Open Questions: Diseases

Ranked research questions extracted from wiki pages and knowledge gaps
Field: GenesProteinsMechanismsTherapeuticsDiseasesPathwaysCell TypesBrain RegionsMethods
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200 questions found for field 'Diseases'
open ⚖ 1500
Propagation mechanisms**: Can we determine the cell-to-cell transmission pathways for alpha-synuclein in MSA? Can we block them therapeutically?
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How does cell-to-cell transmission differ between sporadic and genetic forms of PD?
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What is the therapeutic window for [LRRK2](/entities/lrrk2) kinase inhibition in PD patients?
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What are the optimal timing windows for disease-modifying interventions?
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What is the relationship between sleep disorders and PD pathogenesis?
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How does intestinal permeability affect alpha-synuclein aggregation?
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How can biomarker-defined subtypes guide personalized treatment?
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How can biomarker-defined subtypes guide personalized treatment?**: Emerging data suggests different therapeutic responses based on biomarker profiles (e.g., tau burden, APOE status). How should treat
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What mechanisms drive severe sleep-disordered breathing and stridor progression in high-risk patients?
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How should combination therapies balance anti-aggregation, mitochondrial, and anti-inflammatory targets in MSA?
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What patient-centered endpoints best capture autonomic and quality-of-life benefit beyond motor scales?
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Gene silencing
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Aggregation inhibitors
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Neuroprotective
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Biomarker-guided therapy
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Clinical phenotype documentation
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open ⚖ 1500
Healthcare access research
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How does progranulin insufficiency alter lysosomal and immune function in vulnerable cortical networks?
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Why oligodendrocytes?
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What is the precise sequence of events in preclinical AD?
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What drives the selective vulnerability of specific neuronal populations?
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Can blood biomarkers reliably detect preclinical AD?
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How can we effectively target tau pathology?
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Can combination therapy approaches improve outcomes over monotherapy?
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What is the therapeutic potential of TREM2 modulators?
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How do we address tau pathology beyond antibody approaches?
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How should AD risk be communicated and acted upon?
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Why do Lewy bodies spread in a predictable pattern?
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What determines whether C9orf72 carriers develop FTLD, ALS, or both phenotypes?
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Are there shared therapeutic targets between FTLD and ALS that could benefit both patient populations?
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Wearable sensors
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Artificial intelligence
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Telerehabilitation
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Brain stimulation integration
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Personalized neurofeedback
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Mutation-specific therapies
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Personalized medicine
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Pharmacogenomics
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Gene therapy plus metabolic supplementation
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Cell therapy plus pharmacological agents
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Dietary modification plus pharmacological support
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Carrier screening
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Prenatal diagnosis
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Preimplantation genetic diagnosis
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Newborn screening
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Harmonized diagnostic criteria
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Biomarker-based studies
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Large-scale genomic studies
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Population-based cohort studies
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Genetic profiling
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Precision rehabilitation
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Vaccination impact
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Early intervention
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Risk factor modification
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Epidemiological studies
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Genetic characterization
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Diverse population studies
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Functional validation
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open ⚖ 1500
Gene-environment interactions
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Therapeutic targeting
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open ⚖ 1500
Blood-based biomarkers
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open ⚖ 1500
Imaging biomarkers
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CSF biomarkers
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Combined biomarkers
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Astrocyte-targeting therapies
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Anti-propagation strategies
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Tau aggregation inhibitors
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Anti-inflammatory agents
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Longitudinal cohorts
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Standardization
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Multi-center collaboration
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TDP-43 Pathology
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Genetic Architecture
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Clinical Heterogeneity
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Therapeutic Targets
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ALS Overlap
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Blood-based tests
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Imaging biomarkers
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Genetic testing
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Disease-modifying trials
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Symptomatic agents
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Precision medicine
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International CBD Genetics Consortium
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Clinical trial networks
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Patient registries
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AAV vectors
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CRISPR-Cas13
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Prime editing
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Patient-derived iPSCs
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Cell replacement
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Gene correction
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European Spinocerebellar Ataxia Registry (ESCAR)
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Clinical Research Consortium for SCA (CRC-SCA)
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International Ataxia Research Consortium (IARC)
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Biomarker development:
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Trial enrichment:
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Combination therapies:
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Personalized medicine:
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Genetic subtyping
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Biomarker stratification
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Targeted therapies
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Outcome prediction
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Pathophysiology
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Integrated care
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Is there a common sporadic FTD risk gene yet to be identified?
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What role do epigenetic modifications play in sporadic FTD onset?
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Can polygenic risk scores predict FTD risk in non-carriers of known mutations?
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What determines whether frontal or temporal networks degenerate first?
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Is selective network vulnerability determined by cell-type composition, connectivity patterns, or regional gene expression?
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Can network-based models predict disease progression trajectory?
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What molecular determinants drive divergent phenotypes across behavioral variant Frontotemporal Dementia (bvFTD), semantic PPA, and nonfluent PPA?
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How do MAPT, GRN, and C9orf72 mutations converge on shared circuit failure?
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Which specific tau]/proteins/tau strains map to symptom domains and disease spread patterns?
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What mechanisms determine when FTD pathology extends into motor systems and overlaps with ALS?
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Which fluid and imaging biomarkers are best suited for pre-symptomatic intervention trials?
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How do social cognition network failures emerge before classic executive dysfunction in bvFTD?
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GCI vs. NCI: Chicken or egg?
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Early diagnosis**: How can MSA be distinguished from PD in the first 2-3 years, before classic features emerge?
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GCI vs. NCI: Chicken or egg?**: Does oligodendrocyte pathology drive neuronal loss, or vice versa? What is the primary insult in MSA?
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Why oligodendrocytes?**: What makes oligodendrocytes particularly vulnerable to alpha-synuclein accumulation in MSA compared to PD?
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Therapeutic targets**: What pathways beyond alpha-synuclein are most promising for disease modification? CoQ10, mitochondrial function, myelin repair?
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Heterogeneity**: MSA-P vs MSA-C represent different clinical manifestations of the same disease or distinct subtypes? Can we understand the molecular basis of this subtype variation?
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Co-pathology**: How common is co-occurrence of MSA pathology with AD or DLB pathology? How does co-pathology affect clinical presentation and progression?
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What are the exact mechanisms of prion-like propagation of [alpha-synuclein](/proteins/alpha-synuclein) pathology?
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Can we develop therapies that block propagation without disrupting normal synaptic function?
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How do [GBA](/entities/gba) variants influence disease progression and treatment response?
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Are there protective genetic factors that could be therapeutically mimicked?
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What is the optimal combination of biomarkers for early PD diagnosis?
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Can we identify individuals at risk decades before clinical symptoms appear?
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How do we differentiate PD from other parkinsonian disorders using biomarkers?
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How do we develop combination therapies that target multiple pathological pathways?
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What endpoints should be used in clinical trials for early-stage PD?
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How does autonomic dysfunction relate to alpha-synuclein pathology?
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Could gut-targeted interventions modify PD progression?
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Can treating non-motor symptoms slow overall disease progression?
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What is the role of the [microbiome](/entities/microbiome) in PD susceptibility and progression?
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Why do some individuals with amyloid plaques never develop dementia?
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What biomarker combinations best predict progression?
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Why do amyloid-targeting therapies show limited clinical benefit?
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What is the role of neuroinflammation in AD progression?
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What are the real-world outcomes of amyloid-targeting antibodies?
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Which lifestyle interventions provide meaningful risk reduction?
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Can combination therapy approaches improve outcomes over monotherapy?**: Given the modest effects of amyloid clearance alone, combining anti-amyloid with anti-tau, anti-inflammatory, or synaptic prote
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What is the therapeutic potential of TREM2 modulators?**: TREM2 variants strongly influence AD risk, and TREM2-activating antibodies are in development. What is the optimal timing and patient selectio
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How do we address tau pathology beyond antibody approaches?**: Small molecule tau aggregation inhibitors, antisense oligonucleotides, and gene therapy approaches are in development. Which modality off
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Which molecular events initiate [alpha-synuclein](/proteins/alpha-synuclein) aggregation within oligodendroglia in Multiple System Atrophy?
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How can MSA-P and MSA-C biological subtypes be defined using multimodal biomarkers rather than syndromic labels?
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What mechanisms link dysautonomia onset to later motor and cerebellar decline trajectories?
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How can neurofilament light chain (NfL) and related fluid markers improve short-horizon trial stratification?
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Which assays most reliably distinguish MSA from Parkinson's Disease and Progressive Supranuclear Palsy (PSP)?
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How should substantia nigra, putaminal, and cerebellar imaging biomarkers be integrated into progression models?
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What causal role does iron dyshomeostasis play in disease propagation and therapeutic response?
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Which timing window is most appropriate for disease-modifying intervention before irreversible network-level degeneration?
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How can adaptive platform trials be designed for rare-disease enrollment constraints in MSA?
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What triggers alpha-synuclein misfolding in sporadic PD?
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What determines clinical heterogeneity?
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Can we develop sensitive preclinical detection methods?
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What are reliable progression markers?
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How can we achieve meaningful neuroprotection?
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What is the relationship between alpha-synuclein and tau/beta-amyloid?
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What are the optimal fluid and imaging biomarkers to distinguish FTLD-TDP, FTLD-tau, and FTLD-FUS subtypes in living patients?
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How do TDP-43, tau, and FUS pathologies interact with each other and with co-occurring Alzheimer's disease pathology?
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Can progranulin replacement strategies restore lysosomal function in GRN mutation carriers?
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Can molecular PET ligands reliably detect FTLD-specific protein aggregates in the brain?
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Which genes beyond [GRN](/genes/grn), [MAPT](/genes/mapt), and [C9orf72](/genes/c9orf72) contribute to sporadic and familial FTLD?
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How do [C9orf72](/genes/c9orf72) repeat expansions drive both FTLD and ALS phenotypes, and what determines clinical presentation?
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What biomarkers best predict progression rate and phenotype conversion in behavioral variant FTD?
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How should clinical trials stratify patients by underlying pathology rather than clinical syndrome alone?
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What are the optimal endpoints for FTLD clinical trials given the heterogeneity of clinical presentations?
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What is the role of [microglia](/cell-types/microglia)-mediated neuroinflammation in FTLD pathogenesis and progression?
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How do innate immune pathways interact with TDP-43 and tau pathology in FTLD?
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Can immune-modulating strategies slow disease progression in FTLD subtypes?
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How do TDP-43 pathology mechanisms differ between pure FTLD and FTLD-ALS overlap cases?
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What determines the age of onset variability?
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Why do some patients develop cognitive impairment?
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Can disease progression be slowed with early intervention?
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What is the precise mechanism of LRRK2-auxilin interaction?
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Which plasma biomarker panels are robust enough for clinical deployment before overt motor symptoms?
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How should presymptomatic gene-carrier cohorts be staged for prevention-oriented intervention trials?
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What biomarkers best forecast bulbar versus limb onset and respiratory decline trajectories?
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What is the therapeutic value of targeting non-coding regulatory variation in sporadic ALS?
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How can trial design better account for molecular heterogeneity across SOD1, C9orf72, TARDBP, and FUS biology?
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Which immunological signatures are reproducible and clinically actionable across ALS subtypes?
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Which mechanistic pathways explain resilience in slow-progressing ALS cases?
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How should cell and gene therapies be sequenced with supportive and neuroprotective therapies?
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How can ALS-FTD spectrum phenotypes be integrated into unified endpoint frameworks?
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What combinations of molecular and digital biomarkers should become standard in platform trials?
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Can biomarkers reliably distinguish FTD from AD and primary psychiatric disorders before significant neurodegeneration?
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How should FTD diagnostic criteria be adapted for culturally and linguistically diverse populations?
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Can [blood-based biomarkers](/diagnostics/plasma-biomarkers) (NfL, GFAP, p-tau effectively stratify FTD subtypes?
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What explains the diagnostic delay of 3-4 years commonly seen in behavioral variant FTD?
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Is progranulin replacement sufficient, or has irreversible neurodegeneration already occurred by the time patients are enrolled?
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Can [antisense oligonucleotides targeting C9orf72 repeat RNA benefit FTD patients?
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Are there sporadic FTD drug targets analogous to amyloid in AD?
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How should clinical trial endpoints be standardized across FTD's heterogeneous subtypes?
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Neuroimaging biomarkers
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Biochemical biomarkers
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Clinical biomarkers
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Viral vectors
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Targeted delivery
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