Disruption of mitochondrial complex I induces progressive parkinsonism.

Loss of functional mitochondrial complex I (MCI) in the dopaminergic neurons of the substantia nigra is a hallmark of Parkinson's disease1. Yet, whether this change contributes to Parkinson's disease pathogenesis is unclear2. Here we used intersectional genetics to disrupt the function of MCI in mouse dopaminergic neurons. Disruption of MCI induced a Warburg-like shift in metabolism that enabled neuronal survival, but triggered a progressive loss of the dopaminergic phenotype that was first evident in nigrostriatal axons. This axonal deficit was accompanied by motor learning and fine motor deficits, but not by clear levodopa-responsive parkinsonism-which emerged only after the later loss of dopamine release in the substantia nigra. Thus, MCI dysfunction alone is sufficient to cause progressive, human-like parkinsonism in which the loss of nigral dopamine release makes a critical contribution to motor dysfunction, contrary to the current Parkinson's disease paradigm3,4.

Publisher Correction: Extensive signal integration by the phytohormone protein network.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Extensive signal integration by the phytohormone protein network.

Plant hormones coordinate responses to environmental cues with developmental programs1, and are fundamental for stress resilience and agronomic yield2. The core signalling pathways underlying the effects of phytohormones have been elucidated by genetic screens and hypothesis-driven approaches, and extended by interactome studies of select pathways3. However, fundamental questions remain about how information from different pathways is integrated. Genetically, most phenotypes seem to be regulated by several hormones, but transcriptional profiling suggests that hormones trigger largely exclusive transcriptional programs4. We hypothesized that protein-protein interactions have an important role in phytohormone signal integration. Here, we experimentally generated a systems-level map of the Arabidopsis phytohormone signalling network, consisting of more than 2,000 binary protein-protein interactions. In the highly interconnected network, we identify pathway communities and hundreds of previously unknown pathway contacts that represent potential points of crosstalk. Functional validation of candidates in seven hormone pathways reveals new functions for 74% of tested proteins in 84% of candidate interactions, and indicates that a large majority of signalling proteins function pleiotropically in several pathways. Moreover, we identify several hundred largely small-molecule-dependent interactions of hormone receptors. Comparison with previous reports suggests that noncanonical and nontranscription-mediated receptor signalling is more common than hitherto appreciated.

A cell autonomous regulator of neuronal excitability modulates tau in Alzheimer's disease vulnerable neurons.

Neurons from layer II of the entorhinal cortex (ECII) are the first to accumulate tau protein aggregates and degenerate during prodromal Alzheimer's disease. Gaining insight into the molecular mechanisms underlying this vulnerability will help reveal genes and pathways at play during incipient stages of the disease. Here, we use a data-driven functional genomics approach to model ECII neurons in silico and identify the proto-oncogene DEK as a regulator of tau pathology. We show that epigenetic changes caused by Dek silencing alter activity-induced transcription, with major effects on neuronal excitability. This is accompanied by the gradual accumulation of tau in the somatodendritic compartment of mouse ECII neurons in vivo, reactivity of surrounding microglia, and microglia-mediated neuron loss. These features are all characteristic of early Alzheimer's disease. The existence of a cell-autonomous mechanism linking Alzheimer's disease pathogenic mechanisms in the precise neuron type where the disease starts provides unique evidence that synaptic homeostasis dysregulation is of central importance in the onset of tau pathology in Alzheimer's disease.

Dynamic microglia alterations associate with hippocampal network impairments: A turning point in amyloid pathology progression.

Alzheimer's disease is a progressive neurological disorder causing memory loss and cognitive decline. The underlying causes of cognitive deterioration and neurodegeneration remain unclear, leading to a lack of effective strategies to prevent dementia. Recent evidence highlights the role of neuroinflammation, particularly involving microglia, in Alzheimer's disease onset and progression. Characterizing the initial phase of Alzheimer's disease can lead to the discovery of new biomarkers and therapeutic targets, facilitating timely interventions for effective treatments. We used the AppNL-G-F knock-in mouse model, which resembles the amyloid pathology and neuroinflammatory characteristics of Alzheimer's disease, to investigate the transition from a pre-plaque to an early plaque stage with a combined functional and molecular approach. Our experiments show a progressive decrease in the power of cognition-relevant hippocampal gamma oscillations during the early stage of amyloid pathology, together with a modification of fast-spiking interneuron intrinsic properties and postsynaptic input. Consistently, transcriptomic analyses revealed that these effects are accompanied by changes in synaptic function-associated pathways. Concurrently, homeostasis- and inflammatory-related microglia signature genes were downregulated. Moreover, we found a decrease in Iba1-positive microglia in the hippocampus that correlates with plaque aggregation and neuronal dysfunction. Collectively, these findings support the hypothesis that microglia play a protective role during the early stages of amyloid pathology by preventing plaque aggregation, supporting neuronal homeostasis, and overall preserving the oscillatory network's functionality. These results suggest that the early alteration of microglia dynamics could be a pivotal event in the progression of Alzheimer's disease, potentially triggering plaque deposition, impairment of fast-spiking interneurons, and the breakdown of the oscillatory circuitry in the hippocampus.

Switchable CAR T cell strategy against osteosarcoma.

Immunotherapy with chimeric antigen receptor T (CAR T) cells has changed the treatment of hematological malignances, but they are still a challenge for solid tumors, including pediatric sarcomas. Here, we report a switchable CAR T cell strategy based on anti-FITC CAR T cells and a switch molecule conjugated with FITC for targeting osteosarcoma (OS) tumors. As a potential target, we analyzed the expression of B7-H3, an immune checkpoint inhibitor, in OS cell lines. In addition, we evaluate the capacity of an anti-B7-H3 monoclonal antibody conjugated with FITC (anti-B7-H3-FITC mAb) to control the antitumor activity of anti-FITC CAR T cells. The effector functions of anti-FITC CAR T cells against OS, measured in vitro by tumor cell killing activity and cytokine production, are dependent on the presence of the anti-B7-H3-FITC mAb switch. Moreover, OS cells stimulate anti-FITC CAR T cells migration. In vivo, anti-B7-H3 mAb penetrates in the tumor and binds 143B OS tumor cells. Furthermore, anti-FITC CAR T cells reach tumor region and exert antitumor effect in an OS NSG mouse model only in the presence of the switch molecule. We demonstrate that anti-B7-H3-FITC mAb redirects the cytotoxic activity of anti-FITC CAR T cells against OS tumors suggesting that switchable CAR T cell platforms might be a plausible strategy against OS.

Long-term outcomes of the global tuberculosis and COVID-19 co-infection cohort.

BACKGROUND: Longitudinal cohort data of patients with tuberculosis (TB) and coronavirus disease 2019 (COVID-19) are lacking. In our global study, we describe long-term outcomes of patients affected by TB and COVID-19. METHODS: We collected data from 174 centres in 31 countries on all patients affected by COVID-19 and TB between 1 March 2020 and 30 September 2022. Patients were followed-up until cure, death or end of cohort time. All patients had TB and COVID-19; for analysis purposes, deaths were attributed to TB, COVID-19 or both. Survival analysis was performed using Cox proportional risk-regression models, and the log-rank test was used to compare survival and mortality attributed to TB, COVID-19 or both. RESULTS: Overall, 788 patients with COVID-19 and TB (active or sequelae) were recruited from 31 countries, and 10.8% (n=85) died during the observation period. Survival was significantly lower among patients whose death was attributed to TB and COVID-19 versus those dying because of either TB or COVID-19 alone (p<0.001). Significant adjusted risk factors for TB mortality were higher age (hazard ratio (HR) 1.05, 95% CI 1.03-1.07), HIV infection (HR 2.29, 95% CI 1.02-5.16) and invasive ventilation (HR 4.28, 95% CI 2.34-7.83). For COVID-19 mortality, the adjusted risks were higher age (HR 1.03, 95% CI 1.02-1.04), male sex (HR 2.21, 95% CI 1.24-3.91), oxygen requirement (HR 7.93, 95% CI 3.44-18.26) and invasive ventilation (HR 2.19, 95% CI 1.36-3.53). CONCLUSIONS: In our global cohort, death was the outcome in >10% of patients with TB and COVID-19. A range of demographic and clinical predictors are associated with adverse outcomes.

"SARCOPENIA MEASURED BY ULTRASOUND IN HOSPITALIZED OLDER ADULTS" (ECOSARC): multi-centre, prospective observational study protocol.

BACKGROUND: Measurement of muscle mass and function, and thereafter, screening and diagnosis of sarcopenia, is a challenge and a need in hospitalized older adults. However, it is difficult in complex real-world old patients, because usually they are unable to collaborate with clinical, functional, and imaging testing. Ultrasound measurement of quadriceps rectus femoris (QRF) provides a non-invasive, real-time assessment of muscle quantity and quality, and is highly acceptable to participants with excellent inter-rater and intra-rater variability. However, normative data, protocol standardization, and association with longitudinal outcomes, needs further research and consensus. METHODS: Prospective exploratory multicenter study in older adults admitted to Acute Geriatric Units (AGUs) for medical reasons. 157 subjects from 7 AGUs of Spain were recruited between May 2019 and January 2022. Muscle ultrasound measurements of the anterior vastus of the QRF were acquired on admission and on discharge, using a previously validated protocol, using a Chieson model ECO2 ultrasound system (Chieson Medical Technologies, Co. Ltd, Wimxu District Wuxi, Jiangsu, China). Measurements included the cross-sectional area, muscle thickness in longitudinal view, intramuscular central tendon thickness, echogenicity, and the presence or absence of edema and fasciculations. Functional, nutritional, and DXA measurements were provided. Clinical follow-up was completed at discharge, and 30 and 90 days after discharge. Variations between hospital admission and discharge ultrasound values, and the relationship with clinical variables, will be analyzed using paired t-tests, Wilcoxon tests, or Mc Nemar chi-square tests when necessary. Prevalence of sarcopenia will be calculated, as well as sensitivity and specificity of ultrasound measurements to determine sarcopenia. Kappa analysis will be used to analyze the concordance between measurements, and sensitivity analysis will be conducted for each participating center. DISCUSSION: The results obtained will be of great interest to the scientific geriatric community to assess the utility and validity of ultrasound measurements for the detection and follow-up of sarcopenia in hospitalized older adults, and its association with adverse outcomes. TRIAL REGISTRATION: NCT05113758. Registration date: November 9th 2021. Retrospectively registered.

A Multifaceted Campaign to Combat COVID-19 Misinformation in the Hispanic Community.

At the height of the COVID-19 pandemic, the Public Good Projects, Hispanic Communications Network and World Voices Media joined forces to launch a nationwide, multifaceted campaign which aimed to increase vaccine confidence and decrease misinformation on social media within Hispanic communities. We created a Spanish vaccine misinformation tracking system to detect and assess misinformation circulating in online Spanish conversations. We used our media monitoring findings to work with Hispanic social media (SM) influencers, volunteers, and celebrities to spread pro-vaccine messaging online. We created misinformation-responsive SM assets, newsletters, talking points and trainings for Hispanic-serving community-based organizations (CBOs) to help them respond to misinformation and increase vaccine uptake. We used our misinformation findings to inform the creation of mass media communications such as radio PSAs and op-eds. In Year 1, our new Spanish monitoring system captured and organized 35 M Spanish and 212.7 M English posts about COVID-19 misinformation. We recruited 496 paid influencers, 2 Hispanic celebrities and 1,034 digital volunteers. We sent 70 newsletters to an average of 1539 CBO subscribers, containing 206 talking points and 344 resources (SM assets, toolkits, videos) in English and Spanish to support their outreach. Our radio PSAs reached 26.9 M people and the op-eds reached 2.9 M people. This project shows the proliferation of misinformation circulating in online Spanish conversations. It also shows we were effective at reaching our target audience with fact-based COVID-19 misinformation prebunk and debunk messaging.

Community pharmacist intervention to optimize statin adherence in diabetes care: The GuIDE-S study.

BACKGROUND: Statin use in people with type 2 diabetes (T2D) reduces cardiovascular events, yet adherence remains suboptimal. OBJECTIVE: This study evaluated the impact of a community pharmacist intervention on statin adherence in new users with T2D. METHODS: As part of a quasi-experimental study, community pharmacy staff proactively identified adult patients with T2D who were not prescribed a statin. When appropriate, the pharmacist prescribed a statin via a collaborative practice agreement or facilitated acquisition of a prescription from another prescriber. Patients received individualized education and follow-up and monitoring for 1 year. Adherence was defined as the proportion of days covered (PDC) by a statin over 12 months. Linear and logistic regression were used to compare the effect of the intervention on continuous and a binary adherence threshold, defined as PDC ≥ 80%, respectively. RESULTS: Overall, 185 patients started statin therapy and were matched to 370 control patients for analysis. Adjusted average PDC was 3.1% higher in the intervention group (95% CI -0.037 to 0.098). Patients in the intervention group were 21.2% more likely to have PDC ≥ 80% (95% CI 0.828-1.774). CONCLUSION: The intervention resulted in higher statin adherence than usual care; however, the differences were not statistically significant.

Virulence strategies of an insect herbivore and oomycete plant pathogen converge on host E3 SUMO ligase SIZ1.

Pathogens and pests secrete proteins (effectors) to interfere with plant immunity through modification of host target functions and disruption of immune signalling networks. The extent of convergence between pathogen and herbivorous insect virulence strategies is largely unexplored. We found that effectors from the oomycete pathogen, Phytophthora capsici, and the major aphid pest, Myzus persicae target the host immune regulator SIZ1, an E3 SUMO ligase. We used transient expression assays in Nicotiana benthamiana as well as Arabidopsis mutants to further characterize biological role of effector-SIZ1 interactions in planta. We show that the oomycete and aphid effector, which both contribute to virulence, feature different activities towards SIZ1. While M. persicae effector Mp64 increases SIZ1 protein levels in transient assays, P. capsici effector CRN83_152 enhances SIZ1-E3 SUMO ligase activity in vivo. SIZ1 contributes to host susceptibility to aphids and an oomycete pathogen. Knockout of SIZ1 in Arabidopsis decreased susceptibility to aphids, independent of SNC1, PAD4 and EDS1. Similarly SIZ1 knockdown in N. benthamiana led to reduced P. capsici infection. Our results suggest convergence of distinct pathogen and pest virulence strategies on an E3 SUMO ligase to enhance host susceptibility.

The Influence of Nutritional Status at Diagnosis of Childhood B-Cell Acute Lymphoblastic Leukemia on Survival Rates: Data from a Hispanic Cohort.

The impact of nutritional status at diagnosis of childhood acute lymphoblastic leukemia (ALL) on survival rates was assessed in a Hispanic cohort. Children <16 years with newly diagnosed ALL-B from 2011 to 2019 were studied. Overweight and obesity were classified by body mass index (BMI) and Z-score according to WHO and CDC criteria. BMI, weight percentiles for age and Z-Score were assessed using the WHO Anthro (0-5 years) and AnthroPlus (5-19 years) programs. Cox model was used to estimate risk factors for relapse and death; differences between groups were assessed with Student's T test for parametric and Mann-Whitney U test for non-parametric variables. Disease-free survival (DFS) and overall survival (OS) were determined by the Kaplan-Meier method, calculating time, status, cumulative survival and standard error with a 95% confidence interval. Equal data distribution was estimated with the log-rank test. One-hundred and seventy-two B-ALL children were studied. The overweight-obese group had a non-significant lower DFS (CDC: 54% vs. 60%, p = 0.80; WHO: 57% vs. 64%, p = 0.89) and OS rate (CDC:76% vs. 82%, p = 0.38; WHO:65% vs. 81%, p = 0.13). An association between nutritional status determined by CDC and WHO criteria at diagnosis of B-cell ALL and survival rates was not documented.

A Framework for Using Real-World Data and Health Outcomes Modeling to Evaluate Machine Learning-Based Risk Prediction Models.

OBJECTIVES: We propose a framework of health outcomes modeling with dynamic decision making and real-world data (RWD) to evaluate the potential utility of novel risk prediction models in clinical practice. Lung transplant (LTx) referral decisions in cystic fibrosis offer a complex case study. METHODS: We used longitudinal RWD for a cohort of adults (n = 4247) from the Cystic Fibrosis Foundation Patient Registry to compare outcomes of an LTx referral policy based on machine learning (ML) mortality risk predictions to referral based on (1) forced expiratory volume in 1 second (FEV1) alone and (2) heterogenous usual care (UC). We then developed a patient-level simulation model to project number of patients referred for LTx and 5-year survival, accounting for transplant availability, organ allocation policy, and heterogenous treatment effects. RESULTS: Only 12% of patients (95% confidence interval 11%-13%) were referred for LTx over 5 years under UC, compared with 19% (18%-20%) under FEV1 and 20% (19%-22%) under ML. Of 309 patients who died before LTx referral under UC, 31% (27%-36%) would have been referred under FEV1 and 40% (35%-45%) would have been referred under ML. Given a fixed supply of organs, differences in referral time did not lead to significant differences in transplants, pretransplant or post-transplant deaths, or overall survival in 5 years. CONCLUSIONS: Health outcomes modeling with RWD may help to identify novel ML risk prediction models with high potential real-world clinical utility and rule out further investment in models that are unlikely to offer meaningful real-world benefits.

Nanoparticle-mediated selective Sfrp-1 silencing enhances bone density in osteoporotic mice.

Osteoporosis (OP) is characterized by a loss in bone mass and mineral density. The stimulation of the canonical Wnt/ß-catenin pathway has been reported to promote bone formation, this pathway is controlled by several regulators as secreted frizzled-related protein-1 (Sfrp-1), antagonist of the pathway. Thus, Sfrp-1 silencing therapies could be suitable for enhancing bone growth. However, the systemic stimulation of Wnt/ß-catenin has been correlated with side effects. This work hypothesizes the administration of lipid-polymer NPs (LPNPs) functionalized with a MSC specific aptamer (Apt) and carrying a SFRP1 silencing GapmeR, could favor bone formation in OP with minimal undesired effects. Suitable SFRP1 GapmeR-loaded Apt-LPNPs (Apt-LPNPs-SFRP1) were administered in osteoporotic mice and their biodistribution, toxicity and bone induction capacity were evaluated. The aptamer functionalization of the NPs modified their biodistribution profile showing a four-fold increase in the bone accumulation and a ten-fold decrease in the hepatic accumulation compared to naked LPNPs. Moreover, the histological evaluation revealed evident changes in bone structure observing a more compact trabecular bone and a cortical bone thickness increase in the Apt-LPNPs-SFRP1 treated mice with no toxic effects. Therefore, these LPNPs showed suitable properties and biodistribution profiles leading to an enhancement on the bone density of osteoporotic mice.

Glyphosate-based herbicide induces long-lasting impairment in neuronal and glial differentiation.

Glyphosate-based herbicides (GBH) are among the most sold pesticides in the world. There are several formulations based on the active ingredient glyphosate (GLY) used along with other chemicals to improve the absorption and penetration in plants. The final composition of commercial GBH may modify GLY toxicological profile, potentially enhancing its neurotoxic properties. The developing nervous system is particularly susceptible to insults occurring during the early phases of development, and exposure to chemicals in this period may lead to persistent impairments on neurogenesis and differentiation. The aim of this study was to evaluate the long-lasting effects of a sub-cytotoxic concentration, 2.5 parts per million of GBH and GLY, on the differentiation of human neuroepithelial stem cells (NES) derived from induced pluripotent stem cells (iPSC). We treated NES cells with each compound and evaluated the effects on key cellular processes, such as proliferation and differentiation in daughter cells never directly exposed to the toxicants. We found that GBH induced a more immature neuronal profile associated to increased PAX6, NESTIN and DCX expression, and a shift in the differentiation process toward glial cell fate at the expense of mature neurons, as shown by an increase in the glial markers GFAP, GLT1, GLAST and a decrease in MAP2. Such alterations were associated to dysregulation of key genes critically involved in neurogenesis, including PAX6, HES1, HES5, and DDK1. Altogether, the data indicate that subtoxic concentrations of GBH, but not of GLY, induce long-lasting impairments on the differentiation potential of NES cells.

Oxidative Stress Amelioration of Novel Peptides Extracted from Enzymatic Hydrolysates of Chinese Pecan Cake.

Pecan (Carya cathayensis) is an important economic crop, and its hydrolyzed peptides have been evidenced to reduce the effect of oxidative stress due to their antioxidant capacity. Hence, the protocols of ultrafiltration and gel filtration chromatography were established to obtain bioactive peptides from by-products of C. cathayensis (pecan cake). As measured by DPPH/ABTS radical scavenging, the peptides with less molecular weight (MW) possess higher antioxidant capacity. PCPH-III (MW < 3 kDa) presented higher radical scavenging capacity than PCPH-II (3 kDa < MW < 10 kDa) and PCPH-I (MW > 10 kDa) measured by DPPH (IC50: 111.0 µg/ mL) and measured by ABTs (IC50: 402.9 µg/mL). The secondary structure and amino acid composition varied by their MW, in which PCPH-II contained more α-helices (26.71%) and ß-sheets (36.96%), PCPH-III contained higher ratios of ß-turns (36.87%), while the composition of different secondary of PCPH-I was even 25 ± 5.76%. The variation trend of α-helix and random experienced slightly varied from PCPH-I to PCPH-II, while significantly decreased from PCPH-II to PCPH-III. The increasing antioxidant capacity is followed by the content of proline, and PCPH-III had the highest composition (8.03%). With regard to the six peptides identified by LC-MS/MS, two of them (VYGYADK and VLFSNY) showed stronger antioxidant capacity than others. In silico molecular docking demonstrated their combining abilities with a transcription factor Kelch-like ECH-associated protein 1 (Keap1) and speculated that they inhibit oxidative stress through activating the Keap1-Nrf2-ARE pathway. Meanwhile, increased activity of SOD and CAT­antioxidant markers­were found in H2O2-induced cells. The residue of tyrosine was demonstrated to contribute the most antioxidant capacity of VYGYADK and its position affected less. This study provided a novel peptide screening and by-product utilization process that can be applied in natural product developments.

The potential of pumpkin seed oil as a functional food-A comprehensive review of chemical composition, health benefits, and safety.

The growing interest in foods that can be beneficial to human health is bringing into focus some products that have been used locally for centuries but have recently gained worldwide attention. One of these foods is pumpkin seed oil, which has been used in culinary and traditional medicine, but recent data also show its use in the pharmaceutical and cosmetic industries. In addition, some sources refer to it as a potential functional food, mainly because it is obtained from pumpkin seeds, which contain many functional components. However, the production process of the oil may affect the content of these components and consequently the biological activity of the oil. In this review, we have focused on summarizing scientific data that explore the potential of pumpkin seed oil as a functional food ingredient. We provide a comprehensive overview of pumpkin seed oil chemical composition, phytochemical content, biological activity, and safety, as well as the overview of production processes and contemporary use. The main phytochemicals in pumpkin seed oil with health-related properties are polyphenols, phytoestrogens, and fatty acids, but carotenoids, squalene, tocopherols, and minerals may also contribute to health benefits. Most studies have been conducted in vitro and support the claim that pumpkin seed oil has antioxidant and antimicrobial activities. Clinical studies have shown that pumpkin seed oil may be beneficial in the treatment of cardiovascular problems of menopausal women and ailments associated with imbalance of sex hormones.

Neuroinflammation and Tau Colocalize in vivo in Progressive Supranuclear Palsy.

OBJECTIVE: We examined the relationship between tau pathology and neuroinflammation using [11 C]PK11195 and [18 F]AV-1451 PET in 17 patients with progressive supranuclear palsy (PSP) Richardson's syndrome. We tested the hypothesis that neuroinflammation and tau protein aggregation colocalize macroscopically, and correlate with clinical severity. METHODS: Nondisplaceable binding potential (BPND ) for each ligand was quantified in 83 regions of interest (ROIs). The [11 C]PK11195 and [18 F]AV-1451 BPND values were correlated across all regions. The spatial distributions of [11 C]PK11195 and [18 F]AV-1451 binding were determined by principal component analyses (PCAs), and the loading of each spatial component compared against the patients' clinical severity (using the PSP rating scale). RESULTS: Regional [11 C]PK11195 and [18 F]AV-1451 binding were positively correlated (R = 0.577, p < 0.0001). The PCA identified 4 components for each ligand, reflecting the relative expression of tau pathology or neuroinflammation in distinct groups of brain regions. Positive associations between [11 C]PK11195 and [18 F]AV-1451 components' loadings were found in both subcortical (R = 0.769, p < 0.0001) and cortical regions (R = 0.836, p < 0.0001). There were positive correlations between clinical severity and both subcortical tau pathology (R = 0.667, p = 0.003) and neuroinflammation (R = 0.788, p < 0.001). INTERPRETATION: We show that tau pathology and neuroinflammation colocalize in PSP, and that individual differences in subcortical tau pathology and neuroinflammation are linked to clinical severity. Although longitudinal studies are needed to determine causal associations between these molecular pathologies, we suggest that the combination of tau- and immune-oriented strategies may be useful for effective disease-modifying treatments in PSP. ANN NEUROL 2020;88:1194-1204.

Predicting loss of independence and mortality in frontotemporal lobar degeneration syndromes.

OBJECTIVE: To test the hypothesis that in syndromes associated with frontotemporal lobar degeneration, behavioural impairment predicts loss of functional independence and motor clinical features predict mortality, irrespective of diagnostic group. METHODS: We used a transdiagnostic approach to survival in an epidemiological cohort in the UK, testing the association between clinical features, independence and survival in patients with clinical diagnoses of behavioural variant frontotemporal dementia (bvFTD n=64), non-fluent variant primary progressive aphasia (nfvPPA n=36), semantic variant primary progressive aphasia (svPPA n=25), progressive supranuclear palsy (PSP n=101) and corticobasal syndrome (CBS n=68). A principal components analysis identified six dimensions of clinical features. Using Cox proportional hazards and logistic regression, we identified the association between each of these dimensions and both functionally independent survival (time from clinical assessment to care home admission) and absolute survival (time to death). Analyses adjusted for the covariates of age, gender and diagnostic group. Secondary analysis excluded specific diagnostic groups. RESULTS: Behavioural disturbance, including impulsivity and apathy, was associated with reduced functionally independent survival (OR 2.46, p<0.001), even if patients with bvFTD were removed from the analysis. Motor impairments were associated with reduced absolute survival, even if patients with PSP and CBS were removed from the analysis. CONCLUSION: Our results can assist individualised prognostication and planning of disease-modifying trials, and they support a transdiagnostic approach to symptomatic treatment trials in patients with clinical syndromes associated with frontotemporal lobar degeneration.