Citations

Abstract Positron emission tomography (PET)-based molecular imaging is a clinically important tool for the evaluation of dementia and other neurodegenerative disorders, using radiotracers that target specific molecular and pathophysiological processes. Fluorodeoxyglucose brain PET has historically supported neurodegenerative disorder evaluation through detection of characteristic patterns of regional glucose hypometabolism. In recent years, the molecular imaging of protein aggregates has taken on an increasingly important role. This is evident with the widespread clinical adoption of amyloid PET and early use of tau PET to provide diagnostic and prognostic information for patients with suspected Alzheimer’s disease. Additional classes of radiotracers relevant to neurodegenerative diseases are under active investigation, including those targeting neuroinflammation, synaptic density, and α-synuclein aggregates. We review the major classes of PET radiotracers for neurodegenerative diseases, describing their molecular mechanisms, diagnostic performance, and their current and emerging clinical roles in dementia evaluation. Case examples for clinically used tracers illustrate imaging features relevant to diagnosis and characterization of prognosis and treatment effect. Finally, we discuss early developments and current challenges in the development of theranostic approaches and novel radiotracers for neurodegenerative diseases.

Background Obstructive sleep apnea (OSA)–chronic obstructive pulmonary disease overlap syndrome has been linked to worse cardiovascular outcomes. Preserved ratio impaired spirometry (PRISm) is recognized as an early stage of chronic obstructive pulmonary diseas. However, whether the coexistence of OSA and PRISm confers increased cardiovascular risk remains unknown. Methods Using data from the Sleep Heart Health Study, participants were categorized into 4 groups according to OSA and PRISm status. The primary outcome was major adverse cardiovascular and cerebrovascular events. The secondary outcome was cardiovascular disease mortality. Multivariable Cox regression models were used to evaluate the association of these groups with the risk of cardiovascular outcomes. Results During a median follow‐up of 11.45 years, the incidence of major adverse cardiovascular and cerebrovascular events was 17.00% in non‐OSA with normal lung function, 27.52% in non‐OSA with PRISm, 25.28% in OSA with normal lung function, and 49.40% in OSA with PRISm. After multivariable adjustment, compared with non‐OSA with normal lung function, the adjusted hazard ratios (HRs) for major adverse cardiovascular and cerebrovascular events were 1.20 (95% CI, 0.82–1.75) in non‐OSA with PRISm, 1.04 (95% CI, 0.89–1.21) in OSA with normal lung function, and 1.52 (95% CI, 1.08–2.12) in OSA with PRISm. Corresponding HRs for CVD mortality were 2.02 (95% CI, 1.26–3.24), 1.05 (95% CI, 0.81–1.35), and 2.17 (95% CI, 1.41–3.34), respectively. A significant sex interaction was observed ( P for interaction=0.009), with the association present only in women. Conclusions The coexistence of OSA and PRISm is independently associated with increased risk of adverse cardiovascular outcomes. This association is observed predominantly in women.

Systematic reviews of randomized controlled trials (RCTs) support evidence-based clinical advancement. Clinical trial reporting guidelines, including CONSORT, establish common data elements that support systematic synthesis of published trial outcomes. However, the rapid rise of digital health technologies presents new challenges for reporting guidelines, and substantial real-world reporting heterogeneity has been observed. Therefore, machine-assisted evaluation of reporting adherence offers a pathway for more agile information management to accommodate the diverse and disruptive nature of digital health technology-enabled RCTs. Here, we propose an accelerated retrieval-to-abstraction literature synthesis framework to conduct article screening, text and table data preprocessing, and full-text review using an unmodified pretrained large language model. We apply this methodology in two digital health technology-enabled RCT case studies evaluating adherence to technology and digital health equity guideline reporting items. Large language model performance was on par with inter-annotator agreement F1 scores (≥0.9) in both screening and information-extraction tasks. These findings support the scalability and rigor of accelerated evidence synthesis and demonstrate the importance of common reporting elements across digital health technology-enabled RCTs.

Abstract Glioblastoma (GBM) is a lethal, treatment-resistant brain cancer characterized by diffuse brain invasion, complex neuron-glioma signaling, and cellular, molecular, and spatial heterogeneity. Surgery is the current mainstay of treatment, aimed at maximizing tumor cytoreduction, decompressing the brain to improve neurological function, and providing material for analyses to inform prognostication and adjuvant treatment selection. To accurately model GBM surgical resection and tissue sampling in preclinical animal models, we developed the Maximal Safe Intracranial Surgery (MSIS) system. MSIS integrated a miniaturized neurosurgical resection device and enabled a safe, tunable, and reproducible approach for intracranial tumor resection, multi-regional biopsy, and longitudinal tissue sampling in murine models, with stereotactic, sterile, and high-viability tissue collection. MSIS was applied across five distinct orthotopic brain tumor models to reproducibly generate histologically and radiologically representative models of post-surgical GBM. Similar to humans, increasing the extent of resection correlated with improved animal survival, and recurrent growth patterns varied significantly by model type. Transcriptional profiles of matched primary vs. post-surgical recurrent tumors revealed enrichment of margin-associated transcriptional states consistent with neuron-glioma signaling. Overall, the MSIS system offers opportunities to model the standard-of-care, dissect the spatial and temporal dynamics of GBM, and pair therapeutic discovery with contextual tumor pathobiology.

Odontogenic myxoma (OM) is an uncommon, locally aggressive odontogenic neoplasm with characteristic histologic and clinico-radiographic features but with potential for histologic overlap with other odontogenic and non-odontogenic entities and a non-specific immunoprofile. Widespread loss of heterozygosity (LOH) has been recently described in rare cases of OM. The aim of this study was to determine whether widespread LOH represents a recurrent molecular signature that can be leveraged for clinical decision-making. Allele-specific copy number variation data from chromosomal microarray were generated from 7 OM, comprising a combined prospective and retrospective cohort. Four tumors arose in the mandible and 3 in the maxilla in patients ranging in age from 18 to 94 years (median: 44), with tumor size ranging from 2.2 to 13.0 cm. Variable amounts of fibrous stroma (odontogenic “fibromyxoma”) were present in 4/7 OM, and hypercellularity not typically appreciated in conventional OM was present in 3/7 cases. All OM (7/7) demonstrated widespread LOH, with 5 cases showing a near-haploid/low hypodiploid genomes (multiple monosomies) and 2 cases showing evidence of pseudo-hyperdiploidy due to probable endoreduplication. Both pseudo-hyperdiploid cases were ≥10 cm in size; 1 represented local recurrence. Chromosomes 1 to 3, 6, 9, 11, 13, 15, and 22 demonstrated LOH in ≥75% of cases (chromosomes 1 to 3, 6, and 9 in 100% of cases), while chromosomes 5, 12, 19, and 20 universally retained heterozygosity. Altogether, widespread LOH is a recurrent event in OM and a novel finding in odontogenic pathology, and allele-specific copy number variation analysis can serve as a diagnostic adjunct in challenging cases.

Aging occurs heterogeneously across organs, leading to progressive tissue dysfunction. Cellular senescence is a stress response triggered by age-associated insults, yet the mechanisms regulating senescence and organ aging remain incompletely understood. Here, we defined a role for lysine-specific demethylase 1 (LSD1) in DNA damage–mediated senescence and organ aging. LSD1 was upregulated in aged organs and senescent cells. In response to natural aging or ionizing radiation–induced DNA damage, LSD1 interacted with and demethylated ATM at lysine 3,016, as confirmed using a newly generated ATM-K3016me antibody. This modification sustained ATM phosphorylation, amplified DNA damage signaling, and delayed checkpoint recovery, promoting senescence and organ aging. Inhibition of LSD1 accelerated ATM dephosphorylation via WIP1, enhanced DNA repair, reduced senescence and DNA damage, and prevented irradiation-induced hair graying. Elimination of senescent cells with senolytics reduced LSD1 protein in aged organs, indicating a feedback loop between LSD1 and senescence. Mechanistically, LSD1 underwent autophagosome-lysosome degradation through interaction with LC3 and Beclin1, and autophagy impairment during DNA damage contributed to LSD1 accumulation in senescent cells. This study revealed LSD1 as a key regulator of DNA damage–induced senescence and organ aging and suggested that targeting LSD1 may attenuate senescence, delay organ aging, and prevent hair graying.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited disorder leading to kidney failure. Tolvaptan, the only FDA-approved therapy, modestly slows disease progression but is limited by significant adverse effects, highlighting the need for more effective and better-tolerated treatments. Ciliary polycystins are central to ADPKD pathogenesis. We previously demonstrated that a cilia base-localized pool of CDK6 restricts ciliary polycystin abundance by suppressing axonemal polyglutamylation. However, whether CDK6 inhibition can restore polycystin function and suppress ADPKD progression in vivo remains unknown. Methods: Abemaciclib was tested in in vitro 3D cyst assays and ex vivo metanephric organ cultures. In vivo efficacy of early- and late-stage intervention were assessed in F1(129/B6) Pkd1 R3277C/R3277C mice receiving daily abemaciclib. Tolvaptan served as a therapeutic control. Cyst burden, fibrosis in the kidneys, kidney function, and primary cilia of renal epithelial cells were analyzed at study endpoints. Results: CDK6 was prominently upregulated in cyst-lining cells in human and murine PKD kidneys. At doses substantially lower than those used in oncology, abemaciclib robustly suppressed cyst growth in vitro and ex vivo . In vivo , long-term early treatment arrested cyst progression more effectively than tolvaptan without detectable toxicity. Late intervention largely halted cyst growth in females and reversed cyst progression in males. Mechanistically, abemaciclib restored axonemal polyglutamylation and increased ciliary polycystin levels. Conclusions: Abemaciclib has greater therapeutic efficacy and tolerability than tolvaptan in this preclinical model, largely driven by CDK6 inhibition–mediated restoration of axonemal polyglutamylation and increased ciliary polycystin abundance.