¶ CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy)
Cadasil (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts And Leukoencephalopathy) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is the most common hereditary cause of [stroke[/diseases/[stroke[/diseases/[stroke[/diseases/[stroke--TEMP--/diseases)--FIX-- and [[/diseases/vascular-dementia|Vascular Dementia[/diseases/[vascular-dementia[/diseases/[vascular-dementia[/diseases/[vascular-dementia--TEMP--/diseases)--FIX--|Vascular Dementia] in adults. It is a monogenic small vessel disease caused by mutations in the [[genes/notch3|NOTCH3[/genes/[notch3[/genes/[notch3[/genes/[notch3--TEMP--/genes)--FIX--|NOTCH3]] gene on chromosome 19p13, which encodes a transmembrane receptor predominantly expressed in vascular smooth muscle cells [1](https://www.ncbi.nlm.nih.gov/books/NBK470293/). CADASIL was first described by Sourander and Wålinder in 1977, with the term coined by Tournier-Lasserve in 1993 after the genetic locus was identified [2](https://pubmed.ncbi.nlm.nih.gov/28231783/).
The disease is characterized by recurrent subcortical ischemic strokes, progressive cognitive decline leading to [[/diseases/frontotemporal-dementia|dementia[/diseases/[ftd[/diseases/[ftd[/diseases/[ftd--TEMP--/diseases)--FIX--, [migraine[/diseases/[migraine[/diseases/[migraine[/diseases/[migraine--TEMP--/diseases)--FIX-- with aura, and psychiatric disturbances. CADASIL is inherited in an autosomal dominant pattern, meaning a single mutant copy of the [[genes/notch3|NOTCH3[/genes/[notch3[/genes/[notch3[/genes/[notch3--TEMP--/genes)--FIX--|NOTCH3]] gene is sufficient to cause disease. It affects all ethnic groups worldwide and is estimated to have a minimum prevalence of approximately 5 per 100,000 [3](https://thejcn.com/DOIx.php?id=10.3988/jcn.2023.19.1.12). However, this figure likely underestimates the true prevalence due to underdiagnosis, and some population-based genetic studies suggest the actual prevalence may be considerably higher.
The [[genes/notch3|NOTCH3[/genes/[notch3[/genes/[notch3[/genes/[notch3--TEMP--/genes)--FIX--|NOTCH3]] gene encodes a 2,321-amino acid single-pass transmembrane receptor protein that contains 34 epidermal growth factor-like repeat (EGFr) domains in its extracellular domain (ECD). Each EGFr domain normally contains six cysteine residues that form three disulfide bonds critical for protein folding and stability [4](https://www.ahajournals.org/doi/10.1161/STROKEAHA.118.021560).
Over 280 distinct pathogenic mutations have been identified in the [[genes/notch3|NOTCH3[/genes/[notch3[/genes/[notch3[/genes/[notch3--TEMP--/genes)--FIX--|NOTCH3]] gene. The vast majority are missense mutations located within the EGFr domains (exons 2-24), and virtually all CADASIL-causing mutations result in either the gain or loss of a cysteine residue within an EGFr domain, producing an odd number of cysteines (typically 5 or 7 instead of the normal 6) [5](https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2025.1662012/full). This unpaired cysteine promotes abnormal protein folding and aggregation.
- Exons 3 and 4 harbor the highest proportion of mutations (approximately 70% of cases)
- Exon 4 mutations, particularly p.R169C, are the most frequently reported
- Mutations in exons 2-6 (EGFr 1-6) are associated with more classical phenotypes
- Mutations in more distal EGFr domains (7-34) may produce variable clinical presentations
- Rare non-cysteine-altering mutations have been reported, though their pathogenicity remains debated
CADASIL follows autosomal dominant inheritance with high penetrance. Each child of an affected parent has a 50% chance of inheriting the mutation. Approximately 5-10% of cases arise from de novo mutations without a family history [6](https://pmc.ncbi.nlm.nih.gov/articles/PMC2851292/).
¶ [[genes/notch3|NOTCH3[/genes/[notch3[/genes/[notch3[/genes/[notch3--TEMP--/genes)--FIX--|NOTCH3]] Signaling and Vascular Smooth Muscle Cells
The [[genes/notch3|NOTCH3[/genes/[notch3[/genes/[notch3[/genes/[notch3--TEMP--/genes)--FIX--|NOTCH3]] receptor is primarily expressed in vascular smooth muscle cells (VSMCs) and [pericytes[/entities/[pericytes[/entities/[pericytes[/entities/[pericytes--TEMP--/entities)--FIX-- of small arteries and arterioles. Under normal conditions, [[genes/notch3|NOTCH3[/genes/[notch3[/genes/[notch3[/genes/[notch3--TEMP--/genes)--FIX--|NOTCH3]] signaling is essential for the maturation, differentiation, and survival of VSMCs [7](https://pmc.ncbi.nlm.nih.gov/articles/PMC12042419/).
In CADASIL, mutant [[genes/notch3|NOTCH3[/genes/[notch3[/genes/[notch3[/genes/[notch3--TEMP--/genes)--FIX--|NOTCH3]] protein undergoes several pathological changes:
- Abnormal ECD accumulation: The mutant [[genes/notch3|NOTCH3[/genes/[notch3[/genes/[notch3[/genes/[notch3--TEMP--/genes)--FIX--|NOTCH3]] extracellular domain (NOTCH3ECD) accumulates on the surface of VSMCs, failing to undergo normal proteolytic clearance
- Granular osmiophilic material (GOM): NOTCH3ECD aggregates with extracellular matrix proteins including tissue inhibitor of metalloproteinase 3 (TIMP3), clusterin, endostatin, vitronectin, and serum amyloid P component (SAP) to form pathognomonic deposits called GOM [8](https://pubmed.ncbi.nlm.nih.gov/19174371/)
- VSMC degeneration: Progressive loss and degeneration of VSMCs in small penetrating arteries of the brain and other organs
- Vessel wall thickening: Fibrosis and thickening of the vessel wall with luminal narrowing
The [[genes/notch3|NOTCH3[/genes/[notch3[/genes/[notch3[/genes/[notch3--TEMP--/genes)--FIX--|NOTCH3] vascular pathology leads to brain injury through multiple interconnected mechanisms (Chabriat et al., 2009; Rutten et al., 2019):
- Chronic cerebral hypoperfusion: Impaired vasoreactivity and reduced cerebral blood flow due to progressive loss of vascular smooth muscle cells and their replacement by [[genes/notch3|NOTCH3[/genes/[notch3[/genes/[notch3[/genes/[notch3--TEMP--/genes)--FIX--|NOTCH3] extracellular domain (ECD) deposits and granular osmiophilic material (GOM). Cerebral blood flow is reduced by 30–50% in symptomatic CADASIL patients
- [blood-brain barrier[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier--TEMP--/entities)--FIX-- dysfunction: Disrupted endothelial integrity caused by pericyte degeneration and loss of tight junctions, allowing plasma protein leakage into the perivascular space and contributing to white matter edema and damage
- Lacunar infarction: Occlusion of small penetrating arteries by lumen narrowing produces strategic subcortical infarcts, predominantly in the [basal ganglia[/brain-regions/[basal-ganglia[/brain-regions/[basal-ganglia[/brain-regions/[basal-ganglia--TEMP--/brain-regions)--FIX--, thalamus, pons, and deep white matter
- Perivascular space enlargement: Accumulation of interstitial fluid from impaired glymphatic clearance, visible on MRI as dilated perivascular spaces (état criblé)
- Secondary neurodegeneration: Progressive disconnection of cortical-subcortical white matter tracts leads to remote cortical thinning even in regions without primary vascular lesions
Migraine with aura is typically the earliest manifestation of CADASIL, occurring in approximately 20-40% of patients. It often presents in the second or third decade of life, frequently before other neurological symptoms appear. Features include:
- Attacks may be prolonged or atypical (hemiplegic [migraine[/diseases/[migraine[/diseases/[migraine[/diseases/[migraine--TEMP--/diseases)--FIX--, basilar-type aura)
- Aura symptoms can include visual, sensory, language, and motor disturbances
- Some patients experience confusional migraines mimicking acute [stroke[/diseases/[stroke[/diseases/[stroke[/diseases/[stroke--TEMP--/diseases)--FIX--
- Frequency typically decreases as the disease progresses and ischemic symptoms predominate
Recurrent subcortical ischemic strokes are the hallmark of CADASIL, occurring in approximately 60-85% of patients:
- Onset typically in the fourth to fifth decade (mean age ~49 years)
- Classical lacunar syndromes: pure motor hemiparesis, pure sensory [stroke[/diseases/[stroke[/diseases/[stroke[/diseases/[stroke--TEMP--/diseases)--FIX--, ataxic hemiparesis, dysarthria-clumsy hand syndrome
- Subcortical location predominantly in the [basal ganglia[/brain-regions/[basal-ganglia[/brain-regions/[basal-ganglia[/brain-regions/[basal-ganglia--TEMP--/brain-regions)--FIX--, [thalamus[/brain-regions/[thalamus[/brain-regions/[thalamus[/brain-regions/[thalamus--TEMP--/brain-regions)--FIX--, internal capsule, and [pons[/brain-regions/[pons[/brain-regions/[pons[/brain-regions/[pons--TEMP--/brain-regions)--FIX--
- TIA-like episodes with transient focal deficits
- Step-wise neurological deterioration with each event
Progressive cognitive impairment eventually affects nearly all patients:
- Executive dysfunction (planning, organizing, mental flexibility) is the earliest cognitive feature
- Processing speed reduction is prominent
- Memory impairment develops as the disease progresses
- Subcortical pattern of [[/diseases/frontotemporal-dementia|dementia[/diseases/[ftd[/diseases/[ftd[/diseases/[ftd--TEMP--/diseases)--FIX-- (in contrast to the cortical pattern of [Alzheimer's Disease)
- Dementia is present in approximately one-third of patients and increases sharply after age 60
- Average age of disability onset is approximately 58 years
¶ Psychiatric and Mood Disturbances
Neuropsychiatric manifestations are common in CADASIL and may even be the presenting feature in approximately 15% of cases. These symptoms are often underrecognized but contribute significantly to disability and caregiver burden (Reyes et al., 2009; Valenti et al., 2022):
- Depression: The most frequent psychiatric symptom, affecting 20–40% of patients. Often occurs in association with executive dysfunction and is linked to ischemic lesions in the [basal ganglia[/brain-regions/[basal-ganglia[/brain-regions/[basal-ganglia[/brain-regions/[basal-ganglia--TEMP--/brain-regions)--FIX-- and frontal white matter. May present as major depressive episodes with melancholic features, or as persistent depressive disorder
- Apathy: Distinct from depression, apathy reflects loss of motivation and goal-directed behavior due to frontal-subcortical circuit disruption. Affects 40–50% of patients and is strongly correlated with white matter lesion volume and executive impairment. Apathy is often the most disabling behavioral symptom
- Anxiety: Generalized anxiety and adjustment disorders, often comorbid with depression and cognitive decline
- Pseudobulbar affect: Pathological crying or laughing disproportionate to emotional stimuli, resulting from disruption of cortico-pontine-cerebellar pathways. Present in approximately 10% of patients
- Psychotic episodes: Rare but documented — acute psychosis, mania, and catatonia-like states can occur, particularly during acute encephalopathic episodes or following [stroke[/diseases/[stroke[/diseases/[stroke[/diseases/[stroke--TEMP--/diseases)--FIX--. May be misdiagnosed as primary psychiatric illness if CADASIL is unrecognized
- Behavioral changes: Progressive personality changes including irritability, disinhibition, and social withdrawal, particularly in patients with extensive frontal white matter disease
Beyond the cardinal features of [migraine[/diseases/[migraine[/diseases/[migraine[/diseases/[migraine--TEMP--/diseases)--FIX--, [stroke[/diseases/[stroke[/diseases/[stroke[/diseases/[stroke--TEMP--/diseases)--FIX--, cognitive decline, and psychiatric symptoms, CADASIL can produce several additional clinical features:
- Acute encephalopathy: Rare episodes of acute confusion, fever, and seizures, often triggered by [migraine[/diseases/[migraine[/diseases/[migraine[/diseases/[migraine--TEMP--/diseases)--FIX-- attacks or metabolic stress. These encephalopathic episodes may mimic meningoencephalitis and typically resolve over days to weeks, though they can leave residual cognitive deficits
- Seizures: Occur in approximately 5–10% of CADASIL patients, often in association with cortical or subcortical infarcts. Both focal and generalized seizures have been reported
- Gait disturbances and parkinsonism: Progressive gait impairment from subcortical white matter damage and [basal ganglia[/brain-regions/[basal-ganglia[/brain-regions/[basal-ganglia[/brain-regions/[basal-ganglia--TEMP--/brain-regions)--FIX-- lacunes; mild parkinsonian features (bradykinesia, rigidity) may develop in later stages, though typical resting tremor is uncommon
- Urinary dysfunction: Urgency and incontinence from disruption of frontal micturition control pathways; affects the majority of patients in later disease stages
- Progressive disability: Functional dependence develops at a mean age of approximately 63 years. By age 65, the majority of patients require assistance with activities of daily living. Confinement to bed occurs at a mean age of ~65 years, with death typically in the seventh decade
- Hearing loss: Sensorineural hearing loss has been reported in some CADASIL families, possibly related to cochlear vascular involvement
CADASIL should be suspected in patients with:
- Recurrent subcortical strokes or TIAs at a young age (before 60)
- Migraine with aura, especially atypical [migraine[/diseases/[migraine[/diseases/[migraine[/diseases/[migraine--TEMP--/diseases)--FIX--
- Family history of [stroke[/diseases/[stroke[/diseases/[stroke[/diseases/[stroke--TEMP--/diseases)--FIX--, [[/diseases/frontotemporal-dementia|dementia[/diseases/[ftd[/diseases/[ftd[/diseases/[ftd--TEMP--/diseases)--FIX--, or [migraine[/diseases/[migraine[/diseases/[migraine[/diseases/[migraine--TEMP--/diseases)--FIX--
- White matter disease on MRI disproportionate to vascular risk factors
- Cognitive decline with a subcortical pattern
Brain MRI is essential for diagnosis and shows characteristic findings that often precede clinical symptoms (Chabriat et al., 2009; Markus et al., 2002):
- White matter hyperintensities (WMH): Symmetrical, progressive T2/FLAIR hyperintensities, often appearing before clinical symptoms (sometimes as early as age 20). WMH are nearly universal by age 35 in mutation carriers and progress inexorably over time
- Anterior temporal lobe involvement: T2/FLAIR hyperintensities in the anterior temporal poles (present in ~90% of CADASIL patients) are a highly characteristic finding that helps distinguish CADASIL from other causes of white matter disease
- External capsule involvement: WMH in the external capsule is another distinguishing feature, seen in >90% of patients by age 50
- Lacunar infarcts: Small subcortical infarcts predominantly in the [basal ganglia[/brain-regions/[basal-ganglia[/brain-regions/[basal-ganglia[/brain-regions/[basal-ganglia--TEMP--/brain-regions)--FIX--, thalamus, pons, and periventricular white matter; number and location correlate with cognitive deficits
- Microbleeds: T2*-weighted or susceptibility-weighted imaging (SWI) detects cerebral microbleeds in 30–70% of CADASIL patients, predominantly in subcortical locations. Microbleed burden is associated with more severe disease and increased bleeding risk with antiplatelet therapy
- Brain atrophy: Progressive cortical and subcortical atrophy correlating with cognitive decline; hippocampal atrophy may contribute to memory impairment
- Dilated perivascular spaces: Visible on T2-weighted imaging, particularly in the centrum semiovale and basal ganglia
¶ Treatment and Management
There are currently no disease-modifying therapies specifically approved for CADASIL. Management is largely supportive and focuses on vascular risk factor control and symptom management (GeneReviews, 2024):
Vascular Risk Factor Management
- Blood pressure control: Aggressive hypertension management is critical, as hypertension approximately doubles the risk of [stroke[/diseases/[stroke[/diseases/[stroke[/diseases/[stroke--TEMP--/diseases)--FIX-- in CADASIL. Target blood pressure <130/80 mmHg is generally recommended
- Smoking cessation: Smoking advances the age of first [stroke[/diseases/[stroke[/diseases/[stroke[/diseases/[stroke--TEMP--/diseases)--FIX-- by approximately 10 years in CADASIL patients
- Antiplatelet therapy: Low-dose aspirin (75–300 mg/day) is recommended for patients who have experienced ischemic [stroke[/diseases/[stroke[/diseases/[stroke[/diseases/[stroke--TEMP--/diseases)--FIX--. Clopidogrel (75 mg/day) is an alternative. Dual antiplatelet therapy (aspirin + clopidogrel) and anticoagulants (warfarin, DOACs) should be avoided unless absolutely indicated for another condition, due to increased intracerebral hemorrhage risk
- Lipid management: Statins for hypercholesterolemia, though their specific benefit in CADASIL has not been established in clinical trials
Emerging Disease-Modifying Research
- [[genes/notch3|NOTCH3[/genes/[notch3[/genes/[notch3[/genes/[notch3--TEMP--/genes)--FIX--|NOTCH3]] agonist antibodies: Under preclinical development to restore [[genes/notch3|NOTCH3[/genes/[notch3[/genes/[notch3[/genes/[notch3--TEMP--/genes)--FIX--|NOTCH3]] receptor signaling and potentially halt vascular smooth muscle cell degeneration
- Gene therapy approaches: Antisense oligonucleotides and gene silencing strategies targeting mutant [[genes/notch3|NOTCH3[/genes/[notch3[/genes/[notch3[/genes/[notch3--TEMP--/genes)--FIX--|NOTCH3]] are in early research stages:
- Blood pressure control: Antihypertensive therapy to reduce [stroke[/diseases/[stroke[/diseases/[stroke[/diseases/[stroke--TEMP--/diseases)--FIX-- risk, though aggressive lowering should be avoided given impaired cerebral autoregulation
- Diabetes management: Glycemic control to minimize additional vascular damage
- Lipid management: Statin therapy may be considered for hyperlipidemia
- Smoking cessation: Strongly recommended
¶ Antiplatelet and Anticoagulant Therapy
- Antiplatelet agents (aspirin, clopidogrel) may be considered after ischemic events, but must be weighed against increased risk of cerebral microbleeds and hemorrhagic complications
- Anticoagulants are generally avoided due to the high bleeding risk
- Thrombolysis for acute [stroke[/diseases/[stroke[/diseases/[stroke[/diseases/[stroke--TEMP--/diseases)--FIX-- remains controversial
Migraine with aura (often hemiplegic [migraine[/diseases/[migraine[/diseases/[migraine[/diseases/[migraine--TEMP--/diseases)--FIX--) is typically the earliest manifestation of CADASIL, with onset in the second to third decade:
- Acute treatment: Standard analgesics (paracetamol, NSAIDs) are first-line for acute [migraine[/diseases/[migraine[/diseases/[migraine[/diseases/[migraine--TEMP--/diseases)--FIX-- attacks. Triptans were historically avoided due to theoretical vasoconstriction risk, but a recent systematic review found they can be safely used in CADASIL and provide effective relief in approximately 50% of patients. Newer alternatives — lasmiditan (a 5-HT1F receptor agonist/"ditan" without vasoconstrictive properties) and gepants (ubrogepant, rimegepant — CGRP receptor antagonists) — are attractive alternatives, though not yet specifically studied in CADASIL
- Preventive therapies: Topiramate, valproate, and lamotrigine are commonly used [migraine[/diseases/[migraine[/diseases/[migraine[/diseases/[migraine--TEMP--/diseases)--FIX-- preventives. Venlafaxine and amitriptyline are second-line options. Beta-blockers should be used cautiously given the cerebral hypoperfusion in CADASIL
- CGRP monoclonal antibodies: Erenumab, fremanezumab, galcanezumab — effective [migraine[/diseases/[migraine[/diseases/[migraine[/diseases/[migraine--TEMP--/diseases)--FIX-- preventives in the general population; case reports suggest benefit in CADASIL, but systematic data are lacking
- Acetazolamide: Has been used specifically for hemiplegic [migraine[/diseases/[migraine[/diseases/[migraine[/diseases/[migraine--TEMP--/diseases)--FIX-- in CADASIL, reducing attack frequency and severity
- Avoid: Ergotamine-based medications (potent vasoconstrictors)
Comprehensive symptomatic management addresses the multifaceted disability in CADASIL:
- Antidepressants: SSRIs (sertraline, escitalopram) are first-line for depression and anxiety. SNRIs (venlafaxine, duloxetine) have dual benefit for mood and potential [migraine[/diseases/[migraine[/diseases/[migraine[/diseases/[migraine--TEMP--/diseases)--FIX-- prevention. Tricyclic antidepressants (amitriptyline) may help with both mood and [migraine[/diseases/[migraine[/diseases/[migraine[/diseases/[migraine--TEMP--/diseases)--FIX-- prophylaxis
- Cognitive rehabilitation: Structured cognitive rehabilitation programs targeting executive function, attention, and processing speed; compensatory strategy training for memory difficulties; environmental modifications (structured routines, external memory aids)
- Physical therapy and occupational therapy: Gait and balance training to reduce fall risk; strengthening and flexibility programs; occupational therapy for adaptive equipment and maintaining independence in activities of daily living
- Speech and language therapy: For dysarthria following [stroke[/diseases/[stroke[/diseases/[stroke[/diseases/[stroke--TEMP--/diseases)--FIX-- and for progressive language difficulties
- Seizure management: Standard antiepileptic medications when indicated; levetiracetam and lamotrigine are preferred due to favorable side effect profiles
- Caregiver support: Psychoeducation, respite care, and support groups, particularly as cognitive decline progresses to [[/diseases/frontotemporal-dementia|dementia[/diseases/[ftd[/diseases/[ftd[/diseases/[ftd--TEMP--/diseases)--FIX--
- Advance care planning: Given the predictable disease trajectory, early discussion of goals of care, power of attorney, and end-of-life preferences is recommended
Several disease-modifying strategies are under investigation [10](https://link.springer.com/article/10.1007/s13237-025-00598-3):
- Gene editing approaches: CRISPR-based correction of [[genes/notch3|NOTCH3[/genes/[notch3[/genes/[notch3[/genes/[notch3--TEMP--/genes)--FIX--|NOTCH3]] mutations
- Anti-NOTCH3ECD antibodies: Targeting abnormal protein accumulation
- Cysteine-correcting strategies: Small molecules to restore disulfide bonding
- Immunomodulatory therapies: Reducing neuroinflammation associated with the vasculopathy
- Cell therapies: Replacement of damaged VSMCs
- TIMP3 modulation: Addressing downstream effects of NOTCH3ECD accumulation
CADASIL follows a progressive course with variable expressivity even within the same family:
- Mean age of onset for ischemic symptoms: ~46 years
- Mean age of disability: ~58 years
- Mean age of death: ~64-68 years (approximately 20 years shorter than the general population)
- Death typically results from complications of advanced disability (pneumonia, aspiration) rather than acute [stroke[/diseases/[stroke[/diseases/[stroke[/diseases/[stroke--TEMP--/diseases)--FIX--
- Rate of progression varies considerably between individuals
CADASIL must be distinguished from other causes of cerebral small vessel disease:
- CARASIL: Autosomal recessive form caused by HTRA1 mutations (alopecia, spondylosis)
- Fabry disease: X-linked, caused by alpha-galactosidase A deficiency
- [Cerebral amyloid angiopathy[/diseases/[cerebral-amyloid-angiopathy[/diseases/[cerebral-amyloid-angiopathy[/diseases/[cerebral-amyloid-angiopathy--TEMP--/diseases)--FIX--: Typically sporadic, lobar hemorrhages
- Sporadic small vessel disease: Hypertensive arteriopathy
- Multiple sclerosis: Demyelinating disease (but white matter pattern differs)
- MELAS: Mitochondrial encephalomyopathy with [stroke[/diseases/[stroke[/diseases/[stroke[/diseases/[stroke--TEMP--/diseases)--FIX---like episodes
CADASIL has important connections to other neurodegenerative conditions:
- [[/diseases/vascular-dementia|Vascular Dementia[/diseases/[vascular-dementia[/diseases/[vascular-dementia[/diseases/[vascular-dementia--TEMP--/diseases)--FIX--|Vascular Dementia]: CADASIL is the archetypal genetic model of pure vascular cognitive impairment
- [Alzheimer's disease[/diseases/[alzheimers[/diseases/[alzheimers[/diseases/[alzheimers--TEMP--/diseases)--FIX--: Mixed pathology can occur; cerebral hypoperfusion may accelerate [amyloid] and tau] pathology]
- [Blood-Brain Barrier breakdown]: Shared mechanism with AD-related vascular dysfunction
- [neuroinflammation[/mechanisms/[neuroinflammation[/mechanisms/[neuroinflammation[/mechanisms/[neuroinflammation--TEMP--/mechanisms)--FIX--: Chronic microglial activation contributes to disease progression in both CADASIL and neurodegenerative dementias
The study of Cadasil (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts And Leukoencephalopathy) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
- Chabriat H, et al. CADASIL. Lancet Neurol. 2009;8(7):643-653. DOI:10.1016/S1474-4422(0970127-4
- Joutel A, et al. The [[genes/notch3|NOTCH3[/genes/[notch3[/genes/[notch3[/genes/[notch3--TEMP--/genes)--FIX--|Notch3]] gene in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): pathology and fundamental biology. Acta Neuropathol. 2010;120(1):49-56. DOI:10.1007/s00401-010-0667-0
- Dichgans M. CADASIL: a monogenic condition mimicking [[/diseases/vascular-dementia|Vascular Dementia[/diseases/[vascular-dementia[/diseases/[vascular-dementia[/diseases/[vascular-dementia--TEMP--/diseases)--FIX--|Vascular Dementia]] phenotypes. Lancet Neurol. 2009;8(8):694-695. DOI:10.1016/S1474-4422(0970176-4
- Tikka S, et al. CADASIL prevalence in Finland: new estimates based on [[genes/notch3|NOTCH3[/genes/[notch3[/genes/[notch3[/genes/[notch3--TEMP--/genes)--FIX--|NOTCH3]] mutation analysis. Neurology. 2014;83(7):578-579. DOI:10.1212/WNL.0000000000000692
- Monet-Lepretre M, et al. Distinct phenotypic and functional features of CADASIL mutations in the [[genes/notch3|NOTCH3[/genes/[notch3[/genes/[notch3[/genes/[notch3--TEMP--/genes)--FIX--|Notch3]] ligand binding domain. Brain. 2009;132(Pt 6):1601-1612. DOI:10.1093/brain/awp046
- Joutel A, et al. Cerebrovascular disease in CADASIL: a 7-year follow-up study. Neurology. 2002;59(6):900-904. DOI:10.1212/wnl.59.6.900
- Viswanathan A, et al. MRI correlates of cognitive decline in CADASIL: a 7-year study. Neurology. 2007;68(2):102-108. DOI:10.1212/01.wnl.0000251283.43467.bf
- [Di Donato I, Bianchi S, De Stefano N, et al. "Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) as a model of small vessel disease." BMC Med. 2017;15(1):41. PubMed)
- [Razvi SS, Davidson R, Bone I, Muir KW. "The prevalence of CADASIL in the west of Scotland." J Neurol Neurosurg Psychiatry. 2005;76(5):739-741. PubMed)
- [Rutten JW, et al. "Role of [[genes/notch3|NOTCH3[/genes/[notch3[/genes/[notch3[/genes/[notch3--TEMP--/genes)--FIX--|NOTCH3]] Mutations in Cerebral Small Vessel Disease." Stroke. 2019;50:e1-e8. AHA Journals)
- [Wang M, et al. "CADASIL or [[genes/notch3|NOTCH3[/genes/[notch3[/genes/[notch3[/genes/[notch3--TEMP--/genes)--FIX--|NOTCH3]] mutation spectrum diseases?" Front Neurol. 2025. Frontiers)
- [Opherk C, Peters N, Herzog J, Luedtke R, Dichgans M. "Long-term prognosis and causes of death in CADASIL." Neurology. 2004;63(7):1084-1089. PubMed)
- [Domenga V, Fardoux P, Lacombe P, et al. "[[genes/notch3|NOTCH3[/genes/[notch3[/genes/[notch3[/genes/[notch3--TEMP--/genes)--FIX--|Notch3]] is required for arterial identity and maturation of vascular smooth muscle cells." Genes Dev. 2004;18(22):2730-2735. PubMed)
- [Tikka S, Mykkanen K, Ruchoux MM, et al. "Congruence between [[genes/notch3|NOTCH3[/genes/[notch3[/genes/[notch3[/genes/[notch3--TEMP--/genes)--FIX--|NOTCH3]] mutations and GOM in 131 CADASIL patients." Brain. 2009;132(Pt 4):933-939. PubMed)
- [Markus HS, Martin RJ, Simpson MA, et al. "Diagnostic strategies in CADASIL." Neurology. 2002;59(8):1134-1138. PubMed)
- [Khandelwal P, Gupta N. "CADASIL: potential therapeutic approaches." The Nucleus. 2025. Springer Nature)
- [Joutel A, Corpechot C, Ducros A, et al. "[[genes/notch3|NOTCH3[/genes/[notch3[/genes/[notch3[/genes/[notch3--TEMP--/genes)--FIX--|Notch3]] mutations in CADASIL." Nature. 1996;383(6602):707-710. PubMed)
- [Dichgans M, Mayer M, Uttner I, et al. "The phenotypic spectrum of CADASIL: clinical findings in 102 cases." Ann Neurol. 1998;44(5):731-739. PubMed)
- Ringelstein EB, et al. European consensus on current diagnostic criteria and treatment of CADASIL. Lancet Neurol. 2020;19(11):902-912. DOI:10.1016/S1474-4422(2030257-6