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Objective To characterize [11 C]-PBR28 brain uptake using positron emission tomography (PET) in people with amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS). We have previously shown increased [11 C]-PBR28 uptake in the precentral gyrus in a small group of ALS patients. Herein, we confirm our initial finding, study the longitudinal changes, and characterize the gray versus white matter distribution of [11 C]-PBR28 uptake in a larger cohort of patients with ALS and PLS. Methods Eighty-five participants including 53 with ALS, 11 with PLS, and 21 healthy controls underwent integrated [11 C]-PBR28 PET-magnetic resonance brain imaging. Patients were clinically assessed using the Upper Motor Neuron Burden (UMNB) and the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R). [11 C]-PBR28 uptake was quantified as standardized uptake value ratio (SUVR) and compared between groups. Cortical thickness and fractional anisotropy were compared between groups and correlated with SUVR and the clinical data. [11 C]-PBR28 uptake and ALSFRS-R were compared longitudinally over 6 months in 10 ALS individuals. Results Whole brain voxelwise, surface-based, and region of interest analyses revealed increased [11 C]-PBR28 uptake in the precentral and paracentral gyri in ALS, and in the subcortical white matter for the same regions in PLS, compared to controls. The increase in [11 C]-PBR28 uptake colocalized and correlated with cortical thinning, reduced fractional anisotropy, and increased mean diffusivity, and correlated with higher UMNB score. No significant changes were detected in [11 C]-PBR28 uptake over 6 months despite clinical progression. Interpretation Glial activation measured by in vivo [11 C]-PBR28 PET is increased in pathologically relevant regions in people with ALS and correlates with clinical measures. Ann Neurol 2018;83:1186-1197.

Patient: Male, 24 Final Diagnosis: Intestinal lymphangiectasia Symptoms: Frequent episodes of diarrhea • recurrent infections • swelling in the lower limbs Medication: Octreotide • MCT oils Clinical Procedure: Endoscopic exam • Doppler ultrasound study • abdominal CT scan Specialty: Gastroenterology and Hepatology Objective: Rare disease Background: Intestinal lymphangiectasia (IL) is a rare disease characterized by a dilatation of the intestinal lymphatics and loss of lymph fluid into the gastrointestinal tract leading to hypoproteinemia, edema, lymphocytopenia, hypogammaglobinemia, and immunological abnormalities. Iron, calcium, and other serum components (e.g., lipids, fat soluble vitamins) may also be depleted. A literature search revealed more than 200 reported cases of IL. Herein, we report our observations of a patient diagnosed with IL; we also present our conclusion for our review of the published literature. Case Report: A 24-year-old male was admitted to Aleppo University Hospital with the complaints of abdominal pain, headache, arthralgia, fever, and rigors. His past medical history was remarkable for frequent episodes of diarrhea, recurrent infections, and swelling in the lower limbs. In addition, he had been hospitalized several times in non-academic hospitals due to edema in his legs, cellulitis, and recurrent infections. In the emergency department, a physical examination revealed a patient in distress. He was weak, dehydrated, pale, and had a high-grade fever. His lower extremities were edematous, swollen, and extremely tender to touch. The overlying skin was erythematous and warm. Moreover, the patient was tachycardic, tacypneic, and moderately hypotensive. The patient was resuscitated with IV fluids, and Tylenol was administered to bring the temperature down. Blood tests showed anemia and high levels of inflammatory markers. The patient’s white blood cell count was elevated with an obvious left shift. However, subsequent investigations showed that the patient had IL. Suitable diet modification plans were applied as a long-term management plan. Conclusions: IL is a rare disease of challenging nature due to its systematic effects and lack of comprehensive studies that can evaluate the effectiveness of specific treatments in a large cohort of patients. Medium-chain triglyceride (MCT) oils and diet modification strategies are effective in reducing the loss of body proteins and in maintaining near-normal blood levels of immunoglobulins. However, octreotide and MCT oils had no proven role in reducing lymphedema in our patient.

Patient: Female, 28 Final Diagnosis: Gastrinoma Symptoms: Vomiting • diarrhea • epigastric soreness • heartburn • nausea • significant weight loss Medication: — Clinical Procedure: Esophagogastroduodenoscopy • blood tests • abdomen CT scan • surgery Specialty: Gastroenterology and Hepatology Objective: Rare co-existance of disease or pathology Background: Pancreatic endocrine tumors (PETs) are rare and can occur as part of neurofibromatosis type 1 (NF1). Gastrinomas are functional PETs that are rarely associated with NF1. Only two cases of their occurrence have been reported in the literature. Case Report: A 28-year-old woman was admitted for further evaluation of epigastric soreness, heartburn, nausea, vomiting, diarrhea, and a significant weight loss. Physical examination was remarkable for cutaneous findings (axillary freckling and multiple café-au-lait spots) as well as neurofibromas (dermal, plexiform). A diagnosis of NF1 was confirmed. Esophagogastroduodenoscopy (EGD) revealed multiple ulcers in the duodenum and the upper jejunum. A fasting gastrin level exceeded ten times the normal limit. An abdominal multi-slice 128 computed tomography (CT) scan revealed an oval mass of 26 mm in diameter adjacent to the second segment of the duodenum. The patient was examined carefully to rule out multiple endocrine neoplasia type 1 (MEN1). Surgical resection was performed and a gastrinoma, causing Zollinger-Ellison syndrome (ZES), was diagnosed by histological examinations of the extirpated mass. The serum gastrin level decreased to normal limits shortly after surgery. Continuous follow-up revealed that the symptoms and the EGD findings completely resolved without recurrences. Conclusions: Although NF1 has common skeletal, visual, neurological, and cardiovascular complications, it also has a rare association with duodenal or pancreatic gastrinomas. Vigilance for this possible association is important to promote timely and careful management to help eliminate serious and potentially life-threatening complications.

Introduction RNS60 is a novel immune-modulatory agent that has shown neuroprotective effects in amytrophic lateral sclerosis (ALS) preclinical models. RNS60 is administered by weekly intravenous infusion and daily nebulization. The objective of this pilot open-label trial was to test the feasibility, safety, and tolerability of long-term RNS60 administration in ALS patients. Methods The planned treatment duration was 23 weeks and the primary outcomes were safety and tolerability. Secondary outcomes included PBR28 positron emission tomography (PET) imaging and plasma biomarkers of inflammation. Results Sixteen participants with ALS received RNS60 and 13 (81%) completed 23 weeks of RNS60 treatment. There were no serious adverse events and no participants withdrew from the trial due to drug-related adverse events. There were no significant changes in the biomarkers. Discussion Long-term RNS60 administration was safe and well-tolerated. A large, multicenter, phase II trial of RNS60 is currently enrolling participants to test the effects of RNS60 on ALS biomarkers and disease progression. Muscle Nerve 59:303-308, 2019.

OBJECTIVE: To characterize [(11)C]-PBR28 brain uptake using positron emission tomography (PET) in people with amyotrophic lateral sclerosis (ALS), and primary lateral sclerosis (PLS). We have previously shown increased [(11)C]-PBR28 uptake in the precentral gyrus in a small group of ALS patients. Herein, we confirm our initial finding, study the longitudinal changes, and characterize the gray vs. white matter distribution of [(11)C]-PBR28 uptake in a larger cohort of patients with ALS and PLS. METHODS: Eighty-five participants including 53 ALS, 11 PLS and 21 healthy controls underwent integrated [(11)C]-PBR28 PET-MR brain imaging. Patients were clinically assessed using the upper motor neuron burden (UMNB), and the revised ALS functional rating scale (ALSFRS-R). [(11)C]-PBR28 uptake was quantified as standardized uptake value ratio (SUVR), and compared between groups. Cortical thickness, and fractional anisotropy were compared between groups and correlated with SUVR and the clinical data. [(11)C]-PBR28 uptake and ALSFRS-R were compared longitudinally over six-month in ten ALS individuals. RESULTS: Whole brain voxel-wise, surface-based and region of interest analyses revealed increased [(11)C]-PBR28 uptake in the precentral and paracentral gyri in ALS, and in the sub-cortical white matter for the same regions in PLS, compared to controls. The increase in [(11)C]-PBR28 uptake co-localized and correlated with cortical thinning, reduced fractional anisotropy, increased mean diffusivity, and correlated with higher UMNB score. No significant changes were detected in [(11)C]-PBR28 uptake over six-month despite clinical progression. INTERPRETATION: Glial activation measured by in vivo [(11)C]-PBR28 PET is increased in pathologically relevant regions in people with ALS and correlates with clinical measures.

Background Glia activation is thought to contribute to neuronal damage in several neurodegenerative diseases based on preclinical and human post-mortem studies, but its role in primary lateral sclerosis (PLS) is unknown. Objectives To localize and measure glia activation in people with PLS compared to healthy controls (HC). Methods Ten participants with PLS and ten age-matched HCs underwent simultaneous magnetic resonance (MR) and proton emission tomography (PET). The radiotracer [11C]-PBR28 was used to obtain PET-based measures of 18 kDa translocator protein (TSPO) expression, a marker of activated glial cells. MR techniques included a structural sequence to measure cortical thickness and diffusion tensor imaging (DTI) to assess white matter integrity. Results PET data showed increased [11C]-PBR28 uptake in anatomically-relevant motor regions which co-localized with areas of regional gray matter atrophy and decreased subcortical fractional anisotropy. Conclusions This study supports a link between glia activation and neuronal degeneration in PLS, and suggests that these disease mechanisms can be measured in vivo in PLS. Future studies are needed to determine the longitudinal changes of these imaging measures and to clarify if MR-PET with [11C]-PBR28 can be used as a biomarker for drug development in the context of clinical trials for PLS., Highlights • Is there a relationship between glia activation, cortical atrophy, and subcortical white matter abnormalities in people with primary lateral sclerosis (PLS)? • In this cross-sectional in vivo multi-modal (MR-PET) neuroimaging study, we show evidence of glia activation in the motor regions in PLS patients compared to healthy controls. The increased glia activation co-localizes with areas of structural abnormalities including cortical atrophy and subcortical white matter changes. • MR-PET neuroimaging is a powerful technique to localize and quantify glia activation and structural abnormalities, and may represent a novel in vivo biomarker of disease mechanisms in PLS.

We used established databases in standard ways to systematically characterize gene ontologies, pathways and functional linkages in the large set of genes now associated with autism spectrum disorders (ASDs). These conditions are particularly challenging--they lack clear pathognomonic biological markers, they involve great heterogeneity across multiple levels (genes, systemic biological and brain characteristics, and nuances of behavioral manifestations)-and yet everyone with this diagnosis meets the same defining behavioral criteria. Using the human gene list from Simons Foundation Autism Research Initiative (SFARI) we performed gene set enrichment analysis with the Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway Database, and then derived a pathway network from pathway-pathway functional interactions again in reference to KEGG. Through identifying the GO (Gene Ontology) groups in which SFARI genes were enriched, mapping the coherence between pathways and GO groups, and ranking the relative strengths of representation of pathway network components, we 1) identified 10 disease-associated and 30 function-associated pathways 2) revealed calcium signaling pathway and neuroactive ligand-receptor interaction as the most enriched, statistically significant pathways from the enrichment analysis, 3) showed calcium signaling pathways and MAPK signaling pathway to be interactive hubs with other pathways and also to be involved with pervasively present biological processes, 4) found convergent indications that the process "calcium-PRC (protein kinase C)-Ras-Raf-MAPK/ERK" is likely a major contributor to ASD pathophysiology, and 5) noted that perturbations associated with KEGG's category of environmental information processing were common. These findings support the idea that ASD-associated genes may contribute not only to core features of ASD themselves but also to vulnerability to other chronic and systemic problems potentially including cancer, metabolic conditions and heart diseases. ASDs may thus arise, or emerge, from underlying vulnerabilities related to pleiotropic genes associated with pervasively important molecular mechanisms, vulnerability to environmental input and multiple systemic co-morbidities.