DeCure for Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy
DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for cerebral arteriopathy with subcortical infarcts and leukoencephalopathy — screening already-approved drugs against its 2-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleCerebral arteriopathy with subcortical infarcts and leukoencephalopathy maps to a 2-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for cerebral arteriopathy with subcortical infarcts and leukoencephalopathy is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
notch receptor 3 (NOTCH3) — NOTCH3 is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet apo structuredrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 5CZX · 2.1 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
In a 2007 study of 40 NOTCH3 mutation carriers from 15 families, lacunar infarct lesion load on MRI was the only imaging measure independently associated with cognitive dysfunction after correcting for age (P<0.05). White matter hyperintensity volume and microbleeds showed no independent association. A 2024 study of 24 CADASIL patients and 24 matched controls found that enlarged perivascular space volumes did not differ between groups, but within the CADASIL group larger perivascular space volumes were associated with greater white matter hyperintensity volume (β=0.57, P=0.05), worse Clinical Dementia Rating Sum-of-Boxes scores (β=0.49, P=0.04), and marginally with lower brain parenchymal fraction (β=−0.03, P=0.10). Interaction models confirmed that the effect of enlarged perivascular space volume on these outcomes was significantly stronger in CADASIL patients than in controls.
The same 2024 study measured 7363 plasma proteins. Proteins positively associated with enlarged perivascular space volumes in CADASIL were related to leukocyte migration and inflammation; negatively associated proteins were related to lipid metabolism. Two central hub proteins were identified: CXCL8/IL-8 and CCL2/MCP-1. Higher CCL2/MCP-1 levels were associated with lower brain parenchymal fraction (β=−0.0007, P<0.01), lower Mini-Mental State Examination scores (β=−0.02, P<0.01), and longer Trail Making Test B completion times (β=0.76, P<0.01). Higher CXCL8/IL-8 levels were associated with greater white matter hyperintensity volume (β=42.86, P=0.03). No single protein was associated with all three imaging measures of pathology.
A 2023 iPSC study modelled the neurovascular unit using cells from CADASIL patients. When wild-type mural cells, astrocytes, or neurons were co-cultured with patient-derived brain microvascular endothelial cells, only the wild-type mural cells failed to rescue the impaired barrier function. Patient-derived endothelial cells showed disorganised tight junctions that could not be rescued by wild-type mural cells and were only partially rescued by wild-type astrocytes or neurons. A 2008 review article aimed at psychiatrists provides an overview of diagnostic algorithms and management guidance but reports no new experimental data.
What is still missing: no randomised controlled trial of any drug has been reported in these abstracts; no longitudinal biomarker study has linked the plasma protein findings to clinical progression; the iPSC model has not been used to test a therapeutic intervention; and no validated surrogate endpoint for cognitive decline in CADASIL has been established. Funding for a multicentre trial, a reliable patient stratification method, and a consensus on which imaging or fluid biomarker best tracks disease progression are all lacking.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Stroke · 2007 · 114 citations · open access
Lacunar Infarcts Are the Main Correlate With Cognitive Dysfunction in CADASIL
AbstractBACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy is caused by mutations in the NOTCH3 gene and is clinically characterized by recurrent stroke and cognitive decline. Previous studies have shown an association between white matter hyperintensities on brain MRI and cognitive dysfunction in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. In the general population the presence of lacunar infarcts and microbleeds is also associated with cognitive dysfunction. The objective of this study was to determine to what extent lacunar infarcts and microbleeds on MRI contribute to cognitive decline in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. METHODS: NOTCH3 mutation analysis was performed in 62 symptomatic and asymptomatic members of 15 cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy families. Neuropsychological tests were performed on the same day as the MRI examination. MRI was semi-quantitatively scored for white matter hyperintensities, infarct lesion load, and microbleeds. Regression analysis was performed to test the association between MRI abnormalities and neuropsychological test results. RESULTS: Forty individuals had a NOTCH3 mutation and 22 did not. Severity of cognitive dysfunction in mutation carriers was independently associated with MRI infarct lesion load (P<0.05). In contrast, WMH lesion load and microbleeds were not associated with cognitive dysfunction after correcting for age. CONCLUSIONS: Lacunar infarct lesion load is the most important MRI parameter associated with cognitive dysfunction in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.
Brain Communications · 2024 · 11 citations · open access
Enlarged perivascular spaces are associated with white matter injury, cognition and inflammation in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
AbstractAbstract Enlarged perivascular spaces have been previously reported in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, but their significance and pathophysiology remains unclear. We investigated associations of white matter enlarged perivascular spaces with classical imaging measures, cognitive measures and plasma proteins to better understand what enlarged perivascular spaces represent in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and whether radiographic measures of enlarged perivascular spaces would be of value in future therapeutic discovery studies for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Twenty-four individuals with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and 24 age- and sex-matched controls were included. Disease status was determined based on the presence of NOTCH3 mutation. Brain imaging measures of white matter hyperintensity, brain parenchymal fraction, white matter enlarged perivascular space volumes, clinical and cognitive measures as well as plasma proteomics were used in models. White matter enlarged perivascular space volumes were calculated via a novel, semiautomated pipeline, and levels of 7363 proteins were quantified in plasma using the SomaScan assay. The relationship of enlarged perivascular spaces with global burden of white matter hyperintensity, brain atrophy, functional status, neurocognitive measures and plasma proteins was modelled with linear regression models. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and control groups did not exhibit differences in mean enlarged perivascular space volumes. However, increased enlarged perivascular space volumes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy were associated with increased white matter hyperintensity volume (β = 0.57, P = 0.05), Clinical Dementia Rating Sum-of-Boxes score (β = 0.49, P = 0.04) and marginally with decreased brain parenchymal fraction (β = −0.03, P = 0.10). In interaction term models, the interaction term between cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy disease status and enlarged perivascular space volume was associated with increased white matter hyperintensity volume (β = 0.57, P = 0.02), Clinical Dementia Rating Sum-of-Boxes score (β = 0.52, P = 0.02), Mini-Mental State Examination score (β = −1.49, P = 0.03) and marginally with decreased brain parenchymal fraction (β = −0.03, P = 0.07). Proteins positively associated with enlarged perivascular space volumes were found to be related to leukocyte migration and inflammation, while negatively associated proteins were related to lipid metabolism. Two central hub proteins were identified in protein networks associated with enlarged perivascular space volumes: CXC motif chemokine ligand 8/interleukin-8 and C-C motif chemokine ligand 2/monocyte chemoattractant protein 1. The levels of CXC motif chemokine ligand 8/interleukin-8 were also associated with increased white matter hyperintensity volume (β = 42.86, P = 0.03), and levels of C-C motif chemokine ligand 2/monocyte chemoattractant protein 1 were further associated with decreased brain parenchymal fraction (β = −0.0007, P &lt; 0.01) and Mini-Mental State Examination score (β = −0.02, P &lt; 0.01) and increased Trail Making Test B completion time (β = 0.76, P &lt; 0.01). No proteins were associated with all three studied imaging measures of pathology (brain parenchymal fraction, enlarged perivascular spaces, white matter hyperintensity). Based on associations uncovered between enlarged perivascular space volumes and cognitive functions, imaging and plasma proteins, we conclude that white matter enlarged perivascular space volumes may capture pathologies contributing to chronic brain dysfunction and degeneration in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.
Advances in Psychiatric Treatment · 2008 · 9 citations · open access
CADASIL: a guide to a comparatively unrecognised condition in psychiatry
AbstractThis guide to the neurological disorder cerebral autosomal dominant arteriopathy with subcortical infarcts and leuco encephalopathy (CADASIL) is specifically targeted at psychiatrists. The aims are to enhance awareness, provide educational clinical information and offer practical guidance on management of the disorder. An overview of diagnostic algorithms and recent research is also provided.
INDIGO (University of Illinois at Chicago) · 2023 · 0 citations · open access
Data_Sheet_1_Induced pluripotent stem cell model revealed impaired neurovascular interaction in genetic small vessel disease Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy.pdf
AbstractIntroduction<p>Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is the most common genetic small vessel disease caused by variants in the NOTCH3 gene. Patients with CADASIL experience recurrent strokes, developing into cognitive defect and vascular dementia. CADASIL is a late-onset vascular condition, but migraine and brain MRI lesions appear in CADASIL patients as early as their teens and twenties, suggesting an abnormal neurovascular interaction at the neurovascular unit (NVU) where microvessels meet the brain parenchyma.</p>Methods<p>To understand the molecular mechanisms of CADASIL, we established induced pluripotent stem cell (iPSC) models from CADASIL patients and differentiated the iPSCs into the major NVU cell types including brain microvascular endothelial-like cells (BMECs), vascular mural cells (MCs), astrocytes and cortical projection neurons. We then built an in vitro NVU model by co-culturing different neurovascular cell types in Transwells and evaluated the blood brain barrier (BBB) function by measuring transendothelial electrical resistance (TEER).</p>Results<p>Results showed that, while the wild-type MCs, astrocytes and neurons could all independently and significantly enhance TEER of the iPSC-BMECs, such capability of MCs from iPSCs of CADASIL patients was significantly impaired. Additionally, the barrier function of the BMECs from CADASIL iPSCs was significantly decreased, accompanied with disorganized tight junctions in iPSC-BMECs, which could not be rescued by the wild-type MCs or sufficiently rescued by the wild-type astrocytes and neurons.</p>Discussion<p>Our findings provide new insight into early disease pathologies on the neurovascular interaction and BBB function at the molecular and cellular levels for CADASIL, which helps inform future therapeutic development.</p>
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
