Kai-Yuan Tzen

Gene therapy for aromatic L-amino acid decarboxylase deficiency.

Gene therapy can restore some motor function in patients with aromatic l-amino acid decarboxylase deficiency. Gene Therapy for AADC Deficiency Patients with aromatic l-amino acid decarboxylase (AADC) deficiency cannot produce the neurotransmitter dopamine from its precursor l-DOPA in the brain. Dopamine is a crucial molecule required for normal motor function. There are few treatment options for AADC deficiency, and most patients afflicted with this rare disease die in childhood. In a phase 1 clinical trial, Hwu and colleagues use an adeno-associated virus (AAV) type 2 vector to deliver the AADC gene into a brain area called the putamen in four children with AADC deficiency. Although at first the patients exhibited dyskinesias (abnormal muscle movements), these resolved after a few months and the patients showed improved motor function. One patient after 16 months was able to stand, and the other three patients were able to sit upright with support. Several other symptoms improved as well including mood and oculogyric crises. There were a number of translational challenges for this gene therapy clinical trial. For example, the authors had to work out how to deliver the viral vector carrying the therapeutic gene directly into the putamen, and even then only a small part of the putamen became transduced with the AADC gene. Also, because the patients’ brains had not been able to make dopamine, it was not clear how the neurons would respond once dopamine started to be produced. Despite these challenges, this first-in-human gene therapy clinical trial suggests that targeting localized areas in the brain with a therapeutic gene delivered by an AAV vector could help ameliorate the symptoms of AADC deficiency and may also be useful for treating other diseases caused by lack of a crucial enzyme in brain tissue. Aromatic l-amino acid decarboxylase (AADC) is required for the synthesis of the neurotransmitters dopamine and serotonin. Children with defects in the AADC gene show compromised development, particularly in motor function. Drug therapy has only marginal effects on some of the symptoms and does not change early childhood mortality. Here, we performed adeno-associated viral vector–mediated gene transfer of the human AADC gene bilaterally into the putamen of four patients 4 to 6 years of age. All of the patients showed improvements in motor performance: One patient was able to stand 16 months after gene transfer, and the other three patients achieved supported sitting 6 to 15 months after gene transfer. Choreic dyskinesia was observed in all patients, but this resolved after several months. Positron emission tomography revealed increased uptake by the putamen of 6-[18F]fluorodopa, a tracer for AADC. Cerebrospinal fluid analysis showed increased dopamine and serotonin levels after gene transfer. Thus, gene therapy targeting primary AADC deficiency is well tolerated and leads to improved motor function.

131I-6β-Iodomethyl-19-Norcholesterol SPECT/CT for Primary Aldosteronism Patients with Inconclusive Adrenal Venous Sampling and CT Results

The 2 main causes of primary aldosteronism (PA) are aldosterone-producing adenoma (APA) and idiopathic adrenal hyperplasia (IAH). Dexamethasone-suppression 131I-6β-iodomethyl-19-norcholesterol (NP-59) adrenal scintigraphy can assess the functioning of the adrenal cortex. This study evaluated the diagnostic usefulness of NP-59 SPECT/CT in differentiating APA from IAH and in predicting postadrenalectomy clinical outcome for PA patients who had inconclusive adrenal venous sampling (AVS) and CT results. Methods: We retrospectively reviewed the 31 adrenal lesions of 27 patients (age range, 33–71 y; mean age ± SD, 50.4 ± 10.9 y) who had been clinically confirmed (by saline infusion and captopril tests) to have PA, had inconclusive CT and AVS test results, and had undergone NP-59 imaging before adrenalectomy. The accuracy of NP-59 imaging was determined by comparison with histopathologic findings. Results: NP-59 SPECT/CT gave us 18 true-positive, 3 false-positive, 6 true-negative, and 4 false-negative results. Compared with planar imaging, SPECT/CT significantly improved diagnostic accuracy and prognostic predicting ability (P = 0.0390 and P = 0.0141, respectively). The NP-59 results were negative for 7 of the 23 patients with unilateral adrenal lesions, and none of these 7 patients had shown postsurgical clinical improvement. Conclusion: NP-59 SPECT/CT is an effective imaging tool for differentiating APA from IAH in PA patients whose CT and AVS results are inconclusive. Our results suggest that patients with presurgically negative NP-59 results should be treated medically and that noninvasive NP-59 SPECT/CT may be suited for use as the first lateralization modality after CT in patients with clinically confirmed PA.

Cellular localization of the organic cation transporters, OCT1 and OCT2, in brain microvessel endothelial cells and its implication for MPTP transport across the blood-brain barrier and MPTP-induced dopaminergic toxicity in rodents

J. Neurochem. (2010) 114, 717–727.

Dopamine transporter change in drug-naı̈ve schizophrenia: an imaging study with 99mTc-TRODAT-1

The aim of this study was to use a specific dopamine transporter (DAT) ligand, 99mTc-TRODAT-1 with single photon emission computed tomography (SPECT) to investigate the densities of DAT in the striatal dopaminergic system in patients with schizophrenia. Striatal DAT uptakes were measured in 12 drug-nai;ve schizophrenic patients and 12 age- and sex-matched healthy volunteers. The psychometric tools included the Standardized Clinical Assessment for Neuropsychiatry (SCAN) and the Positive and Negative Syndrome Scale (PANSS). Semiquantitative analyses using the ratio of uptake in caudate, putamen, and striatum to occipital lobe, and left-right asymmetry were performed. Decreased TRODAT uptake in the right striatum and increased uptake in the left striatum were found in the schizophrenics. However, there is no overall difference in the average striatum uptake. The right-left asymmetry of the caudate and putamen DAT binding seen in the healthy control group disappeared in the schizophrenia group. The decreased right uptake and increased left uptake in the striatum might lead to the lack of right-left asymmetry in neuroleptic-nai;ve schizophrenia patients, confirming that the disorder could be due to a disruption in brain lateralization. This is the first report on the use TRODAT to evaluate the DAT density in schizophrenia patients and shows lack of asymmetry in striatal uptake of TRODAT in schizophrenics. The findings also suggest that TRODAT SPECT may be a useful technique to measure dopamine transmission in the human brain and for understanding the pathophysiology of neuropsychiatric disorders.

Use of radioactive iodine for thyroid remnant ablation in well-differentiated thyroid carcinoma to replace thyroid reoperation.

Complete thyroidectomy was recommended for patients with well-differentiated thyroid carcinoma to remove any potential residual contralateral cancer tissue and to facilitate detection of metastatic lesions by radioactive iodide (131I). Unfortunately, 8-32% incidence of severe complications were noted after reoperation. At present, there are still not enough data about the ablative effect of 131I for such conservative surgical treatment of well-differentiated thyroid cancers. The major goal of the present study was to examine the effects of 311I for ablation of thyroid remnants in order to obviate the severe complications associated with reoperation. From January 1977 to December 1995, 210 papillary or follicular thyroid carcinoma patients received subtotal thyroidectomy or lobectomy. After the operation, 46 of the 210 patients received 131I for remnant ablation. At doses of > or = 30 mCi 131I, 38 thyroid remnants were successfully ablated; 25 of 38 (65.8%) patients successfully ablated patients received 30 mCi 131I one-four times. Five patients expired during the follow-up period, including two follicular carcinoma patients who were misinterpreted as having benign lesions in the first operation. Patients in the overall failure versus success group for thyroid remnant ablation revealed increased age, histopathology of follicular carcinoma, higher postoperative 131I uptake in the neck bed, higher postoperative thyroglobulin levels, bigger tumor size, and higher mortality. In conclusion, repeated 30 mCi 131I treatments were adequate for most thyroid remnant ablations following subtotal thyroidectomy or lobectomy in well-differentiated thyroid cancer patients. Misinterpretation of follicular cancer as benign lesions and unresectable tumor comprised the main reasons for mortality.

Plasma tau as a window to the brain—negative associations with brain volume and memory function in mild cognitive impairment and early alzheimer's disease

Neurofibrillary tangles are associated with cognitive dysfunction, and hippocampal atrophy with increased CSF tau markers. However, the plasma tau levels of Alzheimers disease (AD) have not been well studied. We investigated plasma tau by using an immunomagnetic reduction assay in 20 patients with mild cognitive impairment (MCI) due to AD, 10 early AD dementia, and 30 healthy elders (HE). All received a 3D‐brain MRI scan and a set of cognitive function test. We explored their relationships with both brain structure and cognitive functions. Images were analyzed to determine the brain volumes and gray matter densities. Patients with MCI or early AD had significantly increased plasma tau levels compared with HE. Plasma tau levels were negatively associated with the performance of logical memory, visual reproduction, and verbal fluency; also negatively associated with volume of total gray matter, hippocampus, amygdala; and gray matter densities of various regions. Regression analyses indicated that logical memory explained 0.394 and hippocampus volume predicted .608 of the variance of plasma tau levels, both P < 0.001. Education years were negatively associated with the gray matter densities of the supramarginal (r = −0.407), middle temporal gyrus (r = −0.40) and precuneus (r = −0.377; all P < 0.05) in HE; and negatively associated with plasma tau levels in patients (r = −0.626). We propose that plasma tau may serve as a window to both structure and function of the brain. Higher education is a protective factor against AD and is associated with lower plasma tau levels in patients. Hum Brain Mapp 35:3132–3142, 2014.

LRRK2 mutation in familial Parkinson’s disease in a Taiwanese population: clinical, PET, and functional studies

Pathogenic mutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal-dominant familial Parkinsons disease (PD). We performed clinical, imaging, and molecular functional studies in one family with the R1441H and six families with the G2385R variants of Lrrk2. To determine the contribution of these variants to familial PD in Taiwanese, we screened 32 Taiwanese or ethnic Chinese patients with familial PD for four pathogenic substitutions (R1441H, I2012T, I2020T, and G2019S) and one susceptibility polymorphism (G2385R). The frequencies of R1441H and G2385R were 3.7% and 22.2%, respectively. G2019S, I2012T, and I2020T were not detected. The clinical phenotypes and [(18)F]-dopa PET findings for subjects with R1441H or G2385R resembled those of patients with idiopathic PD; however, their lymphoblastoid cell lines showed increased apoptosis following exposure to a proteosome inhibitor. Thus, LRRK2 mutations are rare in Taiwanese with familial PD. Further study is needed to identify causative genes or unique biomarkers for familial PD.

PET Assessment of Myocardial Perfusion Reserve Inversely Correlates with Intravascular Ultrasound Findings in Angiographically Normal Cardiac Transplant Recipients

Cardiac allograft vasculopathy (CAV) is the major determinant of long-term survival after heart transplantation. We aimed to evaluate the efficacy of PET as a noninvasive way to assess the early stages of CAV. Methods: Twenty-seven consecutive patients (20 men and 7 women; mean age ± SD, 46 ± 12 y) who had normal results on coronary angiography and normal left ventricular systolic function (ejection fraction ≥ 60%) were enrolled at 2.5 ± 2.1 y after transplantation. Myocardial blood flow (MBF) was assessed using dynamic 13N-ammonia PET at rest and during adenosine-induced hyperemia, and myocardial perfusion reserve (MPR) was calculated as the ratio of hyperemic MBF to resting MBF. Regional 13N-ammonia PET was assessed using a 5-point scoring system. The intravascular ultrasound (IVUS) measurements for the extent of intimal hyperplasia, including plaque volume index (calculated as [total plaque volume/total vessel volume] × 100%) and maximum area of stenosis, were compared with MPR by linear regression analysis. Results: In 27 angiographically normal cardiac transplant recipients, MBF at rest and during adenosine stress and MPR of the left anterior descending artery distribution correlated strongly with the other 2 coronary artery distribution territories (r ≥ 0.97, P < 0.0001). Summed stress score and summed difference score showed a moderate inverse correlation with MPR (r = −0.41 and −0.49, respectively; P < 0.05) but not with IVUS measurements. MPR correlated inversely with plaque volume index (r = −0.40, P < 0.05) but not with maximal luminal stenosis as assessed by IVUS. In addition, MPR and IVUS measurements gradually inversely changed after heart transplantation (all P < 0.05). Conclusion: This study confirms that CAV is a progressive process, diffusely involving the epicardial and microvascular coronary system. Plaque burden as determined by IVUS agrees well with MPR as assessed by PET in recipients with normal coronary angiography results. This finding suggests that dynamic 13N-ammonia PET is clinically feasible for the early detection of CAV and can be used as a reliable marker of disease progression.

Early restaging whole-body 18 F-FDG PET during induction chemotherapy predicts clinical outcome in patients with locoregionally advanced nasopharyngeal carcinoma

PurposeThis study was undertaken to evaluate the utility of whole-body 18F-FDG PET in monitoring therapeutic effect during induction chemotherapy (IC) and in predicting prognosis in patients with locoregionally advanced nasopharyngeal carcinoma (NPC).MethodsFifty patients who had histologically proven, locoregionally advanced NPC without distant metastasis and had received IC were recruited in this study. The study cohort consisted of 19 females and 31 males (age 17–72 years, mean 45.9±11.9). Whole-body 18F-FDG PET was performed in each patient after completion of one (33 patients) or two (17 patients) courses of IC. Each patient was restaged on the basis of the 18F-FDG PET results. Patients who were downstaged to stage I or II were classified as major responders; the rest were classified as non-major responders.ResultsOnly 1 of the 23 major responders subsequently developed local recurrence. At the time of data analysis, all major responders were alive; by contrast, of the 27 non-major responders, 15 had locoregional recurrence or distant metastasis and nine had died (seven of NPC and two of treatment-related complications). Kaplan-Meier survival analysis showed significantly longer recurrence-free survival and overall survival in major responders (56.4±9.2 and 58.1±2.2 months) as compared with non-major responders (33.7±23.2 and 44.7±20.0 months), with p<0.0001 and p=0.0024, respectively.ConclusionThe results of this study suggest that early restaging by a single whole-body 18F-FDG PET scan after the first or second course of IC is useful for predicting therapeutic response and outcome in patients with locoregionally advanced NPC.

Biodistribution study of [123I] ADAM in mice: correlation with whole body autoradiography

Iodine-123 labeled 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine ([(123)I] ADAM) has been suggested as a promising serotonin transporter (SERT) imaging agent. Much research has been accomplished, mainly focusing on the SERT binding sites in the central nervous system (CNS). However, the biodistribution of [(123)I] ADAM using whole body autoradiography (WBAR) has never been previously described, to the best of our knowledge. In this study, we assayed the biodistribution of [(123)I] ADAM in tissues/organs removed from mice, and measured their radioactivity with a scintillation counter (SC). The results showed that the liver has the highest uptake. On the other hand, the WBAR clearly demonstrated that [(123)I] ADAM was bound to SERT-rich sites including those in the brain stem, lung, adrenal glands and intestinal mucosa. This radiotracer also accumulated in the liver, kidney, and thyroid. The results from both methods were compared; each has its own complementary role in the biodistribution studies. The SC method revealed the total amount of radiotracer accumulation in each organ, and the WBAR demonstrated more anatomical details of the radiotracers distribution. The whole body distribution results of the radioligand using both methods explore the usage of this novel radioligand for most possible SERT binding sites, not only in the CNS but also in the peripheral nervous system and neuroendocrine tissues. These findings suggest that [(123)I] ADAM is a potentially useful imaging agent for SERT.