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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.

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.

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

Background We have previously defined a parkinsonism-related metabolic brain network in rhesus macaques using a high-resolution research positron emission tomography camera. This brief article reports a descriptive pilot study to assess the reproducibility of network activity and regional glucose metabolism in independent parkinsonian macaques using a clinical positron emission tomography/CT camera. Methods [18F]fluorodeoxyglucose PET scans were acquired longitudinally over 3 months in three drug-naive parkinsonian and three healthy control cynomolgus macaques. Group difference and test–retest stability in network activity and regional glucose metabolism were evaluated graphically, using all brain images from these macaques. Results Comparing the parkinsonian macaques with the controls, network activity was elevated and remained stable over 3 months. Normalized glucose metabolism increased in putamen/globus pallidus and sensorimotor regions but decreased in posterior parietal cortices. Conclusions Parkinsonism-related network activity can be reliably quantified in different macaques with a clinical positron emission tomography/CT scanner and is reproducible over a period typically employed in preclinical intervention studies. This measure can be a useful biomarker of disease process or drug effects in primate models of Parkinson's disease. ©2015 International Parkinson and Movement Disorder Society

Parkinson's disease (PD) is associated with distinct metabolic covariance patterns that relate to the motor and cognitive manifestations of the disorder. It is not known, however, how the expression of these patterns relates to measurements of nigrostriatal dopaminergic activity from the same individuals. To explore these associations, we studied 106 PD subjects who underwent cerebral PET with both 18F-fluorodeoxyglucose (FDG) and 18F-fluoro-L-dopa (FDOPA). Expression values for the PD motor- and cognition-related metabolic patterns (PDRP and PDCP, respectively) were computed for each subject; these measures were correlated with FDOPA uptake on a voxel-by-voxel basis. To explore the relationship between dopaminergic function and local metabolic activity, caudate and putamen FDOPA PET signal was correlated voxel-wise with FDG uptake over the entire brain. PDRP expression correlated with FDOPA uptake in caudate and putamen (P

To generate imaging biomarkers from disease-specific brain networks, we have implemented a general toolbox to rapidly perform scaled subprofile modeling (SSM) based on principal component analysis (PCA) on brain images of patients and normals. This SSMPCA toolbox can define spatial covariance patterns whose expression in individual subjects can discriminate patients from controls or predict behavioral measures. The technique may depend on differences in spatial normalization algorithms and brain imaging systems. We have evaluated the reproducibility of characteristic metabolic patterns generated by SSMPCA in patients with Parkinson's disease (PD). We used [(18) F]fluorodeoxyglucose PET scans from patients with PD and normal controls. Motor-related (PDRP) and cognition-related (PDCP) metabolic patterns were derived from images spatially normalized using four versions of SPM software (spm99, spm2, spm5, and spm8). Differences between these patterns and subject scores were compared across multiple independent groups of patients and control subjects. These patterns and subject scores were highly reproducible with different normalization programs in terms of disease discrimination and cognitive correlation. Subject scores were also comparable in patients with PD imaged across multiple PET scanners. Our findings confirm a very high degree of consistency among brain networks and their clinical correlates in PD using images normalized in four different SPM platforms. SSMPCA toolbox can be used reliably for generating disease-specific imaging biomarkers despite the continued evolution of image preprocessing software in the neuroimaging community. Network expressions can be quantified in individual patients independent of different physical characteristics of PET cameras.

Objective Late-life depression (LLD) has a substantial public health impact and is both a risk factor for and a prodrome of dementia. Positron emission tomography (PET) studies of cerebral glucose metabolism have demonstrated sensitivity in evaluating neural circuitry involved in depression, aging, incipient cognitive decline, and dementia. The present study evaluated the long term effects of a course of antidepressant treatment on glucose metabolism in LLD patients. Methods Nine LLD patients and seven non-depressed control subjects underwent clinical and cognitive evaluations as well as brain magnetic resonance imaging and PET studies of cerebral glucose metabolism at baseline, after 8 weeks of treatment with citalopram for a major depressive episode (patients only), and at an approximately 2-year follow-up. Results The majority of LLD patients were remitted at follow-up (7/9). Neither patients nor controls showed significant cognitive decline. The patients showed greater increases in glucose metabolism than the controls in regions associated with mood symptoms (anterior cingulate and insula). Both groups showed decreases in metabolism in posterior association cortices implicated in dementia. Conclusions Longitudinal changes in cerebral glucose metabolism are observed in controls and in LLD patients without significant cognitive decline that are more extensive than the decreases in brain volume. Longer duration follow-up studies and the integration of other molecular imaging methods will have implications for understanding the clinical and neurobiological significance of these metabolic changes. Copyright © 2012 John Wiley & Sons, Ltd.

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 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.

The DYT1 dystonia mutation is associated with an abnormal metabolic brain network characterized by hypermetabolism of the basal ganglia, supplementary motor area, and the cerebellum. In this study, we quantified the activity of this network in carriers of other dystonia mutations to determine whether this functional abnormality is linked to genotype. The findings suggest that the DYT1 metabolic topography is not genotype specific and may be present in carriers of other dystonia mutations.

Persistent dyskinesias in the absence of or with only minimal amounts of dopaminergic medication have been reported after dopamine cell implantation for Parkinson's disease. In this study, we used [ 18 F]fluorodopa (FDOPA) and positron emission tomography to determine whether this complication resulted from specific alterations in dopamine function after transplantation. Caudate and putamen FDOPA uptake values in these patients (DYS+, n = 5) were compared with those obtained in a cohort of age- and disease duration-matched transplant recipients who did not develop this complication (DYS-, n = 12). PET signal for both groups was compared at baseline and at 12 and 24 months after transplantation. We found that putamen FDOPA uptake was significantly increased (p < 0.005) in DYS+ transplant recipients. These increases were predominantly localized to two zones within the left putamen. In addition to the posterodorsal zone in which a prominent reduction in FDOPA uptake was present at baseline, the DYS+ group also displayed a relative increase ventrally, in which preoperative dopaminergic input was relatively preserved. Postoperative FDOPA uptake did not reach supranormal values over the 24-month follow-up period. These findings suggest that unbalanced increases in dopaminergic function can complicate the outcome of neuronal transplantation for parkinsonism.

We used 15 O-labeled water and positron emission tomography to assess the effect of deep brain stimulation of the internal globus pallidus on motor sequence learning in Parkinson's disease. Seven right-handed patients were scanned on and off stimulation while they were performing a motor sequence learning task and a kinematically matched motor execution reference task. The scans were performed after a 12-hour medication washout. Stimulation parameters were adjusted for maximal motor improvement; experimental task parameters were held constant across stimulation conditions. Internal globus pallidus stimulation improved motor ratings by 37% (p < 0.01). During the sequence learning task, stimulation improved performance as measured by several correct anticipatory movements (p < 0.01) and by verbal report (p < 0.001). Concurrent positron emission tomography imaging during learning demonstrated significant (p < 0.01) increases in brain activation with stimulation in the left dorsolateral prefrontal cortex, bilaterally in premotor cortex, and in posterior parietal and occipital association areas. Stimulation did not affect the activity of these regions during the performance of the motor execution reference task. These findings suggest that internal globus pallidus deep brain stimulation can enhance the activity of prefrontal cortico-striato-pallidothalamic loops and related transcortical pathways. Improved sequence learning with stimulation may be directly related to these functional changes.

To develop a method to measure the dynamic response of the serotonin system in vivo, the effects of intravenously administered citalopram (the most selective of the serotonin reuptake inhibitors) on cerebral glucose metabolism were evaluated. Cerebral glucose metabolism was measured with positron emission tomography (PET) in 14 normal subjects scanned after administration of saline placebo and citalopram administered on 2 separate days. Citalopram administration resulted in a decrease in metabolism in the right anterior cingulate gyrus (BA 24/32), right superior (BA 9) and right middle frontal gyrus (BA 6), right parietal cortex (precuneus), right superior occipital gyrus, left thalamus, and right cerebellum. Increased metabolism was observed in the left superior temporal gyrus and left occipital cortex. Alterations in metabolism by acute citalopram administration involved the heteromodal association cortices that also show metabolic alterations in patients with geriatric depression and overlap with the regions affected by antidepressant treatment. Future studies will evaluate how the acute metabolic response to citalopram relates to the metabolic response after chronic treatment in patients with geriatric depression.

SummaryBackground Transarterial embolisation (TAE) is a standard treatment for bleeding hepatocellular adenoma (HCA) and, occasionally, symptomatic HCA involving large tumours. Whether TAE is similarly safe and effective as an elective treatment for bleeding and nonbleeding HCA remains unclear. Aim To investigate the benefits and harms of TAE for bleeding and nonbleeding HCA. Methods PubMed, Scopus, Embase and Cochrane Library databases were systematically searched for studies that examined post-TAE tumour reduction in patients with bleeding or nonbleeding HCA and that were published between January 2000 and January 2017. Results Systematic review of 21 case series involving 1468 patients with HCA in the systematic review identified 140 (9.5%) patients with 189 lesions who received TAE. Of these 140 patients, 66.4% had bleeding HCA and 33.6% had nonbleeding HCA. Intended elective TAE was performed in 27.1% of patients (38.6% of HCA lesions). Adenomatosis was observed in 6.1% of patients, and the rate of β-catenin expression was 4.5%. No malignant transformation was observed among the 189 tumours during a median follow-up time of 40 months. The complete response rate among 70 patients was 10.6%, and the partial response rate was 71.7%. No mortality or severe adverse side effects were reported during the hospitalisation period. Conclusions The available evidence suggests that TAE can be considered safe for elective managment of HCA as well as for management of bleeding HCA. Elective TAE can be regarded as a reasonable alternative to surgery. High-quality prospective studies with long-term follow-up are needed to corroborate and strengthen available evidence.

We studied 6 advanced-stage Parkinson's disease patients with [18F] fluorodeoxyglucose/positron emission tomography before and 3 months after unilateral ablation of the subthalamic nucleus performed with microelectrode mapping. Operative changes in glucose metabolism were assessed by comparing baseline and postoperative scans. We also quantified operative changes in the activity of an abnormal Parkinson's disease-related metabolic network that we had identified in previous [18F] fluorodeoxyglucose/positron emission tomography studies. Following unilateral subthalamic nucleus ablation, a highly significant reduction in glucose utilization was present in the midbrain ipsilateral to the lesion site, most pronounced in the vicinity of the substantia nigra pars reticularis. Significant metabolic reductions were also present in the ipsilateral internal globus pallidus, ventral thalamus, and pons. Operative changes in Parkinson's disease network activity differed significantly for the lesioned and unlesioned hemispheres. In the lesioned hemisphere, network activity declined significantly following surgery, but was unaltered in the contralateral, unlesioned hemisphere. These results suggest that subthalamotomy reduces basal ganglia output through internal globus pallidus/substantia nigra pars reticularis and also influences downstream neural activity in the pons and ventral thalamus. This procedure also reduces the activity of abnormal Parkinson's disease-related metabolic brain networks, suggesting a widespread modulation of motor circuitry.