related disorders.

In the current paper, we describe methodologies for single subject differential diagnosis of degenerative brain disorders using multivariate principal component analysis (PCA) of functional imaging scans. An automated routine utilizing these methods is applied to positron emission tomography (PET) brain data to distinguish several discrete parkinsonian movement disorders with similar clinical manifestations. Disease specific expressions of voxel-based spatial covariance patterns are predetermined using the Scaled Subprofile Model (SSM/PCA) and a scalar measure of the manifestation of each pattern in prospective subject images is subsequently derived. Scores are automatically compared to reference values generated for each pathological condition in a corresponding set of patient and control scans. Diagnostic outcome is optimized using strategies such as the derivation of patterns in a voxel subspace that reflects contrasting image characteristics between conditions, or by using an independent patient population as controls. The prediction models for two, three and four way classification problems using direct scalar comparison as well as classical discriminant analysis are assessed in a composite training population comprised of three different patient classes and normal controls, and validated in a similar independent test population. Results illustrate that highly accurate diagnosis can often be achieved by simple comparison of scores utilizing optimized patterns.

Pre-clinical and human neuropharmacological evidence suggests a role of cholinergic modulation of monoamines as a pathophysiological and therapeutic mechanism in Alzheimer's disease. The present study measured the effects of treatment with the cholinesterase inhibitor and nicotinic receptor modulator, galantamine, on the cerebral metabolic response to the selective serotonin reuptake inhibitor, citalopram. Seven probable Alzheimer's disease patients and seven demographically comparable controls underwent two positron emission tomography (PET) glucose metabolism scans, after administration of a saline placebo infusion (Day 1) and after citalopram (40 mg, IV, Day 2). The scan protocol was repeated in the Alzheimer's disease patients 2 months after titration to a 24 mg galantamine dose. At baseline, cerebral glucose metabolism was reduced in Alzheimer's disease patients relative to controls in right middle temporal, left posterior cingulate and parietal cortices (precuneus and inferior parietal lobule), as expected. Both groups demonstrated acute decreases in cerebral glucose metabolism after citalopram to a greater extent in the Alzheimer's disease patients. In the patients, relative to the controls, citalopram decreased glucose metabolism to a greater extent in middle frontal gyrus (bilaterally), left middle temporal gyrus and right posterior cingulate prior to treatment. Galantamine treatment alone increased metabolism in the right precuneus, right inferior parietal lobule and right middle occipital gyrus. In contrast, during galantamine treatment, citalopram increased metabolism in the right middle frontal gyrus, right post-central gyrus, right superior and middle temporal gyrus and right cerebellum. The combined cerebral metabolic effects of galantamine and citalopram suggest, consistent with preclinical data, a synergistic interaction of cholinergic and serotonergic systems.

The effect of a pharmacologic increase in serotonin concentrations on striatal dopamine (D2) receptor availability has been measured in several studies using positron emission tomography (PET) and the radiotracer [11C]-raclopride as a method for the in vivo imaging of serotonin modulation of striatal dopamine in human subjects. These studies have shown that an acute increase in serotonin concentrations produced a decrease in striatal D2 receptor availability. The current study was undertaken to measure the effects of a more pharmacologically selective serotonergic agent compared to previous studies, the serotonin reuptake inhibitor, citalopram, on striatal D2 receptor availability. Twelve healthy control subjects underwent two PET scans performed on the same day following i.v. administration of saline (Scan 1) and citalopram (Scan 2, 40 mg, i.v.). The [11C]-raclopride data were analyzed with a graphical analysis method using the cerebellum as the input function. Plasma levels of citalopram, cortisol, and prolactin were measured. The citalopram concentrations peaked at the end of infusion (EOI) and remained relatively consistent from 30 min to 3 h postinfusion. An increase in cortisol and prolactin concentrations was observed from the EOI until 60 min after the EOI. A significant decrease in striatal D2 receptor availability was observed after citalopram infusion (−5%), presumably due to an increase in endogenous dopamine concentrations. In summary, i.v. administration of the selective serotonin reuptake inhibitor, citalopram, produced modest reductions in striatal D2 receptor availability, consistent with other human [11C]-raclopride studies using less pharmacologically selective serotonergic agents.

A randomized, placebo controlled study was performed to evaluate whether the onset of the glucose metabolic effects of a selective serotonin reuptake inhibitor (paroxetine) would be accelerated by total sleep deprivation (TSD). Patients were randomly assigned to one of three groups: TSD and paroxetine treatment, TSD and two weeks of placebo followed by paroxetine treatment, or two weeks of paroxetine treatment. Sixteen elderly depressed patients who met DSM-IV criteria for major depressive disorder and nine age-matched comparison subjects underwent Positron Emission Tomography (PET) studies of cerebral glucose metabolism at baseline, post-TSD (or a normal night’s sleep for the paroxetine only group), post-recovery sleep and two weeks post-paroxetine or placebo treatment (patients only). TSD was not consistently associated with a decrease in depressive symptoms between groups nor with decreases in cerebral metabolism in cortical regions that have been associated with rapid and sustained clinical improvement (e.g. anterior cingulate gyrus). The observation of a synergistic antidepressant effect of combined TSD and paroxetine treatment that was observed in a previous “open label”, pilot study was not observed in the present randomized study, consistent with lack of a cerebral metabolic effect in brains regions previously shown to be associated with improvement of depressive symptoms.

We compared the metabolic and neurovascular effects of levodopa (LD) therapy for Parkinson's disease (PD). Eleven PD patients were scanned with both [15O]-H2O and [18F]-fluorodeoxyglucose positron emission tomography in the unmedicated state and during intravenous LD infusion. Images were used to quantify LD-mediated changes in the expression of motor- and cognition-related PD covariance patterns in scans of cerebral blood flow (CBF) and cerebral metabolic rate for glucose (CMR). These changes in network activity were compared with those occurring during subthalamic nucleus (STN) deep brain stimulation (DBS), and those observed in a test–retest PD control group. Separate voxel-based searches were conducted to identify individual regions with dissociated treatment-mediated changes in local cerebral blood flow and metabolism. We found a significant dissociation between CBF and CMR in the modulation of the PD motor-related network by LD treatment (p< 0.001). This dissociation was characterized by reductions in network activity in the CMR scans (p< 0.003) occurring concurrently with increases in the CBF scans (p< 0.01). Flow–metabolism dissociation was also evident at the regional level, with LD-mediated reductions in CMR and increases in CBF in the putamen/globus pallidus, dorsal midbrain/pons, STN, and ventral thalamus. CBF responses to LD in the putamen and pons were relatively greater in patients exhibiting drug-induced dyskinesia. In contrast, flow–metabolism dissociation was not present in the STN DBS treatment group or in the PD control group. These findings suggest that flow–metabolism dissociation is a distinctive feature of LD treatment. This phenomenon may be especially pronounced in patients with LD-induced dyskinesia.

Parkinson's disease (PD) is associated with abnormal activity in spatially distributed neural systems mediating the motor and cognitive manifestations of this disorder. Metabolic PET studies have demonstrated that this illness is characterized by a set of reproducible functional brain networks that correlate with these clinical features.The time at which these abnormalities appear is unknown, as is their relationship to concurrent clinical and dopaminergic indices of disease progression. In this longitudinal study, 15 early stage PD patients (age 58.0 � 10.2 years; Hoehn and Yahr Stage 1.2 � 0.3) were enrolled within 2 years of diagnosis. The subjects underwent multitracer PET imaging at baseline, 24 and 48 months. At each timepoint they were scanned with ( 18 F)-fluorodeoxyglucose (FDG) to assess longitudinal changes in regional glucose utilization and in the expression of the PD-related motor (PDRP) and cognitive metabolic covariance patterns (PDCP). At each timepoint the subjects also underwent PET imaging with ( 18 F)-fluoropropyl CIT (FP-CIT) to quantify longitudinal changes in caudate and putamen dopamine transpor- ter (DAT) binding. Regional metabolic changes across the three timepoints were localized using statistical para- metric mapping (SPM). Longitudinal changes in regional metabolism and network activity, caudate/putamen DAT binding, and Unified Parkinson's Disease Rating Scale (UPDRS) motor ratings were assessed using repeated measures analysis of variance (RMANOVA). Relationships between these measures of disease progression were assessed by computing within-subject correlation coefficients. We found that disease progression was associated with increasing metabolism in the subthalamic nucleus (STN) and internal globus pallidus (GPi) (P50.001), as well as in the dorsal pons and primary motor cortex (P50.0001). Advancing disease was also associated with declining metabolism in the prefrontal and inferior parietal regions (P50.001). PDRP expression was elevated at baseline relative to healthy control subjects (P50.04), and increased progressively over time (P50.0001). PDCP activity also increased with time (P50.0001). However, these changes in network activity were slower than for the PDRP (P50.04), reaching abnormal levels only at the final timepoint. Changes in PDRP activity, but not PDCP activity, correlated with concurrent declines in striatal DAT binding (P50.01) and increases in motor ratings (P50.005). Significant within-subject correlations (P50.01) were also evident between the latter two progression indices. The early stages of PD are associated with progressive increases and decreases in regional metabolism at key nodes of the motor and cognitive networks that characterize the illness. Potential disease-modifying therapies may alter the time course of one or both of these abnormal networks.

The neural basis for the transition from preclinical to symptomatic Huntington's disease (HD) is unknown. We used serial positron emission tomography (PET) imaging in preclinical HD gene carriers (p-HD) to assess the metabolic changes that occur during this period. Twelve p-HD subjects were followed longitudinally with [11C]-raclopride and [18F]-fluorodeoxyglucose PET imaging, with scans at baseline, 18 and 44 months. Progressive declines in striatal D2-receptor binding were correlated with concurrent changes in regional metabolism and in the activity of an HD-related metabolic network. We found that striatal D2 binding declined over time (P < 0.005). The activity of a reproducible HD-related metabolic covariance pattern increased between baseline and 18 months (P < 0.003) but declined at 44 months (P < 0.04). These network changes coincided with progressive declines in striatal and thalamic metabolic activity (P < 0.01). Striatal metabolism was abnormally low at all time points (P < 0.005). By contrast, thalamic metabolism was elevated at baseline (P < 0.01), but fell to subnormal levels in the p-HD subjects who developed symptoms. These findings were confirmed with an MRI-based atrophy correction for each individual PET scan. Increases in network expression and thalamic glucose metabolism may be compensatory for early neuronal losses in p-HD. Declines in these measures may herald the onset of symptoms in gene carriers.

Brain imaging of cerebral blood flow and glucose metabolism has been playing key roles in describing pathophysiology of Parkinson’s disease (PD) and Huntington’s disease (HD), respectively. Many biomarkers have been developed in recent years to investigate the abnormality in molecular substrate, track the time course of disease progression, and evaluate the efficacy of novel experimental therapeutics. A growing body of literature has emerged on neurobiology of these two movement disorders in resting states and in response to brain activation tasks. In this paper, we review the latest applications of these approaches in patients and normal volunteers at rest conditions. The discussions focus on brain mapping studies with univariate and multivariate statistical analyses on a voxel basis. In particular, we present data to validate the reproducibility and reliability of unique spatial covariance patterns related with PD and HD.

Spatial covariance mapping can be used to identify and measure the activity of disease-related functional brain networks. While this approach has been widely used in the analysis of cerebral blood flow and metabolic PET scans, it is not clear whether it can be reliably applied to resting state functional MRI (rs-fMRI) data. In this study, we present a novel method based on independent component analysis (ICA) to characterize specific network topographies associated with Parkinson's disease (PD). Using rs-fMRI data from PD and healthy subjects, we used ICA with bootstrap resampling to identify a PD-related pattern that reliably discriminated the two groups. This topography, termed rs-MRI PD-related pattern (fPDRP), was similar to previously characterized disease-related patterns identified using metabolic PET imaging. Following pattern identification, we validated the fPDRP by computing its expression in rs-fMRI testing data on a prospective case basis. Indeed, significant increases in fPDRP expression were found in separate sets of PD and control subjects. In addition to providing a similar degree of group separation as PET, fPDRP values correlated with motor disability and declined toward normal with levodopa administration. Finally, we used this approach in conjunction with neuropsychological performance measures to identify a separate PD cognition-related pattern in the patients. This pattern, termed rs-fMRI PD cognition-related pattern (fPDCP), was topographically similar to its PET-derived counterpart. Subject scores for the fPDCP correlated with executive function in both training and testing data. These findings suggest that ICA can be used in conjunction with bootstrap resampling to identify and validate stable disease-related network topographies in rs-fMRI. Hum Brain Mapp 38:617-630, 2017. © 2016 Wiley Periodicals, Inc.

The purpose of our study was to test the hypothesis that sorafenib-related dermatologic adverse events (AEs) as an early biomarker can predict the long-term outcomes following the combination therapy of transarterial chemoembolization (TACE) plus sorafenib (TACE-S). The intermediate-stage hepatocellular carcinoma patients who received either TACE-S or TACE-alone treatment were consecutively included into analysis. In the TACE-S group, patients with ≥ grade 2 dermatologic AEs within the first month of sorafenib initiation were defined as responders; whereas those with grade 2 were defined as nonresponders. In the TACE-S group, the median overall survival (OS) of the responders was significantly longer than that of nonresponders (28.9 months vs. 16.8 months, respectively; p = 0.004). Multivariate analysis demonstrated that nonresponders were significantly associated with an increased risk of death compared with responders (HR = 1.9; 95% confidence Interval-CI: 1.3-2.7; p = 0.001). The survival analysis showed that the median OS was 27.9 months (95% CI: 25.0-30.8) among responders treated with TACE-S vs.18.3 months (95% CI: 14.5-22.1) among those who received TACE-alone (p = 0.046). The median time to progression was 13.1 months (95% CI: 4.4-21.8) in the TACE-S group, a duration that was significantly longer than that in the TACE-alone group [5 months (95% CI: 6.4-13.3), p = 0.014]. This study demonstrated that sorafenib-related dermatologic AEs are clinical biomarkers to identify responders from all of the patients for TACE-S therapy. Sorafenib-related dermatologic AEs, clinical biomarkers, can predict the efficacy of TACE-S in future randomized controlled trials.

It has been proposed that deep brain stimulation (DBS) of the subthalamic nucleus (STN DBS) and dopaminergic therapy ameliorate the symptoms of Parkinson's disease through similar functional mechanisms. We examined this notion using PET to compare the metabolic effects of these treatment approaches. Nine Parkinson's disease patients (age 61.7 ± 11.1 years) were scanned ON and OFF STN stimulation and nine others (age 60.0 ± 9.3 years) were scanned ON and OFF an individual titrated intravenous levodopa infusion. The two treatment groups were matched for baseline disease severity as well as clinical response to therapy. Similarities and differences in the effects of treatment on regional metabolism were assessed using statistical parametric mapping (SPM). In addition, we used network analysis to assess the effect of therapy on the expression of an abnormal Parkinson's disease-related spatial covariance pattern (PDRP). We found that both STN DBS and levodopa therapy were associated with significant (P < 0.001) metabolic reductions in the putamen/globus pallidus, sensorimotor cortex and cerebellar vermis, as well as increases in the precuneus (BA 7). The metabolic effects of the two interventions differed in the STN and medial prefrontal cortex, with relative increases with stimulation in the former structure and decreases in the latter. Network quantification disclosed reductions in PDRP activity with both interventions, which correlated with clinical improvement (P < 0.05). The degree of network modulation by therapy did not differ significantly for the two treatment approaches (P > 0.6). These findings support the results of previous imaging studies indicating that effective symptomatic therapies for Parkinson's disease involve a common mechanism. The modulation of pathological brain networks is a critical feature of the treatment response in parkinsonism.

Deep brain stimulation of the subthalamic nucleus (STN DBS) has become an accepted tool for the treatment of Parkinson's disease (PD). Although the precise mechanism of action of this intervention is unknown, its effectiveness has been attributed to the modulation of pathological network activity. We examined this notion using positron emission tomography (PET) to quantify stimulation-induced changes in the expression of a PD-related covariance pattern (PDRP) of regional metabolism. These metabolic changes were also compared with those observed in a similar cohort of patients undergoing STN lesioning. We found that PDRP activity declined significantly (P < 0.02) with STN stimulation. The degree of network modulation with DBS did not differ from that measured following lesioning (P = 0.58). Statistical parametric mapping (SPM) revealed that metabolic reductions in the internal globus pallidus (GPi) and caudal midbrain were common to both STN interventions (P < 0.01), although declines in GPi were more pronounced with lesion. By contrast, elevations in posterior parietal metabolism were common to the two procedures, albeit more pronounced with stimulation. These findings indicate that suppression of abnormal network activity is a feature of both STN stimulation and lesioning. Nonetheless, these two interventions may differ metabolically at a regional level.

A clinical triad of movement, behavioral, and cognitive disorders characterizes Huntington's disease (HD).1–3 However, the neurodegenerative changes of HD precede the onset of clinical signs and may be associated with subclinical alterations in brain physiology. For example, careful neuropsychological testing can detect abnormalities in presymptomatic carriers of the HD gene mutation (p-HD).4–7 In this study, we applied functional imaging methods with atrophy correction to elucidate the mechanisms that may underlie preclinical cognitive changes in HD gene carriers. In earlier imaging studies conducted in the resting state, we used a network approach to demonstrate that HD is associated with an abnormal spatial covariance pattern in both presymptomatic and symptomatic phases of disease.8,9 This reproducible regional topography is characterized by caudate/putamen and temporal hypometabolism associated with occipital hypermetabolism. Other investigators have found widespread cortical involvement in the early stages of symptomatic HD, in addition to the well-known subcortical features of the disease.10–12 Given metabolic abnormalities in brain regions subserving both motor and cognitive functions, we now sought to determine whether p-HD subjects acquire sequential information abnormally. We also sought to understand whether p-HD subjects use the same brain regions as control subjects while performing motor learning tasks, and if not, how the early preclinical pathology of HD alters the neural circuitry of learning-related pathways.

In this study, we tested the hypotheses that (1) the acquisition of sequential information is related to the integrity of dopaminergic input to the caudate nucleus; and (2) the integrity of dopaminergic input to the caudate nucleus correlates significantly with brain activation during sequence acquisition. Twelve early stage Parkinson's disease (PD) patients and six age-matched healthy volunteers were scanned using a dual tracer PET imaging design. All subjects were scanned with [(18)F]fluoropropyl-betaCIT (FPCIT) to measure striatal dopamine transporter (DAT) binding and with [(15)O]water to assess activation during a sequence learning task where movements were made to a repeating sequence of eight targets. Caudate and putamen DAT binding in the PD cohort was reduced by 15% and 43%, respectively. In PD, caudate DAT binding correlated with target acquisition (R = 0.57, P < 0.05), while putamen DAT binding did not correlate with performance. In volunteers, caudate DAT binding correlated with learning-related activation (P < 0.05, corrected for multiple comparisons) in the left dorsolateral and ventral prefrontal cortices, the anterior cingulate and premotor regions, and the right cerebellum. A significant correlation with caudate DAT binding was additionally detected in the right anteromedial thalamus, extending into the rostral midbrain. By contrast, in the PD cohort, most of these regional relationships were lost: Only ventral and dorsolateral prefrontal cortex activation correlated with caudate dopaminergic tone. Our findings suggest that sequence learning is normally associated with tight coupling between dopaminergic input to the caudate and thalamo-cortical functional activity. Despite minimal reductions in nigro-caudate input, PD patients demonstrate a loss of this coupling early in the disease.

We used 15O-labeled water (H215O) positron emission tomography (PET) to study eight Parkinson's disease (PD) patients with unilateral ventral intermediate (Vim) thalamic nucleus deep brain stimulation (DBS) for severe tremor. Triaxial accelerometry (TRIAX) was used during imaging to obtain on-line measures of tremor characteristics. Regional cerebral blood flow (rCBF) scans together with TRIAX recordings were collected in three stimulation conditions (OFF, MID, and ON, corresponding, respectively, to 0%, 50%, and 100% reductions in mean accelerometry signal). Statistical Parametric Mapping (SPM99) revealed significant rCBF reductions during stimulation in the ipsilateral sensorimotor cortex (SMC) and the contralateral cerebellum, as well as concurrent increases in the ipsilateral ventral thalamus (P < 0.05, corrected). Covariate analysis of rCBF with physiological tremor characteristics revealed that tremor acceleration correlated positively with changes in the SMC and supplementary motor cortex ipsilaterally (P < 0.05, uncorrected), and negatively with changes in the ipsilateral cuneus (P < 0.05, corrected). After removing tremor acceleration effects, changes in tremor frequency correlated negatively with changes in the contralateral dentate nucleus and pons (P < 0.05, uncorrected). Our results suggest that Vim DBS for PD tremor modulates the activity of cerebello-thalamo-cortical pathways. Specific tremor characteristics relate to activity in different nodes of this system.