Thomas Schwarzlmüller

Default-Mode Network Functional Connectivity is Closely Related to Metabolic Activity

Over the last decade, the brains 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‐[18F]fluoroglucose positron emission tomography (FDG‐PET), proton magnetic resonance spectroscopy (1H‐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. Hum Brain Mapp 36:2027–2038, 2015.

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 Parkinsons 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 Parkinsons 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.

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.

Mitochondrial DNA homeostasis is essential for nigrostriatal integrity.

Mitochondrial involvement in the pathogenesis of Parkinsons 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 Parkinsons 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 Parkinsons 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.

Progressive striatal necrosis associated with anti-NMDA receptor antibodies

BackgroundWe 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 presentationAn 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.ConclusionThis 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.

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.

A close link between metabolic activity and functional connectivity in the resting human brain

Default-mode network (DMN) functional connectivity and its task-dependent down-regulation have attracted a lot of attention in the field of neuroscience. Nevertheless, the exact underlying mechanisms of DMN functional connectivity, or more specifically, the blood oxygen level-dependent (BOLD) signal, are still not completely understood. To investigate more directly the association between local glucose consumption, local glutamatergic neurotransmission and DMN functional connectivity during rest, the present study combined for the first time 2-Deoxy-2-[18F]fluoroglucose positron emission tomography (FDG-PET), proton magnetic resonance spectroscopy (1H-MRS), and resting-state functional magnetic resonance imaging (rs-fMRI). Seed-based correlation analyses, using a key region of the DMN i.e. the dorsal posterior cingulate cortex as seed, revealed overall striking spatial similarities between fluctuations in FDG-uptake and the BOLD signal. More specifically, a conjunction analysis across both modalities showed that DMN areas as the inferior parietal lobe, angular gyrus, precuneus, middle and medial frontal gyrus were positively correlated with the dorsal posterior cingulate cortex. Furthermore, we could demonstrate that local glucose consumption in the medial frontal gyrus, posterior cingulate cortex and left angular gyrus was associated with functional connectivity within the DMN. We did not find a relationship between glutamatergic neurotransmission and functional connectivity. In line with very recent findings, our results provide further evidence for a close association between local metabolic activity and functional connectivity and enable further insights towards a better understanding of the underlying mechanisms of the BOLD signal.

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.