Comparison of quantitative FDG-PET and MRI in anti-LGI1 autoimmune encephalitis.

OBJECTIVES: Anti-leucine glioma-inactivated protein 1 (anti-LGI1) autoimmune encephalitis (AE) presents as subacute memory loss, behavioral changes, and seizures. Diagnosis and treatment delays can result in long term sequelae, including cognitive impairment. 18F-FDG PET/CT may be more sensitive than MRI in patients with AE. Our objective was to determine if anti-LGI1 is associated with a distinct pattern of FDG uptake and whether this pattern persists following treatment. METHODS: Nineteen18F-FDG PET/CT brain scans (13 pre-treatment, 6 convalescent phase) for 13 patients with anti-LGI1 were studied using NeuroQ™ and CortexID™. The sensitivity of the PET images was compared to MRI. The Z scores of 47 brain regions between the pre-treatment and next available follow-up images during convalescence were compared. RESULTS: All 18F-FDG PET/CT scans demonstrated abnormal FDG uptake, while only 6 (42.9%) pre-treatment brain MRIs were abnormal. The pre-treatment scans demonstrated hypermetabolism in the bilateral medial temporal cortices, basal ganglia, brain stem, and cerebellum and hypometabolism in bilateral medial and mid frontal, cingulate, and parietotemporal cortices. Overall, the brain uptake during convalescence showed improvement of the Z scores towards 0 or normalization of previous hypometabolic activity in medial frontal cortex, inferior frontal cortex, Broca's region, parietotemporal cortex, and posterior cingulate cortex and previous hypermetabolic activity in medial temporal cortices, caudate, midbrain, pons and cerebellum. CONCLUSIONS: Brain FDG uptake was more commonly abnormal than MRI in the pre-treatment phase of anti-LGI1, and patterns of dysmetabolism differed in the pre-treatment and convalescent phases. These findings may expedite the diagnosis, treatment, and monitoring of anti-LGI1 patients.

Quantitative brain 18F-FDG PET/CT analysis in seronegative autoimmune encephalitis.

OBJECTIVE: Brain 18F-FDG PET/CT is a useful diagnostic in evaluating patients with suspected autoimmune encephalitis (AE). Specific patterns of brain dysmetabolism have been reported in anti-NMDAR and anti-LGI1 AE, and the degree of dysmetabolism may correlate with clinical functional status.18FDG-PET/CT abnormalities have not yet been described in seronegative AE. METHODS: We conducted a cross-sectional analysis of brain18FDG-PET/CT data in people with seronegative AE treated at the Johns Hopkins Hospital. Utilizing NeuroQ™ software, the Z-scores of 47 brain regions were calculated relative to healthy controls, then visually and statistically compared for probable and possible AE per clinical consensus diagnostic criteria to previous data from anti-NMDAR and anti-LGI1 cohorts. RESULTS: Eight probable seronegative AE and nine possible seronegative AE were identified. The group only differed in frequency of abnormal brain MRI, which was seen in all of the probable seronegative AE patients. Both seronegative groups had similar overall patterns of brain dysmetabolism. A common pattern of frontal lobe hypometabolism and medial temporal lobe hypermetabolism was observed in patients with probable and possible seronegative AE, as well as anti-NMDAR and anti-LGI1 AE as part of their respective characteristic patterns of dysmetabolism. Four patients had multiple brain18FDG-PET/CT scans, with changes in number and severity of abnormal brain regions mirroring clinical status. CONCLUSIONS: A18FDG-PET/CT pattern of frontal lobe hypometabolism and medial temporal lobe hypermetabolism could represent a common potential biomarker of AE, which along with additional clinical data may facilitate earlier diagnosis and treatment.

Low-dose ketamine infusion for the treatment of multiple sclerosis fatigue (INKLING-MS): Study protocol for a randomized, double-blind, active placebo-controlled phase II trial.

BACKGROUND: Fatigue is one of the most common symptoms of people with Multiple Sclerosis (MS). However, currently-used medications for the treatment of fatigue probably do not work better than a placebo. In a pilot trial, we showed that one infusion of low-dose ketamine significantly improved fatigue severity measured four weeks after the infusion. METHODS: The proposed study is a single-center, phase II, randomized, double-blind, parallel-group, active-placebo-controlled trial of intravenous low-dose ketamine in patients with MS fatigue. Participants will be randomized 1:1:1 into three groups: receiving either one or two infusions of ketamine (0.5 mg/kg over 40 min) or zero to one infusion of the active placebo (midazolam, 0.05 mg/kg over 40 min). Eligibility criteria include adult patients diagnosed with MS based on the latest criteria, complaining of fatigue as one of the main symptoms, and having a screening MFIS score higher than a pre-specified threshold. RESULTS: One hundred and ten participants will be randomized over 30 months at Johns Hopkins MS Center. Complete enrollment is expected by mid-2025. The study's primary outcome will be the MFIS score at the end of week 4, comparing two-thirds of the participants who received ketamine with one-third who received midazolam. The secondary and exploratory outcomes (measured four weeks after the second infusion) will show how long the effects of a single infusion last and if two infusions of ketamine are better than one in improving MS fatigue. CONCLUSION: This study can show whether intervening in the glutamatergic pathways would improves MS fatigue.

Assessment of anti-GAD65-associated cerebellar ataxia with 18F-FDG cerebellar uptake: ROC analysis.

OBJECTIVE: Anti-glutamic acid decarboxylase 65 (anti-GAD65)-associated neurological disorders include two major phenotypes, namely Stiff person syndrome (SPS) and cerebellar ataxia (CA). Considering the potential for better outcomes with prompt immunotherapy, early detection of CA is crucial. Hence, a non-invasive imaging biomarker to detect CA with high specificity is desired. Herein, we evaluated brain 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) PET in detecting CA based on cerebellar uptake using receiver operating characteristic (ROC) analysis and five-fold cross-validation. METHODS: This study was based on STARD 2015 guidelines: thirty patients with anti-GAD65-associated neurological disorders, 11 of whom with CA were studied. Five test sets were created after patients were randomly sorted and divided into 5 equal folds. Each iteration included 24 patients for ROC analysis and 6 patients reserved for testing. The Z scores of left cerebellum, vermis, right cerebellum, and the average of the three regions were used in ROC analysis to determine areas with significant area under the curve (AUC). The cut-off values with high specificity were determined among the 24 patients in each iteration and tested against the reserved 6 patients. RESULTS: Left cerebellum and average of the three regions showed significant AUC above 0.5 in all iterations with left cerebellum being the highest AUC in 4 iterations. Testing the cut-off values of the left cerebellum against the reserved 6 patients in each iteration showed 100% specificity with sensitivities ranging from 0 to 75%. CONCLUSIONS: Cerebellar 18F-FDG PET uptake can differentiate CA phenotypes from patients with SPS with high specificity.

Toxicological assessment and food allergy of silk fibroin derived from Bombyx mori cocoons.

Recent studies have demonstrated silk fibroin protein's (SF) ability to extend the shelf life of foods by mitigating the hallmarks of spoilage, namely oxidation and dehydration. Due to the potential for this protein to become more widespread, its safety was evaluated comprehensively. First, a bacterial reverse mutation test (Ames test) was conducted in five bacterial strains. Second, an in vivo erythrocyte test was conducted with Sprague Dawley rats at doses up to 1,000mg/kg-bw/day. Third, a range-finder study was conducted with Sprague Dawley rats at the highest consumption amount given solubility and oral gavage volume constrains (500mg/kg-bw/day). Fourth, a 28-day sub-chronic study in Sprague Dawley rats was conducted with the high dose set at 500mg/kg-bw/day, as limited by solubility of the protein in a single-gavage per-day study. Fifth, an in vitro pepsin digestion assay was performed to assess the potential for protein allergenicity. Sixth, allergenic potential was further assessed using liquid chromatography-mass spectroscopy for detection of allergenic insect proteins. Seventh, the SF protein sequences were subjected to bioinformatic analyses. Together, these studies raise no mutagenic, genotoxic, toxicological, or allergenic concerns with the oral consumption of silk fibroin.

Histone demethylase PHF8 regulates hypoxia signaling through HIF1α and H3K4me3.

Hypoxia through transcription factor HIF1α plays a critical role in cancer development. In prostate cancer, HIF1α interplays with androgen receptor (AR) to contribute to the progression of this disease to its lethal form-castration-resistant prostate cancer (CRPC). Hypoxia upregulates several epigenetic factors including histone demethylase KDM3A which is a critical co-factor of HIF1α. However, how histone demethylases regulate hypoxia signaling is not fully understood. Here, we report that histone demethylase PHF8 plays an essential role in hypoxia signaling. Knockdown or knockout of PHF8 by RNAi or CRISPR-Cas9 system reduced the activation of HIF1α and the induction of HIF1α target genes including KDM3A. Mechanistically, PHF8 regulates hypoxia inducible genes mainly through sustaining the level of trimethylated histone 3 lysine 4 (H3K4me3), an active mark in transcriptional regulation. The positive role of PHF8 in hypoxia signaling extended to hypoxia-induced neuroendocrine differentiation (NED), wherein PHF8 cooperates with KDM3A to regulate the expression of NED genes. Moreover, we discovered that the role of PHF8 in hypoxia signaling is associated with the presence of full-length AR in CRPC cells. Collectively, our study identified PHF8 as a novel epigenetic factor in hypoxia signaling, and the underlying regulatory mechanisms likely apply to general cancer development involving HIF1α. Therefore, targeting PHF8 can potentially be a novel therapeutic strategy in cancer therapy.