Citations

Introduction This was the first phase 1 study conducted in the United States. It consisted of dose-escalation (part A) and multiple indication-specific cohort expansion (part B), investigating the safety and preliminary efficacy of toripalimab (anti–programmed cell death-1 inhibitor) in patients with advanced malignancies. Methods Patients with advanced malignancies that progressed after treatment with at least one prior line of standard systemic therapy, including the patients with advanced/recurrent cholangiocarcinoma (CCA), received toripalimab 240 mg every 3 weeks in part B. The primary endpoint was safety assessment. Efficacy endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR), progression-free survival (PFS) as assessed by the investigators according to Response Evaluation Criteria in Solid Tumors (version 1.1) and overall survival (OS). Results In part B, 166 patients, including the 42 patients with CCA, were enrolled and received toripalimab. Among the 166 patients, treatment-emergent adverse events (TEAEs) of any grade occurred in 158 (95.2%) patients, and 97 (58.4%) patients experienced TEAEs of Grade 3 or greater. The most common TEAE was fatigue (42.2%). Seven (4.2%) patients experienced TEAEs with a fatal outcome, none of which were identified by investigators as related to toripalimab. Investigator-assessed immune-related adverse events (irAE) of Grade 3 or higher occurred in 7 (4.2%) patients. In the CCA cohort, with the median follow-up of 4.4 months, the ORR and DCR were 4.8% (95% CI: 0.58, 16.16) and 40.5% (95% CI: 25.63, 56.72), respectively; median DoR was 7.8 (range 4.4+ to 7.8) months; median PFS was 2.1 (95% CI: 1.91, 3.88) months; median OS was not estimable. Conclusions Toripalimab had manageable side effects in patients with refractory cholangiocarcinoma and exhibited preliminary evidence of anti-tumor activity. However, further information regarding biomarkers is needed. ClinicalTrials.gov ID: NCT03474640

Importance There is a lack of long-term efficacy and safety data on hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) and on RNA interference (RNAi) therapeutics in general. This study presents the longest-term data to date on patisiran for hATTR-PN. Objective To present the long-term efficacy and safety of patisiran in adults with hATTR-PN. Design, Setting, and Participants This global open-label extension (OLE) of the APOLLO randomized clinical trial and phase 2 OLE study enrolled patients from 43 hospitals or clinical centers across 19 countries between July 2015 and August 2017, with follow-up until November 2022. Of 212 eligible patients with hATTR who completed the phase 3 APOLLO or phase 2 OLE parent studies, 211 enrolled in and 138 completed the global OLE. Intervention Patisiran, 0.3 mg/kg, intravenously once every 3 weeks for up to 5 years. Main Outcomes and Measures Outcomes evaluated at year 5 of the global OLE included disability (polyneuropathy disability [PND] score); polyneuropathy severity (Neuropathy Impairment Score [NIS]), nutritional status (modified body mass index [mBMI]), quality of life (Norfolk Quality of Life–Diabetic Neuropathy [Norfolk QOL-DN]), and Rasch-Built Overall Disability Scale (R-ODS), with no statistical hierarchy. Safety, survival probability, and mortality were also assessed. Results At the global OLE baseline, the mean (SD) age was 61.3 (12.3) years, and 156 patients (73.9%) were male. In 138 patients completing the study, PND scores remained stable or improved in 89 patients (65.0%), NISs showed a mean (SD) change of 10.9 (14.7), and mean (SD) mBMI (calculated as weight in kilograms divided by height in meters squared times serum albumin in grams per liter) increased by 46.4 (120.7) over 5 years from baseline. Norfolk QOL-DN and R-ODS scores showed mean (SD) changes of 4.1 (16.7) and –3.7 (6.2), respectively. Adverse events (AEs) leading to study withdrawal occurred in 47 patients (22.3%). Infusion-related reactions were the most common treatment-related AE (n = 34 [16.1%]). Overall, 41 patients (19.4%) died during the study. Patisiran treatment in the parent study and low familial amyloid polyneuropathy score at parent study baseline were associated with significantly improved survival. Conclusions and Relevance In the longest study of an RNAi therapeutic for any disease, patisiran treatment resulted in modest changes for patients with hATTR-PN with an acceptable safety profile. These results highlight the importance of initiating early treatment for hATTR and the potential of RNAi therapeutics in medicine. Trial Registration ClinicalTrials.gov Identifier: NCT02510261

Abstract There are ~100 genes or copy number variants (CNVs) used in genetic testing for Autism Spectrum Disorder (ASD, or autism). These genes are protein-coding, and the associated phenotypes often extend beyond socio-behavioral traits seen in autism including cognitive/medical complexities, epilepsy, and ADHD. Here, we characterize 27 males with ASD through whole genome sequencing (WGS), delineating X-chromosome microdeletions that implicate the long non-coding RNA (lncRNA) PTCHD1-AS as an ASD-susceptibility gene (OR=2.56, p=0.01). Two Ptchd1-as knockout (KO) murine models, created by removing the evolutionarily conserved exon-3, show ASD-like features in males, increasing repetitive behaviors and impairing typical social behavior and communication without overt cognitive comorbidities or ADHD-like behaviors. Hippocampus-dependent synaptic function, complex learning, and locomotor activity are unaffected in KO mice. Native nuclear-enriched mouse Ptchd1-as showed sustained expression from post-natal day-7 onward in the dorsal striatum, a predominantly GABAergic brain region implicated in ASD. Multi-omics revealed transcriptomic alterations in striatal oligodendrocyte, astrocyte and neurons impacting myelination and plasticity pathways. Disrupting Ptchd1-as led to reductions in conventional Protein Kinase-C, altered Src and GSK3α/β phosphorylation, and an enhancement of synaptic plasticity (long-term potentiation and long-term depression). Together, these findings implicate striatal molecular and circuit level dysregulation via Ptchd1-as in ASD etiology.

AbstractBackgroundSAAs represent a promising biomarker of Lewy Body disease (LBD), with high sensitivity (87.3%, 95%CI: 0.755‐0.947) and specificity (97.2%, 95%CI: 0.922‐0.994) for detection of patients in the Parkinson’s Progression Markers Initiative repository with positive DaT SPECT; and reasonable sensitivity (78.7%, 95%CI: 0.66‐0.88) and specificity (89.5%, 95%CI: 0.78‐0.96 referencing clinical diagnoses in participants included within national research repositories. However, test performance in heterogeneous clinical cohorts is unknown.MethodPatients with typical (n=122) and rapid progressive dementia (n=76) consented to banking of CSF at the time of clinically‐indicated diagnostic lumbar puncture. Clinical data were deidentified and uploaded to a secure research database and clinical (etiologic) diagnoses established by two neurologists following independent review of available records. SAA (SYNTap™) were run on stored CSF by Amprion Diagnostics (San Diego, CA).ResultMedian participant age was 69.1 years (18.4‐86.1); 56.3% were female. CSF was sampled median 1.4 years (0‐10.3) after symptom onset. Pathological alpha‐synuclein was detected in 28/122 patients with typically progressive dementia (including 6/18 patients with presumed LBD; sensitivity 33%, specificity 79%) and 11/76 patients with rapid progressive dementia (including 3/9 patients with presumed LBD; sensitivity 33%, specificity 88%). “Positive” SAA was associated with tremor (OR=3.2, 95%CI: 1.3‐7.8), visual hallucinations (OR=6.14, 95%CI 1.6‐23.6), and REM behavior disorder (OR=3.7, 95%CI: 1.4‐9.5) in patients with typical but not rapid progressive dementia. Brain autopsies were completed in 17 patients: Lewy bodies were detected in 2/3 patients with positive SAA and no patients with negative SAA.Conclusion“Positive” SAA demonstrated reasonable specificity but low sensitivity for the diagnosis of LBD. Additional studies in heterogeneous cohorts with neuropathologic data are needed to optimize clinical applications of SAA.

AbstractBackgroundAlzheimer disease (AD) related cognitive decline occurs at relatively young ages in individuals with Down syndrome (DS, early‐mid 50s) and in those with autosomal dominant mutations (ADAD, 40‐50s). Both groups show similar patterns of amyloid accumulation. We examined if brain volumes are similarly affected by AD pathology in individuals with DS and ADAD.MethodData for cognitively stable and declining participants was obtained from the Alzheimer Biomarker Consortium‐Down Syndrome (ABC‐DS) and the Dominantly Inherited Alzheimer Network (DIAN). Stability/decline was identified based on cognitive testing and interview of individuals and caregivers by trained assessors. Cognitively stable family members without DS/ADAD mutations were recruited as controls from both studies. Participants underwent MRI and amyloid positron emission tomography (PET) scans from which brain volumes and amyloid (centiloids) were derived, respectively. Participants from DIAN had Pittsburgh Compound‐B (PIB) scans, ABC‐DS had PIB or florbetapir. Nonlinear cross‐sectional associations between regional brain volumes and estimated years to onset of cognitive decline (EYO, negative values before onset, positive after) and centiloid were evaluated using generalized additive models while controlling for sex and random effects of family. EYO was set to 52 for all participants with DS and based on parental decline/mutation type for participants with ADAD. EYO for controls was based on the EYO of their family member.ResultData from 239 participants with DS (47 declining), and 340 participants with ADAD (122 declining), and 263 familial controls were included. Higher EYO and centiloid values were associated with lower brain volumes in almost all regions. At earlier EYOs, individuals with DS typically had smaller regional volumes than ADAD or sibling controls, with volume declining linearly across the EYO range. By contrast, ADAD mutation carriers had similar volumes to non‐carriers at early EYOs, with volumes diverging as early as 10 years before decline. Brain volumes and centiloid values were inversely related in ADAD and DSAD. Volume in key cortical regions were similar by the expected year of onset in both groups.ConclusionADAD and DSAD demonstrated different temporal patterns of regional neurodegeneration prior to cognitive change despite being similarly affected by early onset amyloid.

AbstractBackgroundThe prevalence of dementia in populations that are underrepresented in research is projected to increase with population aging. Latino and Black individuals, the largest underrepresented populations in the US, experience a higher dementia burden than non‐Hispanic White individuals, which is not explained by ethnoracial biological factors. Disparities in structural and social determinants of health may contribute to the preponderance of medical conditions known to increase dementia risk, including potentially modifiable factors in Latino and Black communities. To assess the scope of this problem, we measured the frequency of common modifiable dementia risk factors in community‐dwelling, cognitively normal, Latino and Black adults.MethodCognitively normal community‐dwelling Latino and Black adults, ≥45‐years‐old, were enrolled within our longitudinal study of memory and aging at Mayo Clinic in Florida (Jacksonville, FL) and completed a baseline assessment between 3/2022 and 10/2023. Demographics, and self‐reported race/ethnicity and history of dementia risk factors were recorded. Dementia risk factors were objectively sampled through clinical interview (depression: Geriatric Depression Scale ≥5), examination (hypertension: BP >130/80 mmHg; obesity: BMI≥30), and serum analyses (hyperlipidemia: total cholesterol<200mg/dL, HDL>50mg/dL, LDL<100mg/dL, Triglycerides<150mg/dL; diabetes: HbA1C >5.6%, vitamin B12 deficiency: <350 ng/dL).Result86 participants (43 Latino, 43 Black), 65.8 (8.8) years‐old, female (62.8%), with 16 (2.4) years of education were assessed. Dementia risk factors were frequent in Latino and Black participants, including hypertension (63%, 90%; p = 0.005), hyperlipidemia (93%, 89%; p = 0.702), obesity (33%, 44%; p = 0.370), diabetes (60%, 47%; p = 0.370), vitamin B12 deficiency (21%, 21%; p = 0.989), and depression (5%, 24%; p = 0.781). These risk factors were unrecognized or suboptimally managed in a substantial proportion of Latino and Black participants: hypertension (56%, 73%; p = 0.170), hyperlipidemia (80%, 73%; p = 0.591), diabetes (57%, 47%; p = 0.502), vitamin B12 deficiency (21%, 21%; p = 0.789), and depression (5%, 3%; p>0.99).ConclusionPotentially modifiable dementia risk factors were detected in the majority of community‐dwelling Latino and Black cognitively normal older‐adults and were frequently unrecognized or suboptimally managed. Proactive screening for known dementia risk factors may provide opportunities for targeted interventions to improve brain health and decrease dementia disparities in underrepresented populations.

AbstractBackgroundEffect and Safety of Electroconvulsive Therapy plus Usual Care for the Acute Management of Severe Agitation in Dementia (ECT‐AD) is a multi‐site NIA‐funded FDA‐regulated pioneering clinical trial to investigate the effectiveness of electroconvulsive therapy (ECT) in treating severe and treatment‐refractory agitation and aggression among individuals with advanced dementia, a condition that has a profound negative impact on patient quality of life and caregiver burden. Here we present baseline demographics of the patient population in this ongoing trial.MethodTo date we have enrolled 18 participants, with a mean age of 74.1 years, where majority are male (61.1%). The racial composition is predominantly White (94.4%), with Asian representation (5.6%, 1/18), and with 11.1% (2/18) identifying as Hispanic or Latino. Dementia subtypes in our cohort include Alzheimer’s disease (AD, 77.8%), vascular dementia (VaD, 16.7%, 3/18), and frontotemporal dementia (FTD, 5.6%, 1/18).ResultBaseline assessments reveal severe cognitive and functional impairment, as indicated by a mean Mini‐Mental State Examination (MMSE) score of 4.0, Barthel Index (BI) score of 52.2, and SIB‐8 score of 2.9, all consistent with advanced stages of dementia. High mean total scores on the Cohen‐Mansfield Agitation Inventory (CMAI, 75.8), Neuropsychiatric Inventory (NPI) agitation (15.1) and aggression (9.2) scales, and Pittsburgh Agitation Scale (PAS, 7.8), reflect the severe levels of agitation and aggression in our participants.ConclusionThese baseline demographic and clinical data underscore the profound impact of advanced dementia, highlighting the need for innovative treatment approaches like ECT. The ECT‐AD trial offers a critical step towards understanding and improving the management of agitation in dementia, with implications that could enhance current clinical care practices.

Abstract As the healthcare burden caused by an increasingly aging population rapidly rises, a pressing need exists for innovative geroscience research that can elucidate aging mechanisms and precipitate the development of therapeutic interventions to support healthy aging. The Fifth Annual Midwest Aging Consortium Aging Research symposium, held from April 28 to 30, 2024, was hosted by The Ohio State University in Columbus, Ohio, and featured presentations from investigators across the Midwestern United States. This report summarizes the research presented at the symposium, whose topics included cellular senescence and the aging brain, metabolism and metabolic interventions, nutrition, redox mechanisms and biomarkers, and stress mechanisms. Abstract presentations and short talks highlighted early-stage and young investigators, whereas 2 keynote presentations anchored the symposium. Overall, this symposium showed the robustness of aging research in the Midwest and underscored the advantages of a collaborative approach to geroscience research.

Background The prevalence and impact of right ventricular dysfunction (RVD) in degenerative mitral regurgitation (DMR) is unknown. We aimed to determine whether RVD assessed by echocardiography in routine clinical practice is independently associated with mortality in patients with DMR. Methods and Results We used data from the MIDA‐Q (Mitral Regurgitation International DAtabase‐Quantitative) registry, which included patients with isolated DMR due to mitral valve prolapse from January 2003 to January 2020 from 5 tertiary centers across North America, Europe, and the Middle East. A cohort of 2917 (mean age: 66 years, 70.8% male patients, follow‐up: 5.2 [3.3–8.3] years) consecutive patients with severe DMR was included and long‐term mortality was analyzed. RVD, identified in 426 (14.6%) patients, was associated with reduced 8‐year survival (55%±3% versus 77%±1%; P <0.001), overall and in all subgroups of patients, even after comprehensive adjustment including left ventricular dilatation and dysfunction, DMR severity, pulmonary pressures, and surgery (adjusted hazard ratio, 1.44 [95% CI, 1.17–1.77]; P <0.001). This excess mortality was observed under medical management (adjusted hazard ratio, 1.57 [95% CI, 1.20–2.05]; P =0.001) and after surgical correction of mitral regurgitation (adjusted hazard ratio, 1.45 [95% CI, 1.02–2.05]; P =0.039). Patients with RVD undergoing surgery within 3 months of diagnosis experienced a better 8‐year survival (73%±4% versus 43%±4%; P <0.001), even after adjustment (adjusted hazard ratio, 0.44 [95% CI, 0.29–0.67]; P <0.001) despite an increase of 1‐month postoperative mortality (7.1% versus 0.5% for patients without RVD; P <0.001). Conclusions RVD is observed in 14.6% of severe DMR and exhibits a powerful and independent association with excess mortality partially attenuated by mitral surgery. Therefore, assessment of right ventricular systolic function should be included in routine DMR evaluation and in the clinical decision‐making process.