Translocator protein (TSPO)-PET as diagnostic and monitoring tool in COVID-19 related MRI-negative brainstem encephalitis: a case report.

BACKGROUND: Encephalitis and myelitis have been linked to both COVID-19 vaccination and infection, causing symptoms such as reduced consciousness, mental state alterations and seizures. Remarkably, most cases do not show significant structural alterations on MRI scans, which poses a diagnostic challenge. METHODS: We present the diagnostic workup and clinical course of a patient who developed a progressive brainstem syndrome two weeks after COVID-19 vaccination and subsequent infection. We used translocator protein (TSPO)-PET scans for the first time to investigate COVID-related neuroinflammation. RESULTS: The patient developed oculomotor disorder, dysarthria, paresthesia in all distal limbs and spastic-atactic gait. CSF analysis revealed mild lymphocytic pleocytosis with normal protein levels. Brain and spinal cord MRI scans were negative, but TSPO/PET scans showed increased microglia activity in the brainstem, which correlated with the clinical course. Steroid treatment led to clinical improvement, but relapse occurred during prednisone taper after four weeks. Plasmapheresis had no significant effect; however, complete remission was achieved with cyclophosphamide and methotrexate, with normal TSPO signal ten months after onset. CONCLUSIONS: TSPO-PET can be a valuable tool in the diagnostic and therapeutic monitoring of COVID-19-related encephalitis, particularly in cases where MRI scans are negative. Aggressive immunosuppressive therapy can lead to sustained remission.

Assessing the potential anti-neuroinflammatory effect of minocycline in chronic low back pain: Protocol for a randomized, double-blind, placebo-controlled trial.

INTRODUCTION: Both preclinical studies, and more recent clinical imaging studies, suggest that glia-mediated neuroinflammation may be implicated in chronic pain, and therefore might be a potential treatment target. However, it is currently unknown whether modulating neuroinflammation effectively alleviates pain in humans. This trial tests the hypothesis that minocycline, an FDA-approved tetracycline antibiotic and effective glial cell inhibitor in animals, reduces neuroinflammation and may reduce pain symptoms in humans with chronic low back pain. METHODS AND ANALYSIS: This study is a randomized, double-blind, placebo-controlled clinical trial. Subjects, aged 18-75, with a confirmed diagnosis of chronic (≥ six months) low back pain (cLBP) and a self-reported pain rating of at least four out of ten (for at least half of the days during an average week) are enrolled via written, informed consent. Eligible subjects are randomized to receive a 14-day course of either active drug (minocycline) or placebo. Before and after treatment, subjects are scanned with integrated Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) using [11C]PBR28, a second-generation radiotracer for the 18 kDa translocator protein (TSPO), which is highly expressed in glial cells and thus a putative marker of neuroinflammation. Pain levels are evaluated via daily surveys, collected seven days prior to the start of medication, and throughout the 14 days of treatment. General linear models will be used to assess pain levels and determine the treatment effect on brain (and spinal cord) TSPO signal. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT03106740).

The pandemic brain: Neuroinflammation in non-infected individuals during the COVID-19 pandemic.

While COVID-19 research has seen an explosion in the literature, the impact of pandemic-related societal and lifestyle disruptions on brain health among the uninfected remains underexplored. However, a global increase in the prevalence of fatigue, brain fog, depression and other "sickness behavior"-like symptoms implicates a possible dysregulation in neuroimmune mechanisms even among those never infected by the virus. We compared fifty-seven 'Pre-Pandemic' and fifteen 'Pandemic' datasets from individuals originally enrolled as control subjects for various completed, or ongoing, research studies available in our records, with a confirmed negative test for SARS-CoV-2 antibodies. We used a combination of multimodal molecular brain imaging (simultaneous positron emission tomography / magnetic resonance spectroscopy), behavioral measurements, imaging transcriptomics and serum testing to uncover links between pandemic-related stressors and neuroinflammation. Healthy individuals examined after the enforcement of 2020 lockdown/stay-at-home measures demonstrated elevated brain levels of two independent neuroinflammatory markers (the 18 kDa translocator protein, TSPO, and myoinositol) compared to pre-lockdown subjects. The serum levels of two inflammatory markers (interleukin-16 and monocyte chemoattractant protein-1) were also elevated, although these effects did not reach statistical significance after correcting for multiple comparisons. Subjects endorsing higher symptom burden showed higher TSPO signal in the hippocampus (mood alteration, mental fatigue), intraparietal sulcus and precuneus (physical fatigue), compared to those reporting little/no symptoms. Post-lockdown TSPO signal changes were spatially aligned with the constitutive expression of several genes involved in immune/neuroimmune functions. This work implicates neuroimmune activation as a possible mechanism underlying the non-virally-mediated symptoms experienced by many during the COVID-19 pandemic. Future studies will be needed to corroborate and further interpret these preliminary findings.

Longitudinal change in TSPO PET imaging in progressive multiple sclerosis.

The objective of this pilot study was to assess a 2-year change in innate immune burden in 15 progressive multiple sclerosis (MS) patients using PK11195-PET. Sixteen age-matched healthy controls (HC) were included for baseline comparison. PK11195 uptake was higher in MS patients compared to HC within normal-appearing white matter (NAWM) and multiple gray matter regions. In patients, PK11195 uptake increased in NAWM (p = 0.01), cortex (p = 0.04), thalamus (p = 0.04), and putamen (p = 0.02) at 12 months. Among patients remaining at 24 months, there was no further increase in PK11195. Our data suggest that innate immune activity may increase over time in patients with progressive MS.