Neuroprotection of Exendin-4 by Enhanced Autophagy in a Parkinsonian Rat Model of α-Synucleinopathy.

Glucagon-like peptide-1 (GLP-1) receptor stimulation ameliorates parkinsonian motor and non-motor deficits in both experimental animals and patients; however, the disease-modifying mechanisms of GLP-1 receptor activation have remained unknown. The present study investigated whether exendin-4 (a GLP-1 analogue) can rescue motor deficits and exert disease-modifying effects in a parkinsonian rat model of α-synucleinopathy. This model was established by unilaterally injecting AAV-9-A53T-α-synuclein into the right substantia nigra pars compacta, followed by 4 or 8 weeks of twice-daily intraperitoneal injections of exendin-4 (5 µg/kg/day) starting at 2 weeks after AAV-9-A53T-α-synuclein injections. Positron emission tomography/computed tomography (PET/CT) scanning and immunostaining established that treatment with exendin-4 attenuated tyrosine-hydroxylase-positive neuronal loss and terminal denervation and mitigated the decrease in expression of vesicular monoamine transporter 2 within the nigrostriatal dopaminergic systems of rats injected with AAV-9-A53T-α-synuclein. It also mitigated the parkinsonian motor deficits assessed in behavioral tests. Furthermore, through both in vivo and in vitro models of Parkinson's disease, we showed that exendin-4 promoted autophagy and mediated degradation of pathological α-synuclein, the effects of which were counteracted by 3-methyladenine or chloroquine, the autophagic inhibitors. Additionally, exendin-4 attenuated dysregulation of the PI3K/Akt/mTOR pathway in rats injected with AAV-9-A53T-α-synuclein. Taken together, our results demonstrate that exendin-4 treatment relieved behavioral deficits, dopaminergic degeneration, and pathological α-synuclein aggregation in a parkinsonian rat model of α-synucleinopathy and that these effects were mediated by enhanced autophagy via inhibiting the PI3K/Akt/mTOR pathway. In light of the safety and tolerance of exendin-4 administration, our results suggest that exendin-4 may represent a promising disease-modifying treatment for Parkinson's disease.

Associations of Alzheimer's disease risk variants with gene expression, amyloidosis, tauopathy, and neurodegeneration.

BACKGROUND: Genome-wide association studies have identified more than 30 Alzheimer's disease (AD) risk genes, although the detailed mechanism through which all these genes are associated with AD pathogenesis remains unknown. We comprehensively evaluate the roles of the variants in top 30 non-APOE AD risk genes, based on whether these variants were associated with altered mRNA transcript levels, as well as brain amyloidosis, tauopathy, and neurodegeneration. METHODS: Human brain gene expression data were obtained from the UK Brain Expression Consortium (UKBEC), while other data used in our study were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We examined the association of AD risk allele carrier status with the levels of gene expression in blood and brain regions and tested the association with brain amyloidosis, tauopathy, and neurodegeneration at baseline, using a multivariable linear regression model. Next, we analyzed the longitudinal effects of these variants on the change rates of pathology using a mixed effect model. RESULTS: Altogether, 27 variants were detected to be associated with the altered expression of 21 nearby genes in blood and brain regions. Eleven variants (especially novel variants in ADAM10, IGHV1-68, and SLC24A4/RIN3) were associated with brain amyloidosis, 7 variants (especially in INPP5D, PTK2B) with brain tauopathy, and 8 variants (especially in ECHDC3, HS3ST1) with brain neurodegeneration. Variants in ADAMTS1, BZRAP1-AS1, CELF1, CD2AP, and SLC24A4/RIN3 participated in more than one cerebral pathological process. CONCLUSIONS: Genetic variants might play functional roles and suggest potential mechanisms in AD pathogenesis, which opens doors to uncover novel targets for AD treatment.

Forniceal deep brain stimulation in severe Alzheimer's disease: A case report.

BACKGROUND: Forniceal deep brain stimulation (DBS) has been proposed as an alternative treatment for Alzheimer's disease (AD). Previous studies on mild to moderate AD patients demonstrated improvements in cognitive functions brought about by forniceal DBS. Here, we report our longitudinal findings in one severe AD patient for whom the activities of daily living (ADL) rather than cognitive function significantly improved after 3 mo of continuous stimulation. CASE SUMMARY: In 2011, a 62-year-old Chinese male with no previous history of brain injury or other neuropsychological diseases and no family history of dementia developed early symptoms of memory decline and cognitive impairment. Five years later, the symptoms had increased to the extent that they affected his daily living. He lost the ability to work as a businessman and to take care of himself. The patient was given a clinical diagnosis of probable AD and was prescribed donepezil and subsequently memantine, but no improvement in symptoms was observed. The patient then received DBS surgery. After 3 mo of continuous stimulation, the patient's ADL score decreased from 65 points to 47 points, indicating the quality of the patient's daily living improved distinctly. Other scores remained unchanged, suggesting no significant improvement in cognitive function. A follow-up positron emission tomography scan demonstrated perceivable increased glucose metabolism in the classical AD-related brain regions. CONCLUSION: Based on this case we hypothesize that forniceal DBS may improve ADL through elevating regional glucose metabolism in the brain.

Fasudil Promotes α-Synuclein Clearance in an AAV-Mediated α-Synuclein Rat Model of Parkinson's Disease by Autophagy Activation.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder, but the disease-modifying therapies focusing on the core pathological changes are still unavailable. Rho-associated protein kinase (ROCK) has been suggested as a promising target for developing neuroprotective therapies in PD. OBJECTIVE: We aimed to explore the promotion of α-synuclein (α-syn) clearance in a rat model. METHODS: In a rat model induced by unilateral injection of adeno-associated virus of serotype 9 (AAV9) expressing A53T α-syn (AAV9-A53T-α-syn) into the right substantia nigra, we aimed to investigate whether Fasudil could promote α-syn clearance and thereby attenuate motor impairments and dopaminergic deficits. RESULTS: In our study, treatment with Fasudil (5 mg/kg rat weight/day) for 8 weeks significantly improved the motor deficits in the Cylinder and Rotarod tests. In the in vivo positron emission tomography imaging with the ligand 18F-dihydrotetrabenazine, Fasudil significantly enhanced the dopaminergic imaging in the injected striatum of the rat model (p < 0.05 vs. vehicle group, p < 0.01 vs. left striatum in Fasudil group). The following mechanistic study confirmed that Fasudil could promote the autophagic clearance of α-syn by Becline 1 and Akt/mTOR pathways. CONCLUSION: Our study suggested that Fasudil, the ROCK2 inhibitor, could attenuate the anatomical and behavioral lesions in the Parkinsonian rat model by autophagy activation. Our results identify Fasudil as a drug with high translational potential as disease-modifying treatment for PD and other synucleinopathies.

Longitudinal trajectories of Alzheimer's ATN biomarkers in elderly persons without dementia.

BACKGROUND: Models of Alzheimer's disease (AD) pathophysiology posit that amyloidosis [A] precedes and accelerates tau pathology [T] that leads to neurodegeneration [N]. Besides this A-T-N sequence, other biomarker sequences are possible. This current work investigates and compares the longitudinal trajectories of Alzheimer's ATN biomarker profiles in non-demented elderly adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. METHODS: Based on the ATN classification system, 262 individuals were identified before dementia diagnosis and accompanied by baseline and follow-up data of ATN biomarkers (CSF Aß42, p-tau, and FDG-PET). We recorded the conversion processes in ATN biomarkers during follow-up, then analyzed the possible longitudinal trajectories and estimated the conversion rate and temporal evolution of biomarker changes. To evaluate how biomarkers changed over time, we used linear mixed-effects models. RESULTS: During a 6-120-month follow-up period, there were four patterns of longitudinal changes in Alzheimer's ATN biomarker profiles, from all negative to positive through the course of the disease. The most common pattern is that A pathology biomarker first emerges. As well as the classical A-T-N sequence, other "A-first," "T-first," and "N-first" biomarker pathways were found. The N-A-T sequence had the fastest rate of pathological progression (mean 65.00 months), followed by A-T-N (mean 67.07 months), T-A-N (mean 68.85 months), and A-N-T sequences (mean 98.14 months). CONCLUSIONS: Our current work presents a comprehensive analysis of longitudinal trajectories of Alzheimer's ATN biomarkers in non-demented elderly adults. Stratifying disease into subtypes depending on the temporal evolution of biomarkers will benefit the early recognition and treatment.

AFP-producing hepatoid adenocarcinoma of appendix: a case report of 18F-FDG PET/CT.

Hepatoid adenocarcinoma (HAC) is a rare tumor. We described here a rare case of appendix HAC. A 59-year-old man underwent F-18-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for gradually elevated alpha-Fetoprotein level. Multiple masses in the abdominal cavity with moderate FDG uptake were revealed, suggesting malignant tumor with peritoneal metastasis. The patient underwent radical resection, and the postoperative pathological result was HAC originated from the appendix. To our knowledge, it is the first report of HAC of the appendix. Our study suggests that FDG PET/CT may help in detecting the primary tumor and the metastases of HAC.

Metabolic imaging of deep brain stimulation in anorexia nervosa: a 18F-FDG PET/CT study.

OBJECTIVES: Anorexia nervosa (AN), a disorder of unknown etiology, has the highest mortality rate of any psychiatric disorder. Drawing the brain metabolic pattern of AN may help to target the core biological and psychological features of the disorder and to perfect the diagnosis and recovery criteria. In this study, we used 18F-FDG PET to show brain metabolic network for AN. METHODS: Glucose metabolism in 6 AN patients and 12 age-matched healthy controls was studied using 18F-FDG PET. SPM2 was used to compare brain metabolism in AN patients with that in healthy controls. Four of 6 AN patients took deep brain stimulation (DBS) targeted in nucleus accumbens (NAcc). About 3 to 6 months after the surgery, the 4 AN patients took another 18F-FDG PET scan to assess the change in brain glucose metabolism. RESULTS: The SPM (statistical parametric mapping ) analysis showed hypermetabolism in the frontal lobe (bilateral, BA10, BA11, BA47), the limbic lobe (bilateral, hippocampus, and amygdala), lentiform nucleus (bilateral), left insula (BA13), and left subcallosal gyrus (BA25). It also showed hypometabolism in the parietal lobe (bilateral, BA7, BA40). The hypermetabolism in frontal lobe, hippocampus, and lentiform nucleus decreased after NAcc-DBS. CONCLUSIONS: The changes in brain glucose metabolism illustrated the brain metabolic pattern in AN patients. Furthermore, the pattern can be modulated by NAcc-DBS, which confirmed specificity of the pattern. The regions with altered metabolism could interconnect to form a network and integrate information related to appetite. Our study may provide information for targeting the potential candidate brain regions for understanding the pathophysiology of AN and assessing the effects of existing and future treatment approaches.

[Influence of visual and auditory masking on the brain glucose metabolism in an idiopathic tinnitus patient].

OBJECTIVE: To study the influence of the audio-visual block (AB) on the brain glucose metabolism of idiopathic tinnitus patients. METHODS: The brain positron emission tomography (PET) test was performed on one chronic idiopathic tinnitus patient under audio-visual block and non-block (NB) conditions respectively. The visual analysis and statistical parameter mapping (SPM) analysis were both used to detect the brain glucose metabolism difference under AB and NB conditions. RESULTS: Under NB conditions, significant hyperactivity was detected at auditory and visual cortex on both sides of the brain. However, this phenomenon was not shown under AB conditions. Instead, a hyperactivity of brain was presented in the left Wernicke's area. CONCLUSIONS: The generation of chronic idiopathic tinnitus probably has no relationship with the auditory cortex abnormity. Wernicke's area might be involved in the central perception of tinnitus.

Efficacy of conventional whole-body ¹8F-FDG PET/CT in the incidental findings of parotid masses.

OBJECTIVE: The objective of this study was to evaluate the incidence of incidental parotid masses with conventional whole-body ¹8F-deoxyglucose (FDG) PET/CT and assess the ability of PET/CT to characterize these unexpected parotid lesions. METHODS: Fifty eight incidental findings of parotid masses with routine FDG PET/CT whole-body scan were reviewed in this retrospective analysis, which were selected from the patients without any known or suspected parotid disease in our PET center, from June 2005 to May 2009. 51 cases were operated or underwent a biopsy after a short-term PET/CT study; the remaining 7 cases had a follow-up. Parotid mass that showed both noncontrast CT (irregular shape and blurry border) and PET malignant features (high FDG uptake, SUV(max) > 3.0) was considered as positive for malignancy. Correlation of FDG PET/CT with histology or follow-up outcome was performed. RESULTS: Fifty eight unexpected findings of parotid masses accounted for 0.3% of the total cases in 4 years, including 11 (19.0%) malignant tumors and 47 (81.0%) benign lesions. 13 lesions manifested single nodule with malignant CT features and intense FDG activity, of which 6 were proved to be malignant; thus, sensitivity and positive predictive values were 54.5% (6 of 11) and 46.2% (6 of 13), respectively. 45 lesions showed either single nodule with benign CT features, or a low FDG uptake (SUV(max) ≤ 3.0), of which 40 were true negatives; therefore, specificity and negative predictive values were 85.1% (40 of 47) and 88.9% (40 of 45), respectively. All parotid masses except 9 benign and 1 malignant showed a high FDG uptake. Compared with SUV only, combined interpretation of PET and CT results displayed a lower sensitivity (90.9-54.5%), but a higher specificity (19.1-85.1%) and a higher overall accuracy. CONCLUSIONS: Whole-body FDG-PET/CT at the time of surveying the entire body condition is helpful for detecting the asymptomatic parotid masses. Combined noncontrast CT is an essential evidence for improving the diagnostic accuracy of FDG-PET/CT for parotid masses.

Accuracy of 18F-FDG PET/CT for lymph node staging in non-small-cell lung cancers.

BACKGROUND: This retrospective study evaluated the diagnostic accuracy of 2-(F18)-fluoro-2-deoxy-D-glucose-positron emission tomography ((18)F-FDG-PET)/computed tomography (PET/CT) in the preoperative diagnosis of metastatic mediastinal and hilar lymph node in patients with non-small-cell lung cancer (NSCLC). METHODS: A total of 39 patients received preoperative (18)F-FDG PET/CT and the postoperative biopsy. We compared preoperative PET/CT scan results with corresponding intraoperative histopathalogic findings in 39 NSCLC patients. The sensitivity, specificity, accuracy, positive and negative predictive value of (18)F-FDG PET/CT were assessed. RESULTS: Histopathologic examination confirmed metastasis in 57 out of the 208 excised lymph nodes; 23 of the 57 nodes were mediastinal and hilar lymph nodes. The sensitivity, specificity, accuracy, positive predictive value and negative predictive value of PET/CT in the preoperative diagnosis of mediastinal lymph node metastasis in NSCLC patients were 65%, 96.8%, 92%, 78.5% and 90%, respectively. CONCLUSIONS: PET/CT scan showed good accuracy in the preoperative diagnosis of mediastinal and hilar lymph node metastasis in the patients with NSCLC. We recommend that PET/CT scanning be used as a first-line evaluation tool for tumor diagnosis, therapy evaluation and follow-up.

Prognostic value of 2-[18F]fluoro-2-deoxy-D-glucose uptake as measured by PET scan in patients with non-small cell lung cancer.

This study aimed to evaluate the prognostic value of 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) uptake determined by positron emission tomography (PET) in patients with non-small cell lung cancer (NSCLC) in relation to disease stage and/or tumor histology. A retrospective review of 144 patients with newly diagnosed lung cancer undergoing PET imaging was performed. Differences in survival were compared by univariate and multivariate analyses. Univariate analysis identified three prognostic factors: stage, lesion size and the standardized 18F-FDG uptake value. The latter was a better prognostic predictor in lung cancer patients with early-stage disease than in those at advanced stages. Multivariate analysis revealed that the most important prognostic factors were tumor-node-metastasis (TNM) stage and the standardized 18F-FDG uptake value. Patients with standardized uptake values (SUVs) >8 had a 2.5 times higher mortality rate than those with values ≤8. A one-unit increase in SUV corresponded with a 7% increase in the hazard of death. SUVs provided stronger prognostic stratification in patients with adenocarcinoma than in those with squamous cell carcinoma (SCC). Furthermore, the best choice of prognostic predictor differed between the two types of lung cancer: the SUV was best for SCC, while TNM stage was most significant for adenocarcinoma. In conclusion, 18F-FDG uptake in primary lung lesions is an independent prognostic predictor in patients with NSCLC, especially those with adenocarcinoma or early-stage disease. Further stratification of patients with the same TNM stage based on SUVs may allow for the modification of individual treatment strategies, resulting in improved outcome.

[Malignant tumor with false negative 18F-FDG PET image].

OBJECTIVE: To investigate the FDG uptake characteristics, the factors affecting 18F-FDG uptake and the extra CT diagnostic value of 18F-FDG PET/CT scan in the malignant tumor with false negative 18F-FDG PET image. METHODS: The data of PET/CT image in 17 patients with various kinds of cancers were reviewed and analyzed by visual observation and semi-quantity analysis ( SUV). The results were compared with the CT and histopathological diagnosis, respectively. RESULTS: Of 6 well-differentiated HCC patients confirmed by histopathological diagnosis, one had two lesions in the right lobe of the liver. One of these two lesions showed low FDG uptake on 18F-FDG PET scan and low density on CT scan. The other one was not shown on either 18F-FDG PET or plain CT scan. But on enhanced CT scan, these two lesions were found to be inhomogeneous with high density at arterial phase. The false negative 18F-FDG PET images of one gastric signet ring cell carcinoma in the gastric fundus with right adnexa metastasis, 3 renal cell carcinoma, one greater omentum and peritoneal metastatic adenocarcinoma and one well-differentiated prostate cancer were caused by normal physical uptake in the digestive tract or FDG retention in the urinary system due to normal excretion. The size of three metastases was smaller than or equal to 1 cm in diameter, however, two primary lesions of these metastases showed high FDG uptake and only one was negative on either 18F-FDG PET or CT scan. In this series, 68.8% of the primary tumors and 66.7% of metastases were found to show abnormal density on CT scan, and 31. 2% of the primary tumors and 33. 3% of metastases were not detectable on either PET or CT images. CONCLUSION: False negative 18F-FDG PET in malignant tumor may be correlated with the pathologic type, differentiation degree and the lesion size. Combining CT information with PET or paying attention to the scan methods during 8 F-FDG PET examination may reduce the rate of false negative 18F-FDG PET diagnosis in various kinds of malignant tumors.

[Application of 18F-FDG PET/CT scan in following-up of nasopharyngeal carcinoma after radiotherapy].

BACKGROUND & OBJECTIVE: Local relapse,tumor residue, and whole body metastases of nasopharyngeal carcinoma (NPC) after radiotherapy were mainly confirmed by CT, MRI, SPE/CT, and PET examinations. This study was to discuss the value of F-18-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (PET/CT) in detecting suspected recurrence or tumor residue, and whole body metastases of NPC after radiotherapy. METHODS: PET/CT were performed on 38 NPC patients 3-36 months after radiotherapy. The images of PET/CT, CT, and PET were observed. PET standardized uptake value (SUV) was calculated, and SUV of > 2.5 was considered as positive. The Patients were divided into 4 groups by diagnosis: (1) no recurrence/residue, and no whole body metastases; (2) with recurrence/residue, but no whole body metastases; (3) no recurrence/residue, but with whole body metastases; (4) with both recurrence/residue and whole body metastases. Diagnoses of all patients were referred to the proved follow-up clinical information. The following-up time was 6-10 months. RESULTS: The sensitivity, and specificity of PET/CT (100%,and 89.5%) were better than that of CT alone (77.8%, and 84.2%), a litter better than that of PET alone (100%, and 80.0%). CONCLUSIONS: FDG-PET scan is a better tool than CT alone for the detection of recurrene or residue, and whole body metastases of NPC, a litter better than PET alone. PET/CT may provide valuable information for judging whether the focus is metastasis.