The authors developed and applied two new linearized reference tissue models for parametric images of binding potential ( BP) and relative delivery ( R₁) for [¹¹C]DASB positron emission tomography imaging of serotonin transporters in human brain. The original multilinear reference tissue model (MRTM_O) was modified (MRTM) and used to estimate a clearance rate ( k′₂) from the cerebellum (reference). Then, the number of parameters was reduced from three (MRTM) to two (MRTM2) by fixing k′₂. The resulting BP and R₁ estimates were compared with the corresponding nonlinear reference tissue models, SRTM and SRTM2, and one-tissue kinetic analysis (1TKA), for simulated and actual [¹¹C]DASB data. MRTM gave k′₂ estimates with little bias (<1%) and small variability (<6%). MRTM2 was effectively identical to SRTM2 and 1TKA, reducing BP bias markedly over MRTM_O from 12–70% to 1–4% at the expense of somewhat increased variability. MRTM2 substantially reduced BP variability by a factor of two or three over MRTM or SRTM. MRTM2, SRTM2, and 1TKA had R₁ bias <0.3% and variability at least a factor of two lower than MRTM or SRTM. MRTM2 allowed rapid generation of parametric images with the noise reductions consistent with the simulations. Rapid parametric imaging by MRTM2 should be a useful method for human [¹¹C]DASB positron emission tomography studies.

Significance: The pore-forming protein gasdermin D (GSDMD) was recently identified as the principal executioner of pyroptosis (“fiery death”), a type of proinflammatory programmed cell death driven by inflammasomes. Caspase-1 cleaves GSDMD, but whether this process contributes to neuroinflammation is unknown. Here, we report evidence of GSDMD-mediated pyroptosis as a primary mechanism of inflammatory demyelination in the central nervous system during multiple sclerosis (MS), a debilitating and incurable demyelinating disease that causes profound loss of myelin-forming oligodendrocytes. By identifying GSDMD induction and pyroptosis in oligodendrocytes and microglia, we discovered a previously unrecognized mechanism driving neuroinflammation and demyelination. Pharmacologically inhibiting caspase-1 prevented pyroptosis in experimental models of MS, reducing demyelination and neurodegeneration. These findings highlight therapeutic approaches for understanding and treating inflammatory demyelination.

Peak-dose dyskinesias are abnormal movements that usually occur 1 h after oral administration of levodopa, and often complicate chronic treatment of Parkinson's disease. We investigated by PET with [¹¹C]raclopride whether Parkinson's disease progression modifies the striatal changes in synaptic dopamine levels induced by levodopa administration, and whether this modification, if present, could have an impact on the emergence of dyskinesias. We found that, 1 h after oral administration of standard-release 250/25 mg of levodopa/carbidopa, levodopa-induced increases in synaptic dopamine levels (as estimated by striatal changes in [¹¹C]raclopride binding potential) correlated positively with duration of Parkinson's disease symptoms (for the caudate nucleus, r = 0.79, P < 0.001; for the putamen, r = 0.88, P < 0.0001). Patients with peak-dose dyskinesias had larger 1-h increases in synaptic dopamine levels than stable responders, but there were no between-group differences in [¹¹C]raclopride binding 4 h post-levodopa. The corresponding (time × group) interaction term in the repeated measures analysis of covariance was significant, even after adjusting for between-group differences in duration of Parkinson's disease symptoms (for the caudate nucleus, P = 0.030; for the putamen, P = 0.021). Our results indicate that, at the synaptic level, an identical dose of levodopa induces increasingly larger 1-h changes in dopamine levels as Parkinson's disease progresses. Large levodopa-induced increases in synaptic dopamine concentration can lead to dramatic changes in receptor occupancy, which may be responsible for the emergence of peak-dose dyskinesias in Parkinson's disease.