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Objectives: Patients with mild cognitive impairment (MCI) employ compensatory cognitive processes to maintain independence in day-to-day functioning as compared to patients with Alzheimer’s dementia (AD). The dorsolateral prefrontal cortex (DLFPC) supports cognitive compensation in normal aging and MCI. Using Paired Associative Stimulation combined with Electroencephalography (PAS-EEG) we have previously shown that patients with AD have impaired DLPFC plasticity compared to healthy control (HC) individuals. The aim of this study is to examine whether DLPFC plasticity in individuals with MCI is preserved compared to those with AD and HC, serving as a potential mechanism underlying cognitive compensation in MCI.
Methods: We analyzed a combined cross-sectional data of 47 AD, 16 MCI, and 40 HC participants from three different studies that assessed their DLPFC plasticity using PAS-EEG. PAS-EEG assesses DLPFC plasticity via the induction of Long Term Potentiation (LTP)-like activity, thereby referred to as PAS-LTP. Using multiple regression, we compared PAS-LTP in MCI to PAS-LTP in AD and HCs, after adjusting for age andgender.
Results: Among the 47 participants with AD (mean [SD] age = 75.3 [7] years), 29 were women and 18 were men; among the 16 participants with MCI (mean [SD] age = 74.8 [6] years), 11 were women and 5 were men; and among the 40 HCs (mean [SD] age = 76.4 [5.1] years), 22 were women and 18 were men. After adjusting for age and gender, there was an impact of diagnostic group on PAS-LTP [F (2,95) = 4.19, p = 0.018, between-group comparison η2 = 0.81]. Post-hoc comparisons showed that participants with MCI had a higher PAS-LTP (mean [SD] = 1.31 [0.49]) than those with AD (mean [SD] = 1.09 [0.28]) (Bonferroni corrected p = 0.042) but not different from PAS-LTP in HCs (mean [SD] = 1.25 [0.33]) (Bonferroni corrected p = 1.0).
Conclusions: Our findings indicate that plasticity is preserved in the DLPFC among individuals with MCI, supporting the hypothesis that DLPFC plasticity contributes to cognitive compensation towards delaying progression to AD. Thus, further enhancement of longer preservation of DLPFC plasticity in individuals with MCI could further delay the onset of AD in this population.
Accelerating COVID-19 Treatment Interventions and Vaccines (ACTIV) was initiated by the US government to rapidly develop and test vaccines and therapeutics against COVID-19 in 2020. The ACTIV Therapeutics-Clinical Working Group selected ACTIV trial teams and clinical networks to expeditiously develop and launch master protocols based on therapeutic targets and patient populations. The suite of clinical trials was designed to collectively inform therapeutic care for COVID-19 outpatient, inpatient, and intensive care populations globally. In this report, we highlight challenges, strategies, and solutions around clinical protocol development and regulatory approval to document our experience and propose plans for future similar healthcare emergencies.
This manuscript addresses a critical topic: navigating complexities of conducting clinical trials during a pandemic. Central to this discussion is engaging communities to ensure diverse participation. The manuscript elucidates deliberate strategies employed to recruit minority communities with poor social drivers of health for participation in COVID-19 trials. The paper adopts a descriptive approach, eschewing analysis of data-driven efficacy of these efforts, and instead provides a comprehensive account of strategies utilized. The Accelerate COVID-19 Treatment Interventions and Vaccines (ACTIV) public–private partnership launched early in the COVID-19 pandemic to develop clinical trials to advance SARS-CoV-2 treatments. In this paper, ACTIV investigators share challenges in conducting research during an evolving pandemic and approaches selected to engage communities when traditional strategies were infeasible. Lessons from this experience include importance of community representatives’ involvement early in study design and implementation and integration of well-developed public outreach and communication strategies with trial launch. Centralization and coordination of outreach will allow for efficient use of resources and the sharing of best practices. Insights gleaned from the ACTIV program, as outlined in this paper, shed light on effective strategies for involving communities in treatment trials amidst rapidly evolving public health emergencies. This underscores critical importance of community engagement initiatives well in advance of the pandemic.
Deviant sexual interest for children (pedophilia, hebephilia) is associated with a higher risk of sexual offending against children (CSA) and consuming child sexual abuse images (CSAI). There is a general shortage of therapeutic programs for individuals who feel sexually attracted to juvenile bodies and are concerned about their sexual behaviour. Efforts to establish regional centres throughout Germany offering preventive support led to the prevention network “Don’t become an offender” (“Kein Täter werden”).
Objectives
To identify dynamic risk factors (DRFs) and evaluate a treatment programme aiming to reduce CSA and CSAI among potential or existing pedosexual offenders (who have not been legally charged). In addition, changes in the course of therapy are examined to provide information about the accessibility and motivation of the target group and its therapeutic responsiveness.
Methods
Participants undergo standardized diagnostic and treatment procedures. Therapy comprises an outpatient psychotherapy program (group therapy) over the course of approx. 48 weekly sessions, optional individual and partner/relative including sessions, as well as additional pharmaceutical treatment. Assessments are carried out through self- and other-reported psychometric test batteries pre-, during and post-treatment up to a 3.5 year follow-up. The test battery includes clinical questionnaires (WHO-5, CTQ-SF), personality questionnaires (ISK-K, NEO-FFI), sexuality questionnaires (EKK-R, KV-M, MSI, HBI-19) and risk assessment procedures (VRAG-R, STATIC-99, VRS:SO). Main outcome measures are self- and externally-reported DRF changes well as offending behaviour characteristics.
Results
By September 20, 2023, N=12 individuals were enrolled in the treatment program. All individuals had a deviant sexual preference (exclusive/non-exclusive pedo-/hebephilia). Nine individuals reported past and/or current use of CSAI. Of these, two individuals reported at least one CSA in the past. Three had no previous use of CSAI or CSA history.
In the first treatment group (N=6), preliminary results show reduction in dynamic risk factors (e.g., Cognitive Bias, Sexual Compulsivity, Impulsivity) after the first 12 weeks of treatment. The evaluation of additional clinical data is pending.
Conclusions
To date, therapy for individuals with pedophilia or hebephilia has been insufficient – particularly when not offending. Ongoing evaluation of the therapy program should provide further insight into responsiveness and therapeutic motivation of this target group. In particular, the impact of therapy on changing dynamic risk factors for CSA and CSAI remains to be examined.
Postmenopausal women have augmented pressure wave responses to low-intensity isometric handgrip exercise (IHG) due to an overactive metaboreflex (postexercise muscle ischaemia, PEMI), contributing to increased aortic systolic blood pressure (SBP). Menopause-associated endothelial dysfunction via arginine (ARG) and nitric oxide deficiency may contribute to exaggerated exercise SBP responses. L-Citrulline supplementation (CIT) is an ARG precursor that decreases SBP, pulse pressure (PP) and pressure wave responses to cold exposure in older adults. We investigated the effects of CIT on aortic SBP, PP, and pressure of forward (Pf) and backward (Pb) waves during IHG and PEMI in twenty-two postmenopausal women. Participants were randomised to CIT (10 g/d) or placebo (PL) for 4 weeks. Aortic haemodynamics were assessed via applanation tonometry at rest, 2 min of IHG at 30 % of maximal strength, and 3 min of PEMI. Responses were analysed as change (Δ) from rest to IHG and PEMI at 0 and 4 weeks. CIT attenuated ΔSBP (−9 ± 2 v. −1 ± 1 mmHg, P = 0·006), ΔPP (−5 ± 2 v. 0 ± 1 mmHg, P = 0·03), ΔPf (−6 ± 2 v. −1 ± 1 mmHg, P = 0·01) and ΔPb (−3 ± 1 v. 0 ± 1 mmHg, P = 0·02) responses to PEMI v. PL. The ΔPP during PEMI was correlated with ΔPf (r = 0·743, P < 0·001) and ΔPb (r = 0·724, P < 0·001). Citrulline supplementation attenuates the increase in aortic pulsatile load induced by muscle metaboreflex activation via reductions in forward and backward pressure wave amplitudes in postmenopausal women.
Neuropsychiatric symptoms (NPS) are common during the course of neurocognitive disorders. NPS have been previously reported in early and late stages of Alzheimer’s Disease. However, our understanding of NPS in high-risk states for dementia such as mild cognitive impairment (MCI) and major depressive disorder (MDD) is poor.
Objectives
To compare the frequency and factor structure of neuropsychiatric symptoms among individuals with Mild Cognitive Impairment (MCI), Major Depressive Disorder (MDD) in remission, and comorbid MCI and MDD (in remission) (MCI-D).
Methods
We used baseline data from the Prevention of Alzheimer’s Dementia with Cognitive Remediation Plus Transcranial Direct Current Stimulation in Mild Cognitive Impairment and Depression (PACt-MD) study, a multicenter trial across five academic sites in Toronto, Canada (clinical trial No. NCT0238667). We used ANOVA or χ2-test to compare frequency of NPS across groups. We used factor analysis of Neuropsychiatric Inventory Questionnaire (NPI-Q) items in the three groups.
Results
We included 374 participants with a mean age of 72.0 years (SD = 6.3). In the overall sample, at least one NPS was present in 64.2% participants, and 36.1 % had at least moderate severity NPS (36.1%). Depression (54%, χ2 < 0.001) and apathy (28.7%, χ2=0.002) were more prevalent in the MCI-D group as compared to MCI and MDD groups. In factor analysis, NPS grouped differently in MCI, MDD, and MCI-D groups. A “psychotic” subgroup emerged among MCI and MCI-D, but not in MDD. Night-time behaviors and disinhibition grouped differently across all three groups.
Conclusions
Prevalence of NPS seems higher in persons with MCI-D as compared to those with only MCI or MDD. The factor structure of NPS differed between MCI, MDD, and MCI-D groups. Future studies should investigate the association of NPS factors with cognition, function, and illness biomarkers.
Background: Saccade and pupil responses are potential neurodegenerative disease biomarkers due to overlap between oculomotor circuitry and disease-affected areas. Instruction-based tasks have previously been examined as biomarker sources, but are arduous for patients with limited cognitive abilities; additionally, few studies have evaluated multiple neurodegenerative pathologies concurrently. Methods: The Ontario Neurodegenerative Disease Research Initiative recruited individuals with Alzheimer’s disease (AD), mild cognitive impairment (MCI), amyotrophic lateral sclerosis (ALS), frontotemporal dementia, progressive supranuclear palsy, or Parkinson’s disease (PD). Patients (n=274, age 40-86) and healthy controls (n=101, age 55-86) viewed 10 minutes of frequently changing video clips without instruction while their eyes were tracked. We evaluated differences in saccade and pupil parameters (e.g. saccade frequency and amplitude, pupil size, responses to clip changes) between groups. Results: Preliminary data indicates low-level behavioural alterations in multiple disease cohorts: increased centre bias, lower overall saccade rate and reduced saccade amplitude. After clip changes, patient groups generally demonstrated lower saccade rate but higher microsaccade rate following clip change to varying degrees. Additionally, pupil responses were blunted (AD, MCI, ALS) or exaggerated (PD). Conclusions: This task may generate behavioural biomarkers even in cognitively impaired populations. Future work should explore the possible effects of factors such as medication and disease stage.
A theoretical and experimental framework for novel metamaterial with programmable damping properties is presented. This material system is able to switch between elastic-dominated and damping-dominated regimes with different overall stiffness under dynamic loading depending on the external stimulus. The unit cell combines an auxetic and a bellow-like layer separated by an interface through which the amount of media flow can be tuned depending on the lateral strain. A simplified analytical model is derived to analyse the programmable damping effect. The model is further extended with a fluid-dynamics approach to link the effective damping properties with geometrical parameters to aid with the practical design of the metamaterial. Afterward, experiments are conducted on a macroscopic level using laser-sintered unit cells to validate the functionality of the concept both with air and water as media within the unit cells. To conclude the work, initial results on microscopic-level unit cells fabricated by two-photon lithography are introduced to showcase the scalability of the concept. This work provides an experimentally validated theoretical framework for future investigations to design unit cells with programmable damping on different length scales for applications requiring tailored dynamic energy dissipation.
This article positions braille as a writing system worthy of study in its own right and on its own terms. We begin with a discussion of the role of braille in the lives of those who read and write it and a call for more attention to braille in the reading sciences. We then give an overview of the history and development of braille, focusing on its formal characteristics as a writing system, in order to acquaint sighted print readers with the basics of braille and to spark further interest among reading researchers. We then explore how print-centric assumptions and sight-centric motivations have potentially negative consequences, not only for braille users but also for the types of questions researchers think to pursue. We conclude with recommendations for conducting responsible and informed research about braille. We affirm that blindness is most equitably understood as but one of the many diverse ways humans experience the world. Researching braille literacy from an equity and diversity perspective provides positive, fruitful insights into perception and cognition, contributes to the typologically oriented work on the world’s writing systems, and contributes to equity by centering the perspectives and literacy of the people who read and write braille.
This systematic literature review aimed to provide an overview of the characteristics and methods used in studies applying the disability-adjusted life years (DALY) concept for infectious diseases within European Union (EU)/European Economic Area (EEA)/European Free Trade Association (EFTA) countries and the United Kingdom. Electronic databases and grey literature were searched for articles reporting the assessment of DALY and its components. We considered studies in which researchers performed DALY calculations using primary epidemiological data input sources. We screened 3053 studies of which 2948 were excluded and 105 studies met our inclusion criteria. Of these studies, 22 were multi-country and 83 were single-country studies, of which 46 were from the Netherlands. Food- and water-borne diseases were the most frequently studied infectious diseases. Between 2015 and 2022, the number of burden of infectious disease studies was 1.6 times higher compared to that published between 2000 and 2014. Almost all studies (97%) estimated DALYs based on the incidence- and pathogen-based approach and without social weighting functions; however, there was less methodological consensus with regards to the disability weights and life tables that were applied. The number of burden of infectious disease studies undertaken across Europe has increased over time. Development and use of guidelines will promote performing burden of infectious disease studies and facilitate comparability of the results.
Societal concern for animals under human care has influenced our approaches to advance animal welfare in a variety of contexts. The Animal Programs Department at the Columbus Zoo and Aquarium sought partnership with the Center for Human-Animal Interactions Research & Education (CHAIRE) at The Ohio State University to develop a holistic welfare approach for the animals within their department using a focal species, the cheetah (Acinonyx jubatus). A one-year project using the Five Domains Animal Welfare Model collected data over six 60-day periods to evaluate long-term cortisol production and behavioural observations of cheetahs under changing environmental factors. Species and individual histories were incorporated with behavioural observations and hair cortisol production, giving a holistic view of welfare. Cortisol and behavioural data were analysed using linear models to compare cheetahs at population and individual levels. Participation in a cheetah run activity, housing occupancy, and 60-day period were found to influence all behaviours within the population and stereotypic behaviour also differed within individual cheetahs. No differences in hair cortisol concentrations were found for the group, but further analysis revealed differences within individuals throughout the study. No correlation of stereotypic behaviour and cortisol levels were found. This study created a welfare assessment protocol that can be used within zoological institutes and was the first to measure cortisol concentrations in hair in cheetahs.
Seabirds are highly threatened, including by fisheries bycatch. Accurate understanding of offshore distribution of seabirds is crucial to address this threat. Tracking technologies revolutionised insights into seabird distributions but tracking data may contain a variety of biases. We tracked two threatened seabirds (Salvin’s Albatross Thalassarche salvini n = 60 and Black Petrel Procellaria parkinsoni n = 46) from their breeding colonies in Aotearoa (New Zealand) to their non-breeding grounds in South America, including Peru, while simultaneously completing seven surveys in Peruvian waters. We then used species distribution models to predict occurrence and distribution using either data source alone, and both data sources combined. Results showed seasonal differences between estimates of occurrence and distribution when using data sources independently. Combining data resulted in more balanced insights into occurrence and distributions, and reduced uncertainty. Most notably, both species were predicted to occur in Peruvian waters during all four annual quarters: the northern Humboldt upwelling system for Salvin’s Albatross and northern continental shelf waters for Black Petrels. Our results highlighted that relying on a single data source may introduce biases into distribution estimates. Our tracking data might have contained ontological and/or colony-related biases (e.g. only breeding adults from one colony were tracked), while our survey data might have contained spatiotemporal biases (e.g. surveys were limited to waters <200 nm from the coast). We recommend combining data sources wherever possible to refine predictions of species distributions, which ultimately will improve fisheries bycatch management through better spatiotemporal understanding of risks.
Mental health and psychosocial support (MHPSS) staff in humanitarian settings have limited access to clinical supervision and are at high risk of experiencing burnout. We previously piloted an online, peer-supervision program for MHPSS professionals working with displaced Rohingya (Bangladesh) and Syrian (Turkey and Northwest Syria) communities. Pilot evaluations demonstrated that online, peer-supervision is feasible, low-cost, and acceptable to MHPSS practitioners in humanitarian settings.
Objectives
This project will determine the impact of online supervision on i) the wellbeing and burnout levels of local MHPSS practitioners, and ii) practitioner technical skills to improve beneficiary perceived service satisfaction, acceptability, and appropriateness.
Methods
MHPSS practitioners in two contexts (Bangladesh and Turkey/Northwest Syria) will participate in 90-minute group-based online supervision, fortnightly for six months. Sessions will be run on zoom and will be co-facilitated by MHPSS practitioners and in-country research assistants. A quasi-experimental multiple-baseline design will enable a quantitative comparison of practitioner and beneficiary outcomes between control periods (12-months) and the intervention. Outcomes to be assessed include the Kessler-6, Harvard Trauma Questionnaire and Copenhagen Burnout Inventory and Client Satisfaction Questionnaire-8.
Results
A total of 80 MHPSS practitioners will complete 24 monthly online assessments from May 2022. Concurrently, 1920 people receiving MHPSS services will be randomly selected for post-session interviews (24 per practitioner).
Conclusions
This study will determine the impact of an online, peer-supervision program for MHPSS practitioners in humanitarian settings. Results from the baseline assessments, pilot evaluation, and theory of change model will be presented.
Health services research (HSR) is affected by a widespread problem related to service terminology including non-commensurability (using different units of analysis for comparisons) and terminological unclarity due to ambiguity and vagueness of terms. The aim of this study was to identify the magnitude of the terminological bias in health and social services research and health economics by applying an international classification system.
Methods
This study, that was part of the PECUNIA project, followed an ontoterminology approach (disambiguation of technical and scientific terms using a taxonomy and a glossary of terms). A listing of 56 types of health and social services relevant for mental health was compiled from a systematic review of the literature and feedback provided by 29 experts in six European countries. The disambiguation of terms was performed using an ontology-based classification of services (Description and Evaluation of Services and DirectoriEs – DESDE), and its glossary of terms. The analysis focused on the commensurability and the clarity of definitions according to the reference classification system. Interrater reliability was analysed using κ.
Results
The disambiguation revealed that only 13 terms (23%) of the 56 services selected were accurate. Six terms (11%) were confusing as they did not correspond to services as defined in the reference classification system (non-commensurability bias), 27 (48%) did not include a clear definition of the target population for which the service was intended, and the definition of types of services was unclear in 59% of the terms: 15 were ambiguous and 11 vague. The κ analyses were significant for agreements in unit of analysis and assignment of DESDE codes and very high in definition of target population.
Conclusions
Service terminology is a source of systematic bias in health service research, and certainly in mental healthcare. The magnitude of the problem is substantial. This finding has major implications for the international comparability of resource use in health economics, quality and equality research. The approach presented in this paper contributes to minimise differentiation between services by taking into account key features such as target population, care setting, main activities and type and number of professionals among others. This approach also contributes to support financial incentives for effective health promotion and disease prevention. A detailed analysis of services in terms of cost measurement for economic evaluations reveals the necessity and usefulness of defining services using a coding system and taxonomical criteria rather than by ‘text-based descriptions’.
Replication is an important tool used to test and develop scientific theories. Areas of biomedical and psychological research have experienced a replication crisis, in which many published findings failed to replicate. Following this, many other scientific disciplines have been interested in the robustness of their own findings. This chapter examines replication in primate cognitive studies. First, it discusses the frequency and success of replication studies in primate cognition and explores the challenges researchers face when designing and interpreting replication studies across the wide range of research designs used across the field. Next, it discusses the type of research that can probe the robustness of published findings, especially when replication studies are difficult to perform. The chapter concludes with a discussion of different roles that replication can have in primate cognition research.
Background: Eye movements reveal neurodegenerative disease processes due to overlap between oculomotor circuitry and disease-affected areas. Characterizing oculomotor behaviour in context of cognitive function may enhance disease diagnosis and monitoring. We therefore aimed to quantify cognitive impairment in neurodegenerative disease using saccade behaviour and neuropsychology. Methods: The Ontario Neurodegenerative Disease Research Initiative recruited individuals with neurodegenerative disease: one of Alzheimer’s disease, mild cognitive impairment, amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson’s disease, or cerebrovascular disease. Patients (n=450, age 40-87) and healthy controls (n=149, age 42-87) completed a randomly interleaved pro- and anti-saccade task (IPAST) while their eyes were tracked. We explored the relationships of saccade parameters (e.g. task errors, reaction times) to one another and to cognitive domain-specific neuropsychological test scores (e.g. executive function, memory). Results: Task performance worsened with cognitive impairment across multiple diseases. Subsets of saccade parameters were interrelated and also differentially related to neuropsychology-based cognitive domain scores (e.g. antisaccade errors and reaction time associated with executive function). Conclusions: IPAST detects global cognitive impairment across neurodegenerative diseases. Subsets of parameters associate with one another, suggesting disparate underlying circuitry, and with different cognitive domains. This may have implications for use of IPAST as a cognitive screening tool in neurodegenerative disease.
Understanding edge-localised-mode (ELM)-free high-confinement (H-)mode scenarios is vital for developing practical future demonstration reactor scenarios. An argon-seeded EDA H-mode discharge performed in ASDEX Upgrade is computationally studied in detail for the first time with the gyrokinetic GENE code using experimental profiles and magnetic equilibrium as direct code inputs. Linear scans outline dominant instabilities in the regime and reveal distinct ion- and electron-scale wavenumber growth-rate peaks for two local core and two local pedestal top scenarios. Linear ion-scale growth rates are found to be relatively insensitive to the addition of argon, and collisionality scans demonstrate increased sensitivity in the pedestal top. The addition of an argon impurity profile while keeping the input main ion temperature gradient (ITG) largely unchanged is found to reduce ITG-driven turbulence in the outer core. Nonlinear electromagnetic simulations reveal close agreement with experimentally predicted heat fluxes in the core, outline key sensitivities to electron $\beta$ and background $\boldsymbol{E\times B}$ shearing, and reveal gyrokinetic challenges in analysing the quasicoherent mode. Global electrostatic nonlinear simulations reduce local simulated heat transport overpredictions at the pedestal top. A quasilinear analysis finds that there is good core agreement but poor agreement in the pedestal between linear and nonlinear temperature and density fluctuation cross-phases. Local simulation limitations are elucidated and paths forward for future computation are suggested.
The rapid spread of coronavirus disease 2019 (COVID-19) required swift preparation to protect healthcare personnel (HCP) and patients, especially considering shortages of personal protective equipment (PPE). Due to the lack of a pre-existing biocontainment unit, we needed to develop a novel approach to placing patients in isolation cohorts while working with the pre-existing physical space.
Objectives:
To prevent disease transmission to non–COVID-19 patients and HCP caring for COVID-19 patients, to optimize PPE usage, and to provide a comfortable and safe working environment.
Methods:
An interdisciplinary workgroup developed a combination of approaches to convert existing spaces into COVID-19 containment units with high-risk zones (HRZs). We developed standard workflow and visual management in conjunction with updated staff training and workflows. The infection prevention team created PPE standard practices for ease of use, conservation, and staff safety.
Results:
The interventions resulted in 1 possible case of patient-to-HCP transmission and zero cases of patient-to-patient transmission. PPE usage decreased with the HRZ model while maintaining a safe environment of care. Staff on the COVID-19 units were extremely satisfied with PPE availability (76.7%) and efforts to protect them from COVID-19 (72.7%). Moreover, 54.8% of HCP working in the COVID-19 unit agreed that PPE monitors played an essential role in staff safety.
Conclusions:
The HRZ model of containment unit is an effective method to prevent the spread of COVID-19 with several benefits. It is easily implemented and scaled to accommodate census changes. Our experience suggests that other institutions do not need to modify existing physical structures to create similarly protective spaces.
Combination of multiple neurodegenerative proteinopathies is frequent in the elderly. We report the case of an octogenarian who attempted suicide and deceased after hospital admission. Anatomical mapping was performed in several cortical and subcortical brain regions using antibodies against phospho-tau, 4R tau, 3R tau, phospho-TDP-43, ubiquitin, α-synuclein, Aβ and p62. Unexpectedly, histopathologic examination showed prominent subpial, subependymal, grey and white matter, and perivascular aging-related tau astrogliopathy (ARTAG) affecting cortical and subcortical brain regions. This pathology was associated with intermediate Alzheimer’s disease neuropathologic change, cerebral amyloid angiopathy, Lewy-body-type and astroglial synuclein proteinopathy and a multiple system TDP-43 proteinopathy involving also the astroglia. This unusual case of extensive and widespread ARTAG with a complex multiproteinopathy may represent an independent disease entity in the elderly with tau astrogliopathy as the leading force.
Learning Objective
Recognize astroglial protein deposits in neurodegeneration
ABSTRACT IMPACT: Melanoma leptomeningeal disease (LMD) is a devastating subtype of central nervous system (CNS) metastatic disease that is associated with limited treatment options and an extremely poor prognosis, thus requiring the development of preclinical models of LMD for therapeutic development. OBJECTIVES/GOALS:
1. Develop an immunocompetent murine model of melanoma LMD with tumors bearing genetic mutations commonly found in patients, specifically BRAF(V600E)/PTEN-/-
2. Assess the safety of intrathecal (IT) immunotherapy, specifically anti-PD1 antibody (aPD1)
3. Evaluate the therapeutic efficacy of IT aPD1 checkpoint blockade in murine melanoma LMD METHODS/STUDY POPULATION: To develop BRAF(V600E)/PTEN-/- LMD models, we acquired BP, D4M, and D4M-UV2 (irradiated) murine melanoma cell lines and luciferase-tagged them. 1.5x10^4 cells were suspended in 10 uL serum-free media and injected into the cisterna magna of female C57BL/6 mice. Brain and spinal cord were harvested for histologic assessment once mice were moribund. To assess safety of IT aPD1, we injected IT control IgG or IT aPD1 (13 ug, 26 ug, 39 ug) and monitored weights or harvested at days 7 or 14 for IHC staining of inflammation markers. To evaluate therapeutic efficacy of IT aPD1, BP cells were directly injected as above. After 3 days, mice underwent imaging to confirm tumor uptake and randomization to receive 13 ug IT control IgG or aPD1 once + 200 ug systemic (Sys) control IgG or aPD1 (days 0, 3, and 5), and then monitored for survival. RESULTS/ANTICIPATED RESULTS: For LMD development, all mice survived cisternal injection of BP, D4M, and D4M-UV2 cells and median survival was 17, 19, and 30 days, respectively. Presence of leptomeningeal deposits was confirmed for all tumor-bearing mice by IHC for MART1. For safety of IT aPD1, all mice survived the procedure and no mice displayed morbidity or >10% weight loss over 14 days of observation. IHC assessment of brain and spinal cord samples from mice treated with 13 ug aPD1 revealed focal ischemia related to injection site and no other signs of neurological damage or inflammation. IT aPD1 treatment of mice with BP leptomeningeal tumors demonstrated no significant survival advantage, although both IT aPD1 +/- Sys aPD1 had mice live up to days 29 and 26, respectively, compared to both IT control IgG +/- Sys aPD1, for which all mice died by day 22. DISCUSSION/SIGNIFICANCE OF FINDINGS: We demonstrate that cisternal injection of murine BRAF(V600E)/PTEN-/- melanoma cell lines yield LMD with reproducible survival and that treatment with IT aPD1 in this model is feasible and safe. Together these findings establish a new model to facilitate the development of more effective immunotherapy strategies for melanoma patients with LMD.