A Prospective European Trial Comparing Laparotomy, Laparoscopy, Robotic-Assisted, and Transanal Total Mesorectal Excision Procedures in High-Risk Patients with Rectal Cancer: The RESET Trial.

OBJECTIVE: To compare total mesorectal excision (TME) techniques combined with sphincter-sparing procedure in high-risk patients (HRPs). BACKGROUND: TME is the standard treatment for rectal cancer, but can be challenging in HRPs. The available surgical approaches must be compared, especially in HRPs. METHODS: Prospective, observational, multicenter trial to compare laparotomy (OTME), laparoscopy (LTME), robotic-assisted surgery (RTME), and transanal surgery (TaTME) in HRPs. The composite primary outcome included circumferential radial margin (CRM) ≥1mm, TME grade II-III, and absence of Clavien-Dindo grade III-IV complications. Three propensity score analyses were performed (LTME vs. RTME, RTME vs. TaTME, LTME vs. TaTME). RESULTS: 1078 HRPs (75% of men, median body mass index of 27 kg/m2, 50% of tumors in the lower third of the rectum) underwent surgery. The RTME and TaTME groups included patients with more advanced and lower tumors and coloanal anastomosis (P<0.001). Operative time was longer for RTME surgery (P<0.001). Conversion rate was similar for minimally invasive procedures (4.5%). The global R0 resection rate was 96% without difference among techniques. The primary outcome rates were 82.4%, 64.3%, 74.7%, and 80.3% for LTME, OTME, RTME, and TaTME, respectively. None achieved the expected success rate (85%), and propensity score analyses found no differences. Operative results were similar between high- and low-volume inclusion centers only for RTME. CONCLUSIONS: The RESET trial yielded high-quality results despite focusing on HRPs. Minimally invasive procedures showed similar sphincter-sparing procedure outcomes, but LTME included patients with more favorable tumors. Oncologic and functional outcomes will be evaluated at 2 years (ClinicalTrials.gov, ID: NCT03574493).

Menopause hormone therapy significantly alters pathophysiological biomarkers of Alzheimer's disease.

INTRODUCTION: This increasing body of literature indicates that menopause hormonal replacement therapy (MHT) may substantially mitigate the risk of developing late-life cognitive decline due to progressive Alzheimer's disease (AD) pathophysiology. For the first time, we investigated the question whether MHT impacts AD biomarker-informed pathophysiological dynamics in de-novo diagnosed menopausal women. METHODS: We analyzed baseline and longitudinal differences between MHT-taking and -not women in terms of concentrations of core pathophysiological AD plasma biomarkers, validated in symptomatic and cognitively healthy individuals, including biomarkers of (1) the amyloid-ß (Aß) pathway, (2) tau pathophysiology, (3) neuronal loss, and (4) axonal damage and neurodegeneration. RESULTS: We report a prominent and significant treatment response at the Aß pathway biomarker level. Women at genetic risk for AD (APOE e4 allele carriers) have particularly shown favorable results from treatment. DISCUSSION: To our knowledge, we present first prospective clinical evidence on effects of MHT on AD pathophysiology during menopause.

Plasma ß-secretase1 concentrations correlate with basal forebrain atrophy and neurodegeneration in cognitively healthy individuals at risk for AD.

BACKGROUND: Increased ß-secretase 1 (BACE1) protein concentration, in body fluids, is a candidate biomarker of Alzheimer's disease (AD).We reported that plasma BACE1 protein concentrations are associated with the levels of brain amyloidß (Αß) accumulation in cognitively healthy individuals with subjective memory complaint (SMC). METHODS: In 302 individuals from the same cohort, we investigated the cross-sectional and longitudinal association between plasma BACE1 protein concentrations and AD biomarkers of neurodegeneration (plasma t-tau and Neurofilament light chain (NfL), fluorodeoxyglucose-positron emission tomography (FDG-PET), brain volumes in the basal forebrain [BF], hippocampus, and entorhinal cortex). RESULTS: We report a positive longitudinal correlation of BACE1 with both NfL and t-tau, as well as a correlation between annual BACE1 changes and bi-annual reduction of BF volume. We show a positive association between BACE1 and FDG-PET signal at baseline. CONCLUSIONS: The association between plasma BACE1 protein concentrations and BF atrophy we found in cognitively healthy individuals with SMC corroborates translational studies, suggesting a role of BACE1 in neurodegeneration.

Brain Aß load association and sexual dimorphism of plasma BACE1 concentrations in cognitively normal individuals at risk for AD.

INTRODUCTION: Successful development of effective ß-site amyloid precursor protein cleaving enzyme 1 (BACE1)-targeted therapies for early stages of Alzheimer's disease requires biomarker-guided intervention strategies. METHODS: We investigated whether key biological factors such as sex, apolipoprotein E (APOE ε4) allele, and age affect longitudinal plasma BACE1 concentrations in a large monocenter cohort of individuals at risk for Alzheimer's disease. We explored the relationship between plasma BACE1 concentrations and levels of brain amyloid-ß (Aß) deposition, using positron emission tomography global standard uptake value ratios. RESULTS: Baseline and longitudinal mean concentrations of plasma BACE1 were significantly higher in women than men. We also found a positive significant impact of plasma BACE1 on baseline Aß-positron emission tomography global standard uptake value ratios. DISCUSSION: Our results suggest a sexual dimorphism in BACE1-related upstream mechanisms of brain Aß production and deposition. We argue that plasma BACE1 should be considered in further biomarker validation and qualification studies as well as in BACE1 clinical trials.

The association between posterior resting-state EEG alpha rhythms and functional MRI connectivity in older adults with subjective memory complaint.

Resting-state eyes-closed electroencephalographic (rsEEG) alpha rhythms are dominant in posterior cortical areas in healthy adults and are abnormal in subjective memory complaint (SMC) persons with Alzheimer's disease amyloidosis. This exploratory study in 161 SMC participants tested the relationships between those rhythms and seed-based resting-state functional magnetic resonance imaging (rs-fMRI) connectivity between thalamus and visual cortical networks as a function of brain amyloid burden, revealed by positron emission tomography and cognitive reserve, measured by educational attainment. The SMC participants were divided into 4 groups according to 2 factors: Education (Edu+ and Edu-) and Amyloid burden (Amy+ and Amy-). There was a statistical interaction (p < 0.05) between the two factors, and the subgroup analysis using estimated marginal means showed a positive association between the mentioned rs-fMRI connectivity and the posterior rsEEG alpha rhythms in the SMC participants with low brain amyloidosis and high CR (Amy-/Edu+). These results suggest that in SMC persons, early Alzheimer's disease amyloidosis may contrast the beneficial effects of cognitive reserve on neurophysiological oscillatory mechanisms at alpha frequencies and connectivity between the thalamus and visual cortical networks.

Biological Mechanism-based Neurology and Psychiatry: A BACE1/2 and Downstream Pathway Model.

In oncology, comprehensive omics and functional enrichment studies have led to an extensive profiling of (epi)genetic and neurobiological alterations that can be mapped onto a single tumor's clinical phenotype and divergent clinical phenotypes expressing common pathophysiological pathways. Consequently, molecular pathway-based therapeutic interventions for different cancer typologies, namely tumor type- and site-agnostic treatments, have been developed, encouraging the real-world implementation of a paradigm shift in medicine. Given the breakthrough nature of the new-generation translational research and drug development in oncology, there is an increasing rationale to transfertilize this blueprint to other medical fields, including psychiatry and neurology. In order to illustrate the emerging paradigm shift in neuroscience, we provide a state-of-the-art review of translational studies on the ß-site amyloid precursor protein cleaving enzyme (BACE) and its most studied downstream effector, neuregulin, which are molecular orchestrators of distinct biological pathways involved in several neurological and psychiatric diseases. This body of data aligns with the evidence of a shared genetic/biological architecture among Alzheimer's disease, schizoaffective disorder, and autism spectrum disorders. To facilitate a forward-looking discussion about a potential first step towards the adoption of biological pathway-based, clinical symptom-agnostic, categorization models in clinical neurology and psychiatry for precision medicine solutions, we engage in a speculative intellectual exercise gravitating around BACE-related science, which is used as a paradigmatic case here. We draw a perspective whereby pathway-based therapeutic strategies could be catalyzed by highthroughput techniques embedded in systems-scaled biology, neuroscience, and pharmacology approaches that will help overcome the constraints of traditional descriptive clinical symptom and syndrome-focused constructs in neurology and psychiatry.

Determinants of approved acetylcholinesterase inhibitor response outcomes in Alzheimer's disease: relevance for precision medicine in neurodegenerative diseases.

Acetylcholinesterase inhibitors (ChEI) are the global standard of care for the symptomatic treatment of Alzheimer's disease (AD) and show significant positive effects in neurodegenerative diseases with cognitive and behavioral symptoms. Although experimental and large-scale clinical evidence indicates the potential long-term efficacy of ChEI, primary outcomes are generally heterogeneous across outpatient clinics and regional healthcare systems. Sub-optimal dosing or slow tapering, heterogeneous guidelines about the timing for therapy initiation (prodromal versus dementia stages), healthcare providers' ambivalence to treatment, lack of disease awareness, delayed medical consultation, prescription of ChEI in non-AD cognitive disorders, contribute to the negative outcomes. We present an evidence-based overview of determinants, spanning genetic, molecular, and large-scale networks, involved in the response to ChEI in patients with AD and other neurodegenerative diseases. A comprehensive understanding of cerebral and retinal cholinergic system dysfunctions along with ChEI response predictors in AD is crucial since disease-modifying therapies will frequently be prescribed in combination with ChEI. Therapeutic algorithms tailored to genetic, biological, clinical (endo)phenotypes, and disease stages will help leverage inter-drug synergy and attain optimal combined response outcomes, in line with the precision medicine model.

Self-Reported Social Relationship Capacities Predict Motor, Functional and Cognitive Decline in Huntington's Disease.

Huntington's Disease (HD) is an inherited neurodegenerative disease characterized by a combination of motor, cognitive, and behavioral disorders. The social and behavioral symptoms observed in HD patients impact their quality of life and probably explain their relational difficulties, conflicts, and social withdrawal. In this study, we described the development of the Social Relationship Self-Questionnaire (SRSQ), a self-reporting questionnaire that assesses how HD patients perceived their social relationships. The scale was proposed for 66 HD patients at an early stage of the disease, 32 PreHD patients (individuals carrying the mutant gene without motor symptoms), and 66 controls. The HD patients were included in a prospective longitudinal follow-up for an average of 1.07 years with motor, functional, cognitive, and behavioral assessments. Based on the HD patients' answers at baseline, we identified two domains in the SRSQ. The first domain was related to social motivation and correlated with cognitive performance. The second domain was related to emotional insight and correlated with behavioral symptoms such as apathy, anxiety, and irritability. We discovered that both SRSQ domain scores at baseline predicted future motor, functional, and cognitive decline in HD.

Association of plasma Aß40/Aß42 ratio and brain Aß accumulation: testing a whole-brain PLS-VIP approach in individuals at risk of Alzheimer's disease.

Molecular and brain regional/network-wise pathophysiological changes at preclinical stages of Alzheimer's disease (AD) have primarily been found through knowledge-based studies conducted in late-stage mild cognitive impairment/dementia populations. However, such an approach may compromise the objective of identifying the earliest spatial-temporal pathophysiological processes. We investigated 261 individuals with subjective memory complaints, a condition at increased risk of AD, to test a whole-brain, non-a-priori method based on partial least squares in unraveling the association between plasma Aß42/Aß40 ratio and an extensive set of brain regions characterized through molecular imaging of Aß accumulation and cortical metabolism. Significant associations were mapped onto large-scale networks, identified through an atlas and by knowledge, to elaborate on the reliability of the results. Plasma Aß42/40 ratio was associated with Aß-PET uptake (but not FDG-PET) in regions generally investigated in preclinical AD such as those belonging to the default mode network, but also in regions/networks normally not accounted - including the central executive and salience networks - which likely have a selective vulnerability to incipient Aß accumulation. The present whole-brain approach is promising to investigate early pathophysiological changes of AD to fully capture the complexity of the disease, which is essential to develop timely screening, detection, diagnostic, and therapeutic interventions.

MiRNA-15b and miRNA-125b are associated with regional Aß-PET and FDG-PET uptake in cognitively normal individuals with subjective memory complaints.

There is substantial experimental evidence for dysregulation of several microRNA (miRNA) expression levels in Alzheimer's disease (AD). MiRNAs modulate critical brain intracellular signaling pathways and are associated with AD core pathophysiological mechanisms. First, we conducted a real-time quantitative PCR-based pilot study to identify a set of brain-enriched miRNAs in a monocentric cohort of cognitively normal individuals with subjective memory complaints, a condition associated with increased risk of AD. Second, we investigated the impact of age, sex, and the Apolipoprotein E ε4 (APOE ε4) allele, on the identified miRNA plasma concentrations. In addition, we explored the cross-sectional and longitudinal association of the miRNAs plasma concentrations with regional brain metabolic uptake using amyloid-ß (Aß)-positron emission tomography (Aß-PET) and 18F-fluorodeoxyglucose-PET (18F-FDG-PET). We identified a set of six brain-enriched miRNAs-miRNA-125b, miRNA-146a, miRNA-15b, miRNA-148a, miRNA-26b, and miRNA-100. Age, sex, and APOE ε4 allele were not associated with individual miRNA abundance. MiRNA-15b concentrations were significantly lower in the Aß-PET-positive compared to Aß-PET-negative individuals. Furthermore, we found a positive effect of the miRNA-15b*time interaction on regional metabolic 18F-FDG-PET uptake in the left hippocampus. Plasma miRNA-125b concentrations, as well as the miRNA-125b*time interaction (over a 2-year follow-up), were negatively associated with regional Aß-PET standard uptake value ratio in the right anterior cingulate cortex. At baseline, we found a significantly negative association between plasma miRNA-125b concentrations and 18F-FDG-PET uptake in specific brain regions. In an asymptomatic at-risk population for AD, we show significant associations between plasma concentrations of miRNA-125b and miRNA-15b with core neuroimaging biomarkers of AD pathophysiology. Our results, coupled with existing experimental evidence, suggest a potential protective anti-Aß effect of miRNA-15b and a biological link between miRNA-125b and Aß-independent neurotoxic pathways.

Future avenues for Alzheimer's disease detection and therapy: liquid biopsy, intracellular signaling modulation, systems pharmacology drug discovery.

When Alzheimer's disease (AD) disease-modifying therapies will be available, global healthcare systems will be challenged by a large-scale demand for clinical and biological screening. Validation and qualification of globally accessible, minimally-invasive, and time-, cost-saving blood-based biomarkers need to be advanced. Novel pathophysiological mechanisms (and related candidate biomarkers) - including neuroinflammation pathways (TREM2 and YKL-40), axonal degeneration (neurofilament light chain protein), synaptic dysfunction (neurogranin, synaptotagmin, α-synuclein, and SNAP-25) - may be integrated into an expanding pathophysiological and biomarker matrix and, ultimately, integrated into a comprehensive blood-based liquid biopsy, aligned with the evolving ATN + classification system and the precision medicine paradigm. Liquid biopsy-based diagnostic and therapeutic algorithms are increasingly employed in Oncology disease-modifying therapies and medical practice, showing an enormous potential for AD and other brain diseases as well. For AD and other neurodegenerative diseases, newly identified aberrant molecular pathways have been identified as suitable therapeutic targets and are currently investigated by academia/industry-led R&D programs, including the nerve-growth factor pathway in basal forebrain cholinergic neurons, the sigma1 receptor, and the GTPases of the Rho family. Evidence for a clinical long-term effect on cognitive function and brain health span of cholinergic compounds, drug candidates for repositioning programs, and non-pharmacological multidomain interventions (nutrition, cognitive training, and physical activity) is developing as well. Ultimately, novel pharmacological paradigms, such as quantitative systems pharmacology-based integrative/explorative approaches, are gaining momentum to optimize drug discovery and accomplish effective pathway-based strategies for precision medicine. This article is part of the special issue on 'The Quest for Disease-Modifying Therapies for Neurodegenerative Disorders'.

Omics sciences for systems biology in Alzheimer's disease: State-of-the-art of the evidence.

Alzheimer's disease (AD) is characterized by non-linear, genetic-driven pathophysiological dynamics with high heterogeneity in biological alterations and disease spatial-temporal progression. Human in-vivo and post-mortem studies point out a failure of multi-level biological networks underlying AD pathophysiology, including proteostasis (amyloid-ß and tau), synaptic homeostasis, inflammatory and immune responses, lipid and energy metabolism, oxidative stress. Therefore, a holistic, systems-level approach is needed to fully capture AD multi-faceted pathophysiology. Omics sciences - genomics, epigenomics, transcriptomics, proteomics, metabolomics, lipidomics - embedded in the systems biology (SB) theoretical and computational framework can generate explainable readouts describing the entire biological continuum of a disease. Such path in Neurology is encouraged by the promising results of omics sciences and SB approaches in Oncology, where stage-driven pathway-based therapies have been developed in line with the precision medicine paradigm. Multi-omics data integrated in SB network approaches will help detect and chart AD upstream pathomechanistic alterations and downstream molecular effects occurring in preclinical stages. Finally, integrating omics and neuroimaging data - i.e., neuroimaging-omics - will identify multi-dimensional biological signatures essential to track the clinical-biological trajectories, at the subpopulation or even individual level.

In vivo staging of regional amyloid deposition predicts functional conversion in the preclinical and prodromal phases of Alzheimer's disease.

We tested the usefulness of a regional amyloid staging based on amyloid sensitive positron emission tomography to predict conversion to cognitive impairment and dementia in preclinical and prodromal Alzheimer's disease (AD). We analyzed 884 cases, including normal controls, and people with subjective cognitive decline or mild cognitive impairment (MCI), from the Alzheimer's Disease Neuroimaging Initiative with a maximum follow-up of 6 years and 318 cases with subjective memory complaints with a maximum follow-up time of three years from the INveStIGation of AlzHeimer's PredicTors cohort (INSIGHT-preAD study). Cox regression showed a significant association of regional amyloid stages with time to conversion from a cognitively normal to an MCI, and from an MCI to a dementia status. The most advanced amyloid stages identified very-high-risk groups of conversion. All results were robustly replicated across the independent samples. These findings indicate the usefulness of regional amyloid staging for identifying preclinical and prodromal AD cases at very high risk of conversion for future amyloid targeted trials.

Age and sex impact plasma NFL and t-Tau trajectories in individuals with subjective memory complaints: a 3-year follow-up study.

BACKGROUND: Plasma neurofilament light (NFL) and total Tau (t-Tau) proteins are candidate biomarkers for early stages of Alzheimer's disease (AD). The impact of biological factors on their plasma concentrations in individuals with subjective memory complaints (SMC) has been poorly explored. We longitudinally investigate the effect of sex, age, APOE ε4 allele, comorbidities, brain amyloid-ß (Aß) burden, and cognitive scores on plasma NFL and t-Tau concentrations in cognitively healthy individuals with SMC, a condition associated with AD development. METHODS: Three hundred sixteen and 79 individuals, respectively, have baseline and three-time point assessments (at baseline, 1-year, and 3-year follow-up) of the two biomarkers. Plasma biomarkers were measured with an ultrasensitive assay in a mono-center cohort (INSIGHT-preAD study). RESULTS: We show an effect of age on plasma NFL, with women having a higher increase of plasma t-Tau concentrations compared to men, over time. The APOE ε4 allele does not affect the biomarker concentrations while plasma vitamin B12 deficiency is associated with higher plasma t-Tau concentrations. Both biomarkers are correlated and increase over time. Baseline NFL is related to the rate of Aß deposition at 2-year follow-up in the left-posterior cingulate and the inferior parietal gyri. Baseline plasma NFL and the rate of change of plasma t-Tau are inversely associated with cognitive score. CONCLUSION: We find that plasma NFL and t-Tau longitudinal trajectories are affected by age and female sex, respectively, in SMC individuals. Exploring the influence of biological variables on AD biomarkers is crucial for their clinical validation in blood.

Association of plasma YKL-40 with brain amyloid-ß levels, memory performance, and sex in subjective memory complainers.

Neuroinflammation, a key early pathomechanistic alteration of Alzheimer's disease, may represent either a detrimental or a compensatory mechanism or both (according to the disease stage). YKL-40, a glycoprotein highly expressed in differentiated glial cells, is a candidate biomarker for in vivo tracking neuroinflammation in humans. We performed a longitudinal study in a monocentric cohort of cognitively healthy individuals at risk for Alzheimer's disease exploring whether age, sex, and the apolipoprotein E ε4 allele affect plasma YKL-40 concentrations. We investigated whether YKL-40 is associated with brain amyloid-ß (Aß) deposition, neuronal activity, and neurodegeneration as assessed via neuroimaging biomarkers. Finally, we investigated whether YKL-40 may predict cognitive performance. We found an age-associated increase of YKL-40 and observed that men display higher concentrations than women, indicating a potential sexual dimorphism. Moreover, YKL-40 was positively associated with memory performance and negatively associated with brain Aß deposition (but not with metabolic signal). Consistent with translational studies, our results suggest a potentially protective effect of glia on incipient brain Aß accumulation and neuronal homeostasis.

Resting-state posterior alpha rhythms are abnormal in subjective memory complaint seniors with preclinical Alzheimer's neuropathology and high education level: the INSIGHT-preAD study.

Cognitive reserve is present in Alzheimer's disease (AD) seniors with high education attainment making them clinically resilient to extended brain neuropathology and neurodegeneration. Here, we tested whether subjective memory complaint (SMC) seniors with AD neuropathology and high education attainment of the prospective INSIGHT-preAD cohort (Paris) may present abnormal eyes-closed resting state posterior electroencephalographic rhythms around individual alpha frequency peak, typically altered in AD patients. The SMC participants negative to amyloid PET AD markers (SMCneg) with high (over low-moderate) education level showed higher posterior alpha 2 power density (possibly "neuroprotective"). Furthermore, amyloid PET-positive SMC (SMCpos) participants with high (over low-moderate) education level showed higher temporal alpha 3 power density (possibly "neuroprotective") and lower posterior alpha 2 power density (possibly "compensatory"). This effect may reflect cognitive reserve as no differences in brain gray-white matter, and cognitive functions were observed between these SMCpos/SMCneg subgroups. Preclinical Alzheimer's neuropathology may interact with education attainment and neurophysiological mechanisms generating cortical alpha rhythms around individual alpha frequency peak (i.e., alpha 2 and 3) in quiet wakefulness.