Citations

AbstractBackgroundDisruption of default mode network (DMN) connectivity is common in Alzheimer’s disease. We investigated cross‐sectional and one‐year longitudinal changes in DMN sub‐systems in atypical clinical presentations of AD, in relation to age and tau.MethodSixty‐four amyloid‐positive atypical AD (Aty‐AD) patients diagnosed with posterior cortical atrophy (n = 35) or logopenic progressive aphasia (n = 29) were recruited by the Neurodegenerative Research Group. Patients underwent structural and resting‐state functional MRI, and [18F]flortaucipir PET at baseline and one‐year follow‐up. 140 amyloid‐negative cognitively unimpaired (CU) individuals from the Mayo Clinic Study of Aging were included as controls. Global tau SUVR was calculated in a meta‐ROI including parietal, temporal, and occipital regions. DMN connectivity was calculated in native space for posterior (pDMN), ventral (vDMN), anterior ventral (avDMN) and anterior dorsal (adDMN) DMN sub‐systems using the dual regression method. A global measure of DMN connectivity, the Network Failure Quotient (NFQ), was calculated as (vDMN_to_pDMN+ adDMN_to_pDMN)/(pDMN+vDMN). Linear mixed‐effects models were computed for each DMN connectivity measure, including diagnosis (Aty‐AD, CU), age, time and their interaction, and a per‐person random effect. SPM paired t‐tests were run to compare baseline and follow‐up images in Aty‐AD and CU separately. Linear mixed‐effect models were run in the Aty‐AD cohort only to investigate the effect of global baseline tau SUVR on each DMN connectivity measure.ResultMixed‐effects models showed evidence of lower cross‐sectional pDMN and higher adDMN connectivity in Aty‐AD relative to CU, with no significant time effects (Fig. 1). While connectivity in all DMN sub‐systems declined with age in CU, connectivity was higher in older Aty‐AD patients relative to younger, particularly in vDMN and pDMN. A similar trend was observed for NFQ, which was significantly higher in Aty‐AD, with a negative age effect (Fig. 1). In Aty‐AD, voxel‐based analyses showed moderate evidence of decline in vDMN connectivity and increase in avDMN connectivity over time (Fig. 2). Greater baseline global tau SUVR was associated with lower vDMN connectivity, cross‐sectionally and longitudinally (Fig. 3).ConclusionDMN connectivity was altered in Aty‐AD, with strongest alterations in younger patients. The vDMN declined over time, suggesting a shift in DMN connectivity with disease progression that was likely related to tau pathology.

AbstractUnesbulin is being investigated in combination with dacarbazine (DTIC) as a potential therapeutic agent in patients with advanced leiomyosarcoma (LMS). This paper reports the pharmacokinetics (PK) of unesbulin, DTIC, and its unreactive surrogate metabolite 5‐aminoimidazole‐4‐carboxamide (AIC) in 29 patients with advanced LMS. Drug interactions between DTIC (and AIC) and unesbulin were evaluated. DTIC (1000 mg/m2) was administered to patients with LMS via 1‐h intravenous (i.v.) infusion on day 1 of every 21‐day (q21d) cycle. Unesbulin dispersible tablets were administered orally twice weekly (b.i.w.), starting on day 2 of every cycle, except for cycle 2 (C2), where unesbulin was dosed either on day 1 together with DTIC or on day 2, 1 day after DTIC administration. The PK of DTIC, AIC, and unesbulin in cycle 1 (C1) and C2 were estimated using noncompartmental analysis. DTIC and AIC were measurable immediately after the start of infusion and reached maximum plasma concentration (Cmax) immediately or shortly after end of infusion at 1.0 and 1.4 h (time to Cmax), respectively. Co‐administration of unesbulin orally at 200 mg or above with DTIC inhibited cytochrome P450 (CYP)1A2‐mediated DTIC metabolism, resulting in 66.7% reduction of AIC exposures. Such inhibition could be mitigated when unesbulin was dosed the day following DTIC infusion. Repeated unesbulin dosing demonstrated evidence of clinical CYP1A2 induction and increased AIC Cmax by 69.4% and area under concentration‐time curve to infinity by 57.9%. No meaningful difference in unesbulin PK was observed between C2 and C1. The combination therapy of 1000 mg/m2 i.v. DTIC q21d and 300 mg unesbulin b.i.w. in a staggered regimen is well‐tolerated in patients with LMS.

Abstract Objectives VEXAS syndrome is an adult-onset autoinflammatory disease caused by a somatic pathogenic mutation in the UBA1 (ubiquitin-like modifier activating enzyme 1) gene. Patients present with rheumatologic manifestations and cytopenias and may have an increased predisposition to myelodysplastic syndrome (MDS) and plasma cell neoplasms. Prior studies have reported on the peripheral blood and bone marrow findings in patients with VEXAS syndrome. Due to the protean clinical presentation and lack of specificity of morphologic features (eg, vacuoles in early erythroid and granulocytic precursors), an optimal screening methodology to identify these patients in a timely fashion is desirable. Methods To further evaluate and describe the salient diagnostic morphologic features in VEXAS syndrome, we carried out a comprehensive study of the largest single-institution cohort to date. Diagnostic and follow-up bone marrow biopsy specimens from 52 male patients with molecularly identified VEXAS syndrome underwent central review. Results Cytopenias were common in all cases, primarily macrocytic anemia, monocytopenia, and thrombocytopenia. Bone marrow aspirate and biopsy were often hypercellular, with an increased myeloid/erythroid ratio, granulocytic hyperplasia with left shift, erythroid left shift, and megakaryocyte hyperplasia, which exhibited a range of striking morphologic findings. Distinctly vacuolated myeloid and erythroid precursors were seen in more than 95% of cases. Conclusions Our data reveal potential novel diagnostic features, such as a high incidence of monocytopenia and distinct patterns of atypical megakaryopoiesis, that appear different from dysmegakaryopoiesis typically associated with MDS. In our experience, those findings are suggestive of VEXAS, in the appropriate clinical context.

Abstract Transactive response DNA-binding protein 43 (TDP-43) pathology is categorized as type A-E in frontotemporal lobar degeneration and as type α-β in Alzheimer disease (AD) based on inclusion type. We screened amygdala slides of 131 cases with varying ages at death, clinical/neuroimaging findings, and AD neuropathologic changes for TDP-43 pathology using anti-phospho-TDP-43 antibodies. Seven cases (5%) only showed atypical TDP-43 inclusions that could not be typed. Immunohistochemistry and immunofluorescence assessed the atypical star-shaped TDP-43 pathology including its distribution, species, cellular localization, and colocalization with tau. All 7 had died at an extremely old age (median: 100 years [IQR: 94–101]) from nonneurological causes and none had dementia (4 cognitively unimpaired, 3 with amnestic mild cognitive impairment). Neuroimaging showed mild medial temporal involvement. Pathologically, the star-shaped TDP-43-positive inclusions were found in medial (subpial) amygdala and, occasionally, in basolateral regions. Hippocampus only showed TDP-43-positive neurites in the fimbria and subiculum while the frontal lobe was free of TDP-43 inclusions. The star-shaped inclusions were better detected with antibodies against N-terminal than C-terminal TDP-43. Double-labeling studies confirmed deposition of TDP-43 within astrocytes and colocalization with tau. We have identified a novel TDP-43 pathology with star-shaped morphology associated with superaging, with a homogeneous clinicopathologic picture, possibly representing a novel, true aging-related TDP-43 pathology.