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The current research paradigm for Huntington's disease is based on participants with overt clinical phenotypes and does not address its pathophysiology nor the biomarker changes that can precede by decades the functional decline. We have generated a new research framework to standardise clinical research and enable interventional studies earlier in the disease course. The Huntington's Disease Integrated Staging System (HD-ISS) comprises a biological research definition and evidence-based staging centred on biological, clinical, and functional assessments. We used a formal consensus method that involved representatives from academia, industry, and non-profit organisations. The HD-ISS characterises individuals for research purposes from birth, starting at Stage 0 (ie, individuals with the Huntington's disease genetic mutation without any detectable pathological change) by using a genetic definition of Huntington's disease. Huntington's disease progression is then marked by measurable indicators of underlying pathophysiology (Stage 1), a detectable clinical phenotype (Stage 2), and then decline in function (Stage 3). Individuals can be precisely classified into stages based on thresholds of stage-specific landmark assessments. We also demonstrated the internal validity of this system. The adoption of the HD-ISS could facilitate the design of clinical trials targeting populations before clinical motor diagnosis and enable data standardisation across ongoing and future studies.

Maternal immune activation (MIA) disrupts the central innate immune system during a critical neurodevelopmental period. Microglia are primary innate immune cells in the brain although their direct influence on the MIA phenotype is largely unknown. Here we show that MIA alters microglial gene expression with upregulation of cellular protrusion/neuritogenic pathways, concurrently causing repetitive behavior, social deficits, and synaptic dysfunction to layer V intrinsically bursting pyramidal neurons in the prefrontal cortex of mice. MIA increases plastic dendritic spines of the intrinsically bursting neurons and their interaction with hyper-ramified microglia. Treating MIA offspring by colony stimulating factor 1 receptor inhibitors induces depletion and repopulation of microglia, and corrects protein expression of the newly identified MIA-associated neuritogenic molecules in microglia, which coalesces with correction of MIA-associated synaptic, neurophysiological, and behavioral abnormalities. Our study demonstrates that maternal immune insults perturb microglial phenotypes and influence neuronal functions throughout adulthood, and reveals a potent effect of colony stimulating factor 1 receptor inhibitors on the correction of MIA-associated microglial, synaptic, and neurobehavioral dysfunctions.

Sleep is a stereotyped and well-preserved series of neurophysiological states that are essential for overall health and brain functioning. Emerging research suggests that sleep disturbances are not only associated with but also causally contribute to neurodegenerative disease onset and progression. This mini-review examines some of the current knowledge and evidence for relationships between sleep abnormalities and Alzheimer’s disease within context of possible uses and limitations of sleep biomarkers for evaluation of Alzheimer’s disease. Understanding these relationships could lead to readily accessible and easily quantifiable biomarkers of Alzheimer’s dementia.

The role of Arc in synaptic plasticity and memory consolidation has been investigated for many years with recent evidence that defects in the expression or activity of this immediate-early gene may also contribute to the pathophysiology of brain disorders including schizophrenia and fragile X syndrome. These results bring forward the concept that reversing Arc abnormalities could provide an avenue to improve cognitive or neurological impairments in different disease contexts, but how to achieve this therapeutic objective has remained elusive. Here, we present results from a chemogenomic screen that probed a mechanistically diverse library of small molecules for modulators of BDNF-induced Arc expression in primary cortical neurons. This effort identified compounds with a range of influences on Arc, including promoting its acetylation—a previously uncharacterized post-translational modification of this protein. Together, our data provide insights into the control of Arc that could be targeted to harness neuroplasticity for clinical applications. The activity-regulated cytoskeleton-associated protein (Arc) has been implicated in synaptic plasticity and memory consolidation. Here the authors show that Arc acetylation regulates its stability and identify small molecules that modulate Arc expression.

At early developmental stages, correlated neuronal activity is thought to exert a critical control on functional and structural refinement of synaptic connections. In the hippocampus, between postnatal day 2 (P2) and P6, network-driven giant depolarizing potentials (GDPs) are generated by the synergistic action of glutamate and GABA, which is depolarizing and excitatory. Here the rising phase of GDPs was used to trigger Schaffer collateral stimulation in such a way that synchronized network activity was coincident with presynaptic activation of afferent input. This procedure produced a persistent increase in spontaneous and evoked α-amino-3-hydroxy-5-methyl-4-isoxadepropionic acid-mediated glutamatergic currents, an effect that required calcium influx through postsynaptic L-type calcium channels. No potentiation was observed when a delay of 3 sec was introduced between GDPs and afferent stimulation. Pairing-induced potentiation was prevented by scavengers of endogenous BDNF or tropomyosin-related kinase receptor B (TrkB) receptor antagonists. Blocking TrkB receptors in the postsynaptic cell did not prevent the effects of pairing, suggesting that BDNF, possibly secreted from the postsynaptic cell during GDPs, acts on TrkB receptors localized on presynaptic neurons. Application of exogenous BDNF mimicked the effects of pairing on synaptic transmission. In addition, pairing-induced synaptic potentiation was blocked by ERK inhibitors, suggesting that BDNF activates the MAPK/ERK cascade, which may lead to transcriptional regulation and new protein synthesis in the postsynaptic neuron. These results support the hypothesis that, during a critical period of postnatal development, GABAA-mediated GDPs are instrumental in tuning excitatory synaptic connections and provide insights into the molecular mechanisms involved in this process.

Interest in drug development for rare diseases has expanded dramatically since the Orphan Drug Act was passed in 1983, with 40% of new drug approvals in 2019 targeting orphan indications. However, limited quantitative understanding of natural history and disease progression hinders progress and increases the risks associated with rare disease drug development. Use of international data standards can assist in data harmonization and enable data exchange, integration into larger datasets, and a quantitative understanding of disease natural history. The US Food and Drug Administration (FDA) requires the use of Clinical Data Interchange Consortium (CDISC) Standards in new drug submissions to help the agency efficiently and effectively receive, process, review, and archive submissions, as well as to help integrate data to answer research questions. Such databases have been at the core of biomarker qualification efforts and fit‐for‐purpose models endorsed by the regulators. We describe the development of CDISC therapeutic area user guides for Duchenne muscular dystrophy and Huntington’s disease through Critical Path Institute consortia. These guides describe formalized data structures and controlled terminology to map and integrate data from different sources. This will result in increased standardization of data collection and allow integration and comparison of data from multiple studies. Integration of multiple data sets enables a quantitative understanding of disease progression, which can help overcome common challenges in clinical trial design in these and other rare diseases. Ultimately, clinical data standardization will lead to a faster path to regulatory approval of urgently needed new therapies for patients.

Background To help improve the Alzheimer’s disease (AD) therapeutics research and development process, the Critical Path for Alzheimer’s Disease (CPAD) Consortium at the Critical Path Institute (C‐Path) provides a neutral framework for the drug development industry, regulatory agencies, academia, and patient advocacy organizations to collaborate. CPAD’s extensive track record of developing regulatory‐grade quantitative drug development tools motivates sponsors to share patient‐level data and neuroimages from clinical trials. CPAD leverages these data and uses C‐Path’s core competencies in data management and standardization, quantitative modeling, and regulatory science to develop tools that help de‐risk decision making in AD drug development. Method Clinical data are curated, standardized, and aggregated into analysis subsets, which are used to develop disease progression models that form the basis for clinical trial simulation (CTS) tools. Such tools help optimize patient and endpoint selection, and the design of efficacy studies. CPAD’s database includes raw neuroimages from contemporary datasets, which are used to lead two pre‐competitive efforts, in collaboration with leading academic and industry experts, to 1) test and validate a tau‐PET quantification method that harmonizes derived measures across tracers and cohorts, and 2) explore and evaluate the readiness of tau‐PET as a surrogate marker in AD drug development to support accelerated drug approval. Result As of November 2023, CPAD’s clinical trial repository contains 73 studies with over 100,000 individual de‐identified patient records, with a rich source of key AD biomarkers (biofluids and imaging). Different linear and non‐linear mixed effects models have been fit based on relevant biomarker combinations, characterizing the time course of clinically relevant outcome measures. To harmonize tau‐PET quantification, two different methods (a Centiloid‐like approach and a Joint Propagation model) were tested and validated across multiple tracers, cohorts and studies. A data and research plan has been drafted to explore and evaluate the readiness of tau‐PET as a surrogate marker in AD. Conclusion The precompetitive collaboration by CPAD is fundamental to the generation of actionable quantitative drug development tools for accelerating and advancing AD drug development and building consensus among stakeholders that provide confidence to sponsors for the adoption of the tools.

Neurological disorders represent some of the most challenging therapeutic areas for successful drug approvals. The escalating global burden of death and disability for such diseases represents a significant worldwide public health challenge, and the rate of failure of new therapies for chronic progressive disorders of the nervous system is higher relative to other non-neurological conditions. However, progress is emerging rapidly in advancing the drug development landscape in both rare and common neurodegenerative diseases. In October 2022, the Critical Path Institute (C-Path) and the US Food and Drug Administration (FDA) organized a Neuroscience Annual Workshop convening representatives from the drug development industry, academia, the patient community, government agencies, and regulatory agencies regarding the future development of tools and therapies for neurological disorders. This workshop focused on five chronic progressive diseases: Alzheimer's disease, Parkinson's disease, Huntington's disease, Duchenne muscular dystrophy, and inherited ataxias. This special conference report reviews the key points discussed during the three-day dynamic workshop, including shared learnings, and recommendations that promise to catalyze future advancement of novel therapies and drug development tools.

BackgroundHD is an inherited autosomal dominant neurodegenerative disease. While there is biological certainty that individuals with a pathogenic expansion in the huntingtin gene (HTT) will develop the signs and symptoms of HD within a normal lifespan, this is not reflected in present terminology. Current staging methods do not address disease progression before an overt clinical phenotype, despite well-accepted biomarkers of neurodegeneration predating clinical diagnosis.AimsTo propose a new HD framework, referred to as the HD-ISS, that comprises an HD biological research definition and evidence-based staging centered on prognostic biological, clinical, and functional landmarks.MethodsThis framework is the result of a formal consensus process by the HD-RSC’s Regulatory Science Forum (RSF), a working group of expert representatives from industry and academia. Observational data was employed to calculate ‘cut-offs’ using the extreme values in models of the control population to define the HD-ISS Stages and to evaluate the framework.ResultsThe HD-ISS defines HD biologically as the presence of the expanded HTT gene. The HD-ISS landmarks demonstrate robust prognostic value to classify individuals into each Stage and data-driven landmark thresholds to define Stage boundaries that are not CAG-dependent. Individual study visits, participant Stage progression, and longitudinal models of Stage progression align with the natural history of HD and with increased CAG predicting accelerated transitions.ConclusionsThe RSF has developed a biological definition of HD and an evidence-based staging system that encompass the full course of the disease and are unconstrained by concepts such as ‘manifest’ or ‘pre-manifest.’ The HD-ISS is intended for research settings to allow clinical trials earlier in the disease course, and provides a new structure to anchor and harmonize clinical study populations. The immediate use of the HD-ISS will allow for further validation.