Citations

Abstract Translational large-animal models that can accommodate human-scale implantable devices are essential for advancing neuromodulation therapies in epilepsy. This study establishes a kainic acid (KA)-induced porcine model of mesial temporal lobe epilepsy (mTLE) using clinical imaging, stereotactic surgery, and a fully implantable neural stimulation and recording (INSR) device designed for humans. Seven pigs (six KA-treated and one saline control) underwent MRI-guided stereotactic implantation of electrodes targeting bilateral hippocampus (HPC) and anterior thalamus (ANT), followed by intra-hippocampal KA or saline infusion. Local field potentials (LFP) were recorded continuously with synchronized video monitoring. Seizures and LFP interictal epileptiform-like discharges (IEDs) were quantified using validated automated detectors. Histology was performed in the saline control and the longest surviving KA-treated pig. Intra-hippocampal KA infusion induced acute status epilepticus in all (6/6) treated pigs. Four animals survived to chronic monitoring with spontaneous seizures observed in three pigs (2,733 seizures; mean duration of 27.2 ± 17.6 seconds). IEDs were observed in bilateral HPC of all animals, including saline control, with higher rates in the lesioned HPC (p <0.0001). While the IED morphology is consistent with epileptiform activity; IEDs alone are not specific for epilepsy and physiological transients (e.g. sharp-wave ripples) and injury-related hyperexcitability or strain-specific hyperexcitability cannot be excluded. Histological analysis revealed patchy neuronal loss and cytoarchitectural changes in HPC. This porcine model reproduces electrophysiological features of human mTLE. This approach provides a powerful translational bridge for developing and testing next-generation INSR and neuromodulation strategies in freely behaving large animals.

Abstract The largest risk factor for dementia is age. Heterochronic blood exchange studies have uncovered age-related blood factors that demonstrate ‘pro-aging’ or ‘pro-youthful’ effects on the mouse brain. The clinical relevance and combined effects of these factors for humans is unclear. We examined five previously identified brain rejuvenation factors in cerebrospinal fluid of adults with autosomal dominant forms of frontotemporal dementia and sporadic Alzheimer’s disease. Our frontotemporal dementia cohort included 100 observationally followed adults carrying autosomal dominant frontotemporal dementia mutations (Mage = 49.6; 50% female; 43% C9orf72, 24% GRN, 33% MAPT) and 62 non-carriers (Mage = 52.6; 45% female) with cerebrospinal fluid analysed on Somascan, and longitudinal (Mvisits = 3 years, range 1–7 years) neuropsychological and functional assessments and plasma neurofilament light chain. Our Alzheimer’s disease cohort included 35 adults with sporadic Alzheimer’s disease (Mage = 69.4; 60% female) and 56 controls (Mage = 68.8, 50% female) who completed the same cerebrospinal fluid and clinical outcome measures cross-sectionally. Levels of C-C motif chemokine ligand 11, C-C motif chemokine ligand 2, beta-2-micorglobulin, bone gamma-carboxyglutamate protein (aka Osteocalcin) and colony stimulating factor 2 in cerebrospinal fluid were linearly combined into a composite score, with higher values reflecting ‘pro-youthful’ levels. In genetic frontotemporal dementia, higher baseline cerebrospinal fluid rejuvenation proteins predicted slower decline across cognitive, functional, and neurofilament light chain trajectories; estimates were similar across genotypes. In transdiagnostic analyses, higher cerebrospinal fluid rejuvenation proteins associated with better functional, cognitive, and neurofilament light chain outcomes in adults with sporadic Alzheimer’s disease. Proteins with pre-clinical evidence for brain rejuvenation show translational clinical relevance in adults with Alzheimer’s disease and related dementias and warrant further investigation.

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.

Introduction. Non-cystic fibrosis bronchiectasis is a complex medical condition with multiple etiologies, characterized by chronic productive cough and radiologic evidence of airway lumen dilation and wall thickening. Associated exacerbations and declining lung function contribute to increasing disability and mortality. There are no data about the prevalence of non-cystic fibrosis bronchiectasis etiologies in the Colombian population.Objective. To investigate non-cystic fibrosis bronchiectasis etiology and clinical characteristics in adults evaluated in the southwest of Colombia.Materials and methods. We conducted a cross-sectional, non-interventional study. Subjects diagnosed with non-cystic fibrosis bronchiectasis were referred to by theirhealthcare providers and then enrolled between October 2018 and April 2021. Medical records and radiological studies were evaluated. Participants underwent laboratory tests, including complete blood count, serum immunoglobulin levels, and, in some cases, additional tests.Results. We included 161 subjects. The average age was 50 years old, and 59% were females. Bronchiectasis etiology was identified in 84.6% of the cases. Postinfectious(34.6%) and immune disorders (25.3%), represented by autoimmunity (13.6%) and immunodeficiency (11.7%), were the leading causes. Gender differences were noted in autoimmune (females: 18.8% versus males: 6.1%, p = 0.021) and immunodeficiency-related bronchiectasis (males: 21.2% versus females 5.2%, p = 0.002). Immunodeficiencies-associated bronchiectases were more frequent in subjects under 50 years of age, while chronic obstructive pulmonary disease-associated bronchiectases were common in subjects over 50 years of age.Discussion. The etiologies of non-cystic fibrosis bronchiectasis in Colombia are diverse, exhibiting notable differences from other global regions. Serum immunoglobulin levels and clinical immunologist consultation should be prioritized in diagnosing patients with unclear bronchiectasis etiology, particularly those with recurrent sinopulmonary infections.

AbstractBackgroundHarmonization of the two most commonly used Tau PET tracers, 18F‐Flortaucipir and 18F‐MK6240 has proven to be complex. Unlike the centiloid scale for amyloid tracers, Tau PET SUVRs of the two tracers are not linearly comparable and vary markedly in dynamic range and sensitivity.MethodTau PET SUVRs for Braak stage (1‐6) in 18F‐MK6240 and 18F‐Flortaucipir were obtained from the Longitudinal multicenter head‐to‐head harmonization of tau‐PET tracers (HEAD) project. For training, we used 13 amyloid confirmed AD, 24 amyloid confirmed MCI and 66 amyloid negative controls. To assess linearity and correlations with neuropsychological tests, we included the training data as well as 74 subjects of unknown or inconsistent amyloid status. Two methods of generating outcome measures were used. (1) As a stand‐in for Tau load, similar to the centiloid scale, a score of 100, 50 or 0 was given to participants of the training set by multiplying CDR score by 100. Hierarchical and ridge regression were performed for each tracer using PET‐Braak SUVRs as predictive variables. Regression coefficients were used to calculate an outcome measure for all participants. (2) Principal component analysis (PCA) was applied for each tracer to the vectors of PET‐Braak regional SUVR of the training subset. Projections along the principal axis were calculated for both modalitiesResultHierarchical, ridge regression and PCA all yielded composite measures with good linear dependence between the two tracers (r2 for hierarchical, ridge and PCA were 0.84, 0.80, 0.80, respectively). Regions remaining in the hierarchical regression analyses varied between tracers: predictive regions for 18F‐MK6240 were PET‐Braak 1, 4 and 5, while 18F‐Flortaucipir used only PET‐Braak 1 and 5. Composite measures correlated well with MMSE and total MOCA score with all composite measures r < ‐0.61.ConclusionWhile both tracers may have different sensitivities to regional Tau distributions and disease stages, weighting multiple regions differently for each tracer gives a composite score linearly comparable across tracers that correlates with neuropsychological measures. This study is limited by the low total tau load and impairment level of all participants and would benefit from the inclusion of patients with more disease progression.

AbstractBackgroundPatterns of regional atrophy and hypometabolism have been observed in dementia with Lewy bodies (DLB). However, determinants of regional vulnerability to structural and functional neurodegeneration remain largely unexplored. First, we investigated the association between regional gene expression and grey matter volumes in probable DLB patients. Since hypometabolism presumably precedes overt brain atrophy, we additionally investigate the association between regional gene expression and hypometabolism in DLB.MethodTo investigate the association between gene expression and regional volumes, 165 DLB patients along with 165 age‐ and sex‐matched healthy controls from three European centres and the Mayo Clinic (USA) were included. Regional volumes were quantified from MRI using SPM12 in 112 cortical, subcortical, and cerebellar brain regions, and compared between groups, using w‐scores. Regional expression data of seven genes involved in the formation and degradation of pathological protein aggregates (APOE, APP, BIN1, GBA, MAPT, SNCA, TMEM175) was extracted from six healthy donors from the Allen Human Brain Atlas and correlated with regional volumetric w‐scores. To assess the predictive value of regional gene expression on regional volumes we used Gaussian stepwise backwards linear regression including all seven genes as predictors. To investigate the association between gene expression and hypometabolism, we are currently applying the same analysis pipeline to FDG‐PET data of 139 DLB patients from 8 European centres.ResultMost brain regions showed lower volumes in DLB patients compared to healthy controls, with differences being most pronounced in occipital and parietal lobes. Regional expression of APOE correlated positively with regional volumes in DLB. Conversely, regional expression of MAPT correlated negatively with regional volumes. Both APOE and MAPT gene expression were significant predictors of regional volumes in the regression analysis. None of the other gene expression values was significantly associated with regional volumes in DLB.ConclusionOur findings show that regional expression of genes associated with the abnormal accumulation of amyloid and tau, common co‐pathologies in DLB, partially account for the brain atrophy pattern observed in DLB patients. Analyses are ongoing for the hypometabolism pattern. Our finding emphasises the relevance of co‐pathologies in predicting atrophy progression and identifying potential targets for future disease‐modifying treatments.

Abstract Purpose Medical student education in geriatrics is a critical need for every doctor-in-training as the population ages, with fewer than 7,000 geriatricians, and older patients, who now approach 20% of the U.S. population, having unique health care needs. This study presents the updated competencies in geriatrics for graduating medical students, framed by the Geriatrics 5Ms (Mind, Mobility, Medications, Multicomplexity, and What Matters Most). Method From 2019–2022, a working group of the American Geriatrics Society (AGS) drafted the updated medical student geriatrics education competencies, using a modified Delphi approach. The working group reviewed the literature, conducted an initial survey of working group members, and drafted and refined proposed updates to the competencies. The 27 resulting competencies were disseminated as a national survey to geriatrics experts and medical school education deans. Following the national survey, the competencies were updated and presented at the 2021 AGS Annual Scientific Meeting and open to public comment before they were finalized. Results The 27 updated geriatrics competencies for medical students included several new competencies, such as a focus on health equity, frailty, deprescribing, and patient priorities. A total of 211 respondents completed the national survey, including geriatrics experts (187/398, response rate: 47.0%) and education deans (24/191, response rate: 12.6%). All 27 proposed competencies met the predetermined threshold of 70% cumulative agreement, with a range of 93.0% (174/187) to 100% (187/187) among geriatrics experts and 87.5% (21/24) to 100% (24/24) among education deans. Conclusions The updated Geriatrics Competencies for Graduating Medical Students met with broad agreement among the geriatrics experts and medical school education deans who responded to the national survey. By focusing on the Geriatrics 5Ms, the competencies highlight key knowledge and skills graduating medical students need for the first day of internship to be prepared to deliver age-friendly care to older adults under their care.