Default-mode network functional connectivity is closely related to metabolic activity.

Over the last decade, the brain's default-mode network (DMN) and its function has attracted a lot of attention in the field of neuroscience. However, the exact underlying mechanisms of DMN functional connectivity, or more specifically, the blood-oxygen level-dependent (BOLD) signal, are still incompletely understood. In the present study, we combined 2-deoxy-2-[(18) F]fluoroglucose positron emission tomography (FDG-PET), proton magnetic resonance spectroscopy ((1) H-MRS), and resting-state functional magnetic resonance imaging (rs-fMRI) to investigate more directly the association between local glucose consumption, local glutamatergic neurotransmission and DMN functional connectivity during rest. The results of the correlation analyzes using the dorsal posterior cingulate cortex (dPCC) as seed region showed spatial similarities between fluctuations in FDG-uptake and fluctuations in BOLD signal. More specifically, in both modalities the same DMN areas in the inferior parietal lobe, angular gyrus, precuneus, middle, and medial frontal gyrus were positively correlated with the dPCC. Furthermore, we could demonstrate that local glucose consumption in the medial frontal gyrus, PCC and left angular gyrus was associated with functional connectivity within the DMN. We did not, however, find a relationship between glutamatergic neurotransmission and functional connectivity. In line with very recent findings, our results lend further support for a close association between local metabolic activity and functional connectivity and provide further insights towards a better understanding of the underlying mechanism of the BOLD signal.

Severe nigrostriatal degeneration without clinical parkinsonism in patients with polymerase gamma mutations.

The role of mitochondria in the pathogenesis of neurodegeneration is an area of intense study. It is known that defects in proteins involved in mitochondrial quality control can cause Parkinson's disease, and there is increasing evidence linking mitochondrial dysfunction, and particularly mitochondrial DNA abnormalities, to neuronal loss in the substantia nigra. Mutations in the catalytic subunit of polymerase gamma are among the most common causes of mitochondrial disease and owing to its role in mitochondrial DNA homeostasis, polymerase gamma defects are often considered a paradigm for mitochondrial diseases generally. Yet, despite this, parkinsonism is uncommon with polymerase gamma defects. In this study, we investigated structural and functional changes in the substantia nigra of 11 patients with polymerase gamma encephalopathy. We characterized the mitochondrial DNA abnormalities and examined the respiratory chain in neurons of the substantia nigra. We also investigated nigrostriatal integrity and function using a combination of post-mortem and in vivo functional studies with dopamine transporter imaging and positron emission tomography. At the cellular level, dopaminergic nigral neurons of patients with polymerase gamma encephalopathy contained a significantly lower copy number of mitochondrial DNA (depletion) and higher levels of deletions than normal control subjects. A selective and progressive complex I deficiency was seen and this was associated with a severe and progressive loss of the dopaminergic neurons of the pars compacta. Dopamine transporter imaging and positron emission tomography showed that the degree of nigral neuronal loss and nigrostriatal depletion were severe and appeared greater even than that seen in idiopathic Parkinson's disease. Despite this, however, none of our patients showed any signs of parkinsonism. The additional presence of both thalamic and cerebellar dysfunction in our patients suggested that these may play a role in counteracting the effects of basal ganglia dysfunction and prevent the development of clinical parkinsonism.

High cardiac background activity limits 99mTc-MIBI radioguided surgery in aortopulmonary window parathyroid adenomas.

BACKGROUND: Radioguided surgery using 99m-Technetium-methoxyisobutylisonitrile (99mTc-MIBI) has been recommended for the surgical treatment of mediastinal parathyroid adenomas. However, high myocardial 99mTc-MIBI uptake may limit the feasibility of radioguided surgery in aortopulmonary window parathyroid adenoma. CASE PRESENTATION: Two female patients aged 72 (#1) and 79 years (#2) with primary hyperparathyroidism caused by parathyroid adenomas in the aortopulmonary window were operated by transsternal radioguided surgery. After intravenous injection of 370 MBq 99mTc-MIBI at start of surgery, the maximum radioactive intensity (as counts per second) was measured over several body regions using a gamma probe before and after removal of the parathyroid adenoma. Relative radioactivity was calculated in relation to the measured ex vivo radioactivity of the adenoma, which was set to 1.0. Both patients were cured by uneventful removal of aortopulmonary window parathyroid adenomas of 4400 (#1) and 985 mg (#2). Biochemical cure was documented by intraoperative measurement of parathyroid hormone as well as follow-up examination. Ex vivo radioactivity over the parathyroid adenomas was 196 (#1) and 855 counts per second (#2). Before parathyroidectomy, relative radioactivity over the aortopulmonary window versus the heart was found at 1.3 versus 2.6 (#1) and 1.8 versus 4.8 (#2). After removal of the adenomas, radioactivity within the aortopulmonary window was only slightly reduced. CONCLUSION: High myocardial uptake of 99mTc-MIBI limits the feasibility of radioguided surgery in aortopulmonary parathyroid adenoma.

Progressive striatal necrosis associated with anti-NMDA receptor antibodies.

BACKGROUND: We report a case of childhood onset, generalized dystonia due to slowly progressive bilateral striatal necrosis associated with anti-N-methyl-D-aspartate receptor (NMDAR) antibodies. This clinical phenotype has not been previously associated with NMDA receptor autoimmunity. CASE PRESENTATION: An eighteen year old man presented with a history of childhood-onset, progressive generalized dystonia. Clinical examination revealed a pure generalized dystonia with no cognitive or other neurological findings. Magnetic resonance imaging showed bilateral high T2 signal striatal lesions, which were slowly progressive over a period of nine years. New parts of the lesion showed restricted water diffusion suggesting cytotoxic oedema. Positron emission tomography of the brain showed frontal hypermetabolism and cerebellar hypometabolism. Antibodies against the NR1 subunit of the NMDA receptor were detected in the patient's serum and cerebrospinal fluid. There was no neoplasia or preceding infection or vaccination. CONCLUSION: This is the first report of chronic progressive bilateral striatal necrosis associated with anti-NMDAR antibodies. Our findings expand the clinical spectrum of disease associated with anti-NMDAR antibodies and suggest that these should be included in the work-up of dystonia with striatal necrosis.

Is there a role for PET-CT and SPECT-CT in pediatric oncology?

During the last decade, hybrid imaging has revolutionized nuclear medicine. Multimodal camera systems, integrating positron emission tomography (PET) or single photon emission computed tomography (SPECT) with computed tomography (CT) now combine the contrast provided by tumor-avid radioactive drugs with the anatomic precision of CT. While PET-CT to a great extent has replaced single-modality PET in adult oncology, the use of PET-CT in children has been controversial, since even the lowest dose CT protocols adds approximately 2 mSv to the radiation dose of about 4 mSv from the PET-study with F-18-fluorodeoxyglucose (F-18-FDG). The article describes the current techniques used, discusses radiation doses and gives an overview of current indications for PET-CT and SPECT-CT in children. Hybrid imaging with a tumor-avid radioactive drug provides extremely high contrast between tumor and background tissues, while the CT component helps to locate the lesion anatomically. Currently both PET-CT and SPECT-CT play a role in pediatric oncology; PET-CT using F-18-FDG particularly for staging and follow-up of lymphoma and brain cancer, bone and soft tissue sarcomas; SPECT-CT with I-123-metaiodobenzylguanidine (MIBG) for tumors of the sympathetic nervous system such as neuroblastoma and pheochromocytoma while the remaining neuroendocrine tumors are imaged with radioactively labeled somatostatin analogues. To reduce radiation dose, a low-dose CT in combination with ultrasound and/or magnetic resonance imaging for the assessment of anatomy is often preferred.

The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson's disease.

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.

Evaluation of a new e-learning framework for teaching nuclear medicine and radiology to undergraduate medical students.

BACKGROUND: Radiology and nuclear medicine have traditionally been taught in a series of lectures and seminars concluded by an examination testing knowledge rather than skills. PURPOSE: To emphasize skills in the students' learning process, we developed and evaluated a new e-learning framework for teaching medical imaging. MATERIAL AND METHODS: The framework consists of electronic lectures, a learning management system (LMS), and a diagnostic viewing system. Students were to review positron emission tomography/computed tomography (PET/CT) examinations of five cases of lung cancer. The framework was evaluated in an objective structured clinical examination (OSCE) taken by 139 undergraduate students at the end of their third year, and in a comparative survey of two groups of 85 and 84 students in the fifth and sixth year who were taught the same oncology course with and without mandatory PET/CT exercises, respectively. RESULTS: Of the 139 third-year students, 134 (96%) passed the OSCE PET/CT station according to the predefined criteria. While 85/85 (100%) of the fifth-year students had taken exercises when they were mandatory, only 2/84 (2%) of the sixth-year students had reviewed the cases on a voluntary basis (P < 0.001). Of the 25 survey responders in the fifth year, 24 (96%) agreed that the mandatory PET/CT exercises had promoted their learning while the sixth-year students, whose course concluded with a multiple-choice examination, emphasized the utility of online lectures. CONCLUSION: The new e-learning framework teaches students basic competency in PET/CT navigation and interpretation and is associated with a high degree of student satisfaction.

Quantitative and clinical impact of MRI-based attenuation correction methods in [18F]FDG evaluation of dementia.

BACKGROUND: Positron emission tomography/magnetic resonance imaging (PET/MRI) is a promising diagnostic imaging tool for the diagnosis of dementia, as PET can add complementary information to the routine imaging examination with MRI. The purpose of this study was to evaluate the influence of MRI-based attenuation correction (MRAC) on diagnostic assessment of dementia with [18F]FDG PET. Quantitative differences in both [18F]FDG uptake and z-scores were calculated for three clinically available (DixonNoBone, DixonBone, UTE) and two research MRAC methods (UCL, DeepUTE) compared to CT-based AC (CTAC). Furthermore, diagnoses based on visual evaluations were made by three nuclear medicine physicians and one neuroradiologist (PETCT, PETDeepUTE, PETDixonBone, PETUTE, PETCT + MRI, PETDixonBone + MRI). In addition, pons and cerebellum were compared as reference regions for normalization. RESULTS: The mean absolute difference in z-scores were smallest between MRAC and CTAC with cerebellum as reference region: 0.15 ± 0.11 σ (DeepUTE), 0.15 ± 0.12 σ (UCL), 0.23 ± 0.20 σ (DixonBone), 0.32 ± 0.28 σ (DixonNoBone), and 0.54 ± 0.40 σ (UTE). In the visual evaluation, the diagnoses agreed with PETCT in 74% (PETDeepUTE), 67% (PETDixonBone), and 70% (PETUTE) of the patients, while PETCT + MRI agreed with PETDixonBone + MRI in 89% of the patients. CONCLUSION: The MRAC research methods performed close to that of CTAC in the quantitative evaluation of [18F]FDG uptake and z-scores. Among the clinically implemented MRAC methods, DixonBone should be preferred for diagnostic assessment of dementia with [18F]FDG PET/MRI. However, as artifacts occur in DixonBone attenuation maps, they must be visually inspected to assure proper quantification.

Mitochondrial DNA homeostasis is essential for nigrostriatal integrity.

Mitochondrial involvement in the pathogenesis of Parkinson's disease has been suggested by multiple studies, but the mechanisms involved remain unresolved. Here, we sought to identify which mitochondrial defects are associated with degeneration of the nigrostriatal system. Nigrostriatal integrity was assessed in vivo by dopamine transporter (DAT) imaging in twenty-one patients with mitochondrial disorders of different molecular aetiology including: maternally inherited mitochondrial DNA (mtDNA) point mutations, primary single mtDNA deletions, nuclear-encoded disorders of mtDNA replication and maintenance due to mutations in POLG or C10orf2 (Twinkle), and mutations in other nuclear mitochondrial genes including the mitochondrial aspartyl-tRNA synthetase (DARS2) and ADCK3 genes. Patients with mitochondrial disease were compared with twenty patients with Parkinson's disease and eighteen controls. Nigrostriatal degeneration occurred exclusively in patients with defective mtDNA replication and maintenance. In these patients, nigrostriatal degeneration was progressive and at least as severe as in patients with advanced Parkinson's disease. None of the patients with other mitochondrial defects showed evidence of nigral involvement. Our findings demonstrate that dopaminergic neurons of the substantia nigra are specifically vulnerable to defective mtDNA replication/repair or quality control and not to primary point mutations of mtDNA. These results support the hypothesis that accumulating somatic mtDNA damage plays an important role in neurodegeneration.

Combined variants in reading epilepsy; coexisting anterior and posterior variants camouflaged as heat cramps where the patient finds his own diagnosis searching the internet.

Reading epilepsy is a form of reflex-induced seizures. Two entities are postulated as part of a clinical spectrum; one anterior variant with jaw jerks and orofacial myoclonia and another posterior variant with visual symptoms and alexia or dyslexia. We present a case with suggestible evidence of both conditions coexisting within the same patient, a finding that, to our knowledge, has not been previously reported. The diagnosis in this specific case was contributed to by the patient searching the internet.

Novel SLC19A3 Promoter Deletion and Allelic Silencing in Biotin-Thiamine-Responsive Basal Ganglia Encephalopathy.

BACKGROUND: Biotin-thiamine responsive basal ganglia disease is a severe, but potentially treatable disorder caused by mutations in the SLC19A3 gene. Although the disease is inherited in an autosomal recessive manner, patients with typical phenotypes carrying single heterozygous mutations have been reported. This makes the diagnosis uncertain and may delay treatment. METHODS AND RESULTS: In two siblings with early-onset encephalopathy dystonia and epilepsy, whole-exome sequencing revealed a novel single heterozygous SLC19A3 mutation (c.337T>C). Although Sanger-sequencing and copy-number analysis revealed no other aberrations, RNA-sequencing in brain tissue suggested the second allele was silenced. Whole-genome sequencing resolved the genetic defect by revealing a novel 45,049 bp deletion in the 5'-UTR region of the gene abolishing the promoter. High dose thiamine and biotin therapy was started in the surviving sibling who remains stable. In another patient two novel compound heterozygous SLC19A3 mutations were found. He improved substantially on thiamine and biotin therapy. CONCLUSIONS: We show that large genomic deletions occur in the regulatory region of SLC19A3 and should be considered in genetic testing. Moreover, our study highlights the power of whole-genome sequencing as a diagnostic tool for rare genetic disorders across a wide spectrum of mutations including non-coding large genomic rearrangements.

Excellent response of intramedullary Erdheim-Chester disease to vemurafenib: a case report.

BACKGROUND: Erdheim-Chester disease is a rare histiocytosis characterized by multi-systemic organ involvement. Immune-modulating agents such as interferon-alpha have limited success and the disorder is progressive and causes high morbidity and mortality. Treatment with the BRAF-inhibitor vemurafenib has recently produced substantial improvement in three patients with Erdheim-Chester disease expressing the p. V600E BRAF mutation. The disorder commonly affects the central nervous system and it is not yet known whether vemurafenib can reverse intra-axial infiltration and the resulting neurological impairment. CASE PRESENTATION: In this work, we report for the first time an excellent clinical response to vemurafenib in a Norwegian patient with debilitating progressive spastic paraparesis due to intra-axial infiltration of the thoracic spinal cord. The patient had been unresponsive to interferon-alpha. Low dose vemurafenib (720 mg daily) for a period of three months resulted in significant tumor shrinkage by >60% and regression of contrast enhancement and fluorodeoxyglucose uptake on positron-emission tomography. The patient's spastic paraparesis and gait function improved dramatically. She currently walks unaided and reports a substantially improved quality of life. CONCLUSION: Our findings show that vemurafenib therapy, even at low doses, can be effective for the treatment of intra-axial central nervous system involvement in BRAF-positive Erdheim-Chester disease.

SPECT/CT hybrid imaging; with which CT?

AIM: The aim of this study is to show the practical use of, and to discuss the rationale for, high-end computed tomography (CT) integrated with intrinsic low-resolution single-photon emission tomography (SPECT). MATERIALS AND METHODS: All examinations performed on three new SPECT/CT systems with diagnostic CT capabilities were recorded retrospectively. The use of CT was classified as low-dose, using the CT with restraint as to the tube current and radiation dose, or diagnostic, with an optimum use of the CT, using CT protocols as used in ordinary radiological practice. The number of low-dose CT was compared with the number of diagnostic CT examinations. The report is based on 436 patient examinations from three hospitals in Norway with recently installed SPECT/CT systems, the time of use varying from 6 months to 2 years. The examinations performed were myocardial perfusion (45%), various tumors (thyroid, parathyroid, neuroendocrine 37%), malignant skeletal disease (12%), brain perfusion (4%), sentinel nodes in breast cancer (1%) and gastrointestinal bleeding (1%). RESULTS: Of the 436 patients, 431 had a low-dose CT for attenuation correction, anatomic localisation and, also for diagnosis, whereas five patients had a diagnostic CT. In these series, as was found in recent literature, the diagnostic potential of the CT was seldom used to its capacity and always in predetermined diagnostic situations. CONCLUSION: There is a low degree of utilization of the diagnostic capabilities of the CT in the SPECT/CT context, for a number of reasons. This raises questions about the cost-benefit of investing in high-end CT for SPECT/CT applications.