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Cited by 37Cerebrovascular and genetic disordersGenetic Neurodegenerative DiseasesIntracerebral and Subarachnoid Hemorrhage Research

Clinical and research applications of magnetic resonance imaging in the study of CADASIL

Open access
Schoemaker, Dorothee, Quiroz, Yakeel T., Torrico-Teave, Heirangi, Arboleda-Velasquez, Joseph F.·2019·Neuroscience Letters
DOI 10.1016/j.neulet.2019.01.014PMC PMC6661177
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Abstract

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is an inherited small vessel disease that leads to early cerebrovascular events and functional disability. It is the most common single-gene disorder leading to stroke. Magnetic resonance imaging (MRI) is a central component of the diagnosis and monitoring of CADASIL. Here we provide a descriptive review of the literature on three important aspects pertaining to the use of MRI in CADASIL. First, we review past research exploring MRI markers for this disease. Secondly, we describe results from studies investigating associations between neuroimaging abnormalities and neuropathology in CADASIL. Finally, we discuss previous findings relating MRI markers to clinical symptoms. This review thus provides a summary of the current state of knowledge regarding the use of MRI in CADASIL as well as suggestions for future research.

AI snapshot

Written from the paper’s full text.

TL;DR

This descriptive review summarizes how MRI is used in CADASIL for diagnosis, for understanding underlying pathology, and for relating imaging markers to clinical symptoms. It concludes that no single MRI marker reliably distinguishes CADASIL from other small vessel diseases, while lacunes and brain atrophy are the most consistent imaging correlates of disability and cognitive impairment.

Key findings

  • Core MRI abnormalities in CADASIL include white matter hyperintensities, subcortical infarcts, and cerebral microbleeds; these can be seen in most patients over age 35 and may appear 10–15 years before clinical symptoms.
  • Anterior temporal pole white matter hyperintensities have been reported with high diagnostic performance in some studies—sensitivity 90% and specificity 100% in one comparison with sporadic leukoaraiosis, and sensitivity 89% and specificity 86% for moderate/severe involvement in another—but such features are not sufficiently sensitive or specific overall, and external capsule lesions have lower specificity.
  • Lacunes and brain atrophy are the MRI markers most consistently linked to poorer cognition and disability; in contrast, findings for white matter hyperintensities and cerebral microbleeds are mixed, with some studies showing associations and others not.
  • Few studies directly connect MRI findings to neuropathology; examples include postmortem work on iron deposition in the caudate and putamen, neuronal apoptosis related to white matter hyperintensity extent, and temporal pole hyperintensities attributed to enlarged perivascular spaces plus myelin and axonal damage.

Methods

  • Design: a descriptive literature review covering three areas—MRI markers for diagnosis, MRI–neuropathology associations, and MRI–clinical symptom associations.
  • Data: previously published studies, including imaging cohorts, longitudinal follow-ups, postmortem case series, and single-case reports; no new primary data were collected.
  • Analysis: narrative synthesis of findings across studies, with attention to diagnostic sensitivity/specificity, pathological correlates, and clinical correlations.

Limitations

  • The paper states that systematic research linking MRI markers to pathology in CADASIL is scarce, that clinical–imaging associations are inconsistent and need replication, and that no proposed MRI marker is sufficiently sensitive or specific for reliable differential diagnosis.
  • The paper notes limitations in cited studies, including small samples, autopsy cases without available MRI, and subjective assessment of brain atrophy in one family-based study.
  • Evident from the text: as a descriptive review, it does not report a systematic search strategy, inclusion criteria, or quantitative meta-analysis, and it relies on heterogeneous studies with varying designs and outcome measures.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.neulet.2019.01.014

Cites

80 of 80 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 210 cited sources checked · 0 supported · 0 flagged

  • Findingreasoning

    Among MRI markers in CADASIL, lacunes and brain atrophy show the most consistent association with cognitive and functional outcomes.

    “In this literature, the presence and extent of lacunes and brain atrophy has been the most consistently associated with cognitive and/or functional outcomes in CADASIL.”
    • Also stated in: § Conclusion · hedged
      “Finally, the review of studies investigating relationships between MRI markers and clinical symptoms in CADASIL indicates that lacunes and brain atrophy are the most robustly related to disability and cognitive status.”
    Quote in the paperSubstantial claim
  • Findingreasoning

    The radiological features of CADASIL are largely similar to those of other white matter diseases, including multiple sclerosis and sporadic small vessel disease.

    “The review of studies investigating potential MRI markers for CADASIL indicates that it shares largely similar radiological features with other diseases affecting white matter integrity, such as multiple sclerosis or sporadic forms of SVD (as an illustration, see Figure 1).”
    Quote in the paperSubstantial claim
  • Findingnone given

    Few studies have systematically examined how MRI markers relate to pathology in CADASIL.

    “This review also points to the lack of research systematically examining associations between MRI markers and pathology in CADASIL.”
    Quote in the paperSubstantial claim
  • Findingnone given

    Many studies have examined links between MRI markers and clinical symptoms in CADASIL.

    “To summarize, many studies have related MRI markers to clinical symptoms in CADASIL.”
    Quote in the paperNot a substantial claim
  • Findingreasoning

    Anterior temporal pole and external capsule involvement may raise suspicion for CADASIL.

    “Accordingly, while the involvement of the anterior temporal pole and external capsule can suggest the presence of CADASIL, none of the proposed MRI markers is sufficiently sensitive or specific to support the differential or accurate diagnosis of this disease.”
    Quote in the paperSubstantial claim
  • May combine two claims. 25
  • Classified as probably not a substantial claim. 9
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingnone given

    Findings on the relationship between MRI markers and clinical symptoms in CADASIL are sometimes inconsistent across studies and require replication.

    “However, these results are at times inconsistent across studies and need replication.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    MRI is a central component in the diagnosis of CADASIL and is routinely used to document small vessel disease in patients.

    “Magnetic Resonance Imaging (MRI) is a central component of the diagnosis of CADASIL and is routinely used to document SVD in patients [66].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [66] Stojanov D, Aracki-Trenkic A, Vojinovic S, Ljubisavljevic S, Benedeto-Stojanov D, Tasic A, Vujnovic S, Imaging characteristics of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), Bosnian journal of basic medical sciences 15 (2015) 1. PMC4365670 25725137

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisenone given

    CADASIL is an inherited small vessel disease that causes early cerebrovascular events and functional disability.

    “Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is an inherited small vessel disease that leads to early cerebrovascular events and functional disability.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    MRI abnormalities in CADASIL appear at a variable age but are observed in the vast majority of patients older than 35 years.

    “While MRI abnormalities appear at a variable age in CADASIL, they can be observed in the vast majority of patients aged above 35 years [6].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Chabriat H, Joutel A, Dichgans M, Tournier-Lasserve E, Bousser M-G, Cadasil, The Lancet Neurology 8 (2009) 643– 653. 19539236 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In CADASIL patients, white matter hyperintensities are predominantly periventricular, in the anterior temporal pole, external capsule, and frontal and parietal areas, and the pattern is often symmetrical.

    “In CADASIL patients, these studies have reported the presence of WMH predominantly in the periventricular region, anterior temporal pole, external capsule as well as frontal and parietal areas. The pattern of lesions is often described as symmetrical.”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [15] De Guio F, Reyes S, Vignaud A, Duering M, Ropele S, Duchesnay E, Chabriat H, Jouvent E, In vivo high-resolution 7 Tesla MRI shows early and diffuse cortical alterations in CADASIL, PloS one 9 (2014) e106311. 25165824 PMC4148432 source

      Not checked in the free run.

    • cites [25] Fattapposta F, Restuccia R, Pirro C, Malandrini A, Locuratolo N, Amabile G, Bianco F, Early diagnosis in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): the role of MRI, Functional neurology 19 (2004) 239– 242. 15776792

      Not checked in the free run.

    • cites [27] He D, Chen D, Li X, Hu Z, Yu Z, Wang W, The comparisons of phenotype and genotype between CADASIL and CADASIL-like patients and population-specific evaluation of CADASIL scale in China, The journal of headache and pain 17 (2016) 55. 27206574 PMC4875019 source

      Not checked in the free run.

    • cites [38] Liem MK, Lesnik Oberstein SA, Haan J, van der Neut IL, van den Boom R, Ferrari MD, van Buchem MA, van der Grond J, Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: progression of MR abnormalities in prospective 7-year follow-up study, Radiology 249 (2008) 964– 971. 18840792 source

      Not checked in the free run.

    • cites [43] Markus H, Martin R, Simpson M, Dong Y, Ali N, Crosby A, Powell J, Diagnostic strategies in CADASIL, Neurology 59 (2002) 1134– 1138. 12395806 source

      Not checked in the free run.

    • cites [51] Nannucci S, Pescini F, Bertaccini B, Bianchi S, Ciolli L, Valenti R, Dotti M, Federico A, Inzitari D, Pantoni L, Clinical, familial, and neuroimaging features of CADASIL-like patients, Acta Neurologica Scandinavica 131 (2015) 30– 36. 25109394 source

      Not checked in the free run.

    • cites [58] Pantoni L, Pescini F, Nannucci S, Sarti C, Bianchi S, Dotti M, Federico A, Inzitari D, Comparison of clinical, familial, and MRI features of CADASIL and NOTCH3-negative patients, Neurology 74 (2010) 57– 63. 20038773 source

      Not checked in the free run.

    • cites [65] Skehan SJ, Hutchinson M, MacErlaine DP, Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: MR findings, American journal of neuroradiology 16 (1995) 2115– 2119. 8585503 PMC8337226

      Not checked in the free run.

    • cites [70] van den Boom R, Lesnik Oberstein SA, van Duinen SG, Bornebroek M, Ferrari MD, Haan J, van Buchem MA, Subcortical lacunar lesions: an MR imaging finding in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, Radiology 224 (2002) 791– 796. 12202716 source

      Not checked in the free run.

    • cites [76] Yousry TA, Seelos K, Mayer M, Brüning R, Uttner I, Dichgans M, Mammi S, Straube A, Mai N, Filippi M, Characteristic MR lesion pattern and correlation of T1 and T2 lesion volume with neurologic and neuropsychological findings in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), American journal of neuroradiology 20 (1999) 91– 100. 9974062

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Macroscopic examination of affected brain tissue in CADASIL shows diffuse myelin rarefaction, subcortical lacunes, and cortical apoptosis.

    “Macroscopic examinations of affected brain tissues have revealed the presence of diffuse myelin rarefaction, lacunes mostly affecting subcortical areas, and cortical apoptosis [6, 28].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [6] Chabriat H, Joutel A, Dichgans M, Tournier-Lasserve E, Bousser M-G, Cadasil, The Lancet Neurology 8 (2009) 643– 653. 19539236 source

      Not checked in the free run.

    • cites [28] Herve D, Chabriat H, Cadasil, Journal of geriatric psychiatry and neurology 23 (2010) 269– 276. 21045164 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The core MRI abnormalities in CADASIL include white matter hyperintensities, subcortical infarcts, and cerebral microbleeds.

    “The core MRI abnormalities observed in CADASIL have been described in several reports and include the presence of white matter hyperintensities (WMH), subcortical infarcts and cerebral microbleeds (CM) [66].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [66] Stojanov D, Aracki-Trenkic A, Vojinovic S, Ljubisavljevic S, Benedeto-Stojanov D, Tasic A, Vujnovic S, Imaging characteristics of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), Bosnian journal of basic medical sciences 15 (2015) 1. PMC4365670 25725137

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The pathological hallmarks of CADASIL include degeneration of vascular smooth muscle cells and pericytes and granular osmiophilic material within vessels.

    “The pathological hallmarks of CADASIL include the degeneration of vascular smooth muscle cells and pericytes as well as the presence of granular osmiophilic material (GOM) within vessels [6, 28].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [6] Chabriat H, Joutel A, Dichgans M, Tournier-Lasserve E, Bousser M-G, Cadasil, The Lancet Neurology 8 (2009) 643– 653. 19539236 source

      Not checked in the free run.

    • cites [28] Herve D, Chabriat H, Cadasil, Journal of geriatric psychiatry and neurology 23 (2010) 269– 276. 21045164 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The mean age of onset of clinical symptoms in CADASIL is around 35 to 40 years.

    “Although the clinical presentation of CADASIL varies considerably between affected individuals, the mean age of onset of clinical symptoms is around 35 to 40 years [14, 17].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [14] Davous P, CADASIL: a review with proposed diagnostic criteria, European Journal of Neurology 5 (1998) 219– 233. 10210836 source

      Not checked in the free run.

    • cites [17] Desmond DW, Moroney JT, Lynch T, Chan S, Chin SS, Mohr J, The natural history of CADASIL: a pooled analysis of previously published cases, Stroke 30 (1999) 1230– 1233. 10356105 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CADASIL presents with migraines with aura, cognitive impairment, gait abnormality, and mood disturbance.

    “CADASIL presents with various neurological and psychiatric symptoms including migraines with aura, cognitive impairment, gait abnormality and mood disturbance [6].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Chabriat H, Joutel A, Dichgans M, Tournier-Lasserve E, Bousser M-G, Cadasil, The Lancet Neurology 8 (2009) 643– 653. 19539236 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Corpus callosum involvement is rare in sporadic small vessel disease but has been described in a small proportion of CADASIL cases.

    “Involvement of the corpus callosum, which is rare in sporadic forms of SVD, has been described in CADASIL individuals, but often in a small proportion of cases.”
    Quote in the paperNot a substantial claim0 of 10 sources checked
    • cites [15] De Guio F, Reyes S, Vignaud A, Duering M, Ropele S, Duchesnay E, Chabriat H, Jouvent E, In vivo high-resolution 7 Tesla MRI shows early and diffuse cortical alterations in CADASIL, PloS one 9 (2014) e106311. 25165824 PMC4148432 source

      Not checked in the free run.

    • cites [25] Fattapposta F, Restuccia R, Pirro C, Malandrini A, Locuratolo N, Amabile G, Bianco F, Early diagnosis in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): the role of MRI, Functional neurology 19 (2004) 239– 242. 15776792

      Not checked in the free run.

    • cites [27] He D, Chen D, Li X, Hu Z, Yu Z, Wang W, The comparisons of phenotype and genotype between CADASIL and CADASIL-like patients and population-specific evaluation of CADASIL scale in China, The journal of headache and pain 17 (2016) 55. 27206574 PMC4875019 source

      Not checked in the free run.

    • cites [38] Liem MK, Lesnik Oberstein SA, Haan J, van der Neut IL, van den Boom R, Ferrari MD, van Buchem MA, van der Grond J, Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: progression of MR abnormalities in prospective 7-year follow-up study, Radiology 249 (2008) 964– 971. 18840792 source

      Not checked in the free run.

    • cites [43] Markus H, Martin R, Simpson M, Dong Y, Ali N, Crosby A, Powell J, Diagnostic strategies in CADASIL, Neurology 59 (2002) 1134– 1138. 12395806 source

      Not checked in the free run.

    • cites [51] Nannucci S, Pescini F, Bertaccini B, Bianchi S, Ciolli L, Valenti R, Dotti M, Federico A, Inzitari D, Pantoni L, Clinical, familial, and neuroimaging features of CADASIL-like patients, Acta Neurologica Scandinavica 131 (2015) 30– 36. 25109394 source

      Not checked in the free run.

    • cites [58] Pantoni L, Pescini F, Nannucci S, Sarti C, Bianchi S, Dotti M, Federico A, Inzitari D, Comparison of clinical, familial, and MRI features of CADASIL and NOTCH3-negative patients, Neurology 74 (2010) 57– 63. 20038773 source

      Not checked in the free run.

    • cites [65] Skehan SJ, Hutchinson M, MacErlaine DP, Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: MR findings, American journal of neuroradiology 16 (1995) 2115– 2119. 8585503 PMC8337226

      Not checked in the free run.

    • cites [70] van den Boom R, Lesnik Oberstein SA, van Duinen SG, Bornebroek M, Ferrari MD, Haan J, van Buchem MA, Subcortical lacunar lesions: an MR imaging finding in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, Radiology 224 (2002) 791– 796. 12202716 source

      Not checked in the free run.

    • cites [76] Yousry TA, Seelos K, Mayer M, Brüning R, Uttner I, Dichgans M, Mammi S, Straube A, Mai N, Filippi M, Characteristic MR lesion pattern and correlation of T1 and T2 lesion volume with neurologic and neuropsychological findings in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), American journal of neuroradiology 20 (1999) 91– 100. 9974062

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MRI signal abnormalities in asymptomatic CADASIL individuals are less severe and less diffuse than in symptomatic patients, suggesting an association between abnormality severity and increasing symptoms.

    “MRI signal abnormalities in asymptomatic individuals are less severe and less diffuse than in symptomatic patients, suggesting an association between the severity of these abnormalities and increasing symptomatology [6].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Chabriat H, Joutel A, Dichgans M, Tournier-Lasserve E, Bousser M-G, Cadasil, The Lancet Neurology 8 (2009) 643– 653. 19539236 source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    Dichgans et al. (2002) acquired MRI in 16 CADASIL patients and postmortem pathological examinations in seven different patients, but no autopsied case had MRI data, so imaging-pathology relationships were not directly assessed.

    “MRI scans were acquired in 16 CADASIL patients, while postmortem pathological examinations were performed on seven different patients. Because none of the autopsied cases had available MRI data, this study was mostly observational and relationships between imaging and pathological variables were not directly assessed.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Dichgans M, Holtmannspotter M, Herzog J, Peters N, Bergmann M, Yousry TA, Cerebral microbleeds in CADASIL: a gradient-echo magnetic resonance imaging and autopsy study, Stroke 33 (2002) 67– 71. 11779891 source

      Not checked in the free run.

  • The quote only partly states this claim.

    Premisecitation

    Viswanathan et al. (2006) observed apoptotic neurons in all four CADASIL patients at autopsy.

    “Apoptotic neurons were observed in all cases at autopsy.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [72] Viswanathan A, Gray F, Bousser M-G, Baudrimont M, Chabriat H, Cortical neuronal apoptosis in CADASIL, Stroke 37 (2006) 2690– 2695. 17008611 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Anterior temporal involvement appears less common in subjects with cysteine-sparing NOTCH3 mutations, although the role of cysteine-sparing mutations in CADASIL pathogenesis remains debated.

    “For example, anterior temporal involvement appears to be less common in subjects with cysteine-sparing NOTCH3 mutations, although the role of cysteine-sparing mutations in the pathogenesis of CADASIL remains a matter of debate [26, 35, 44–46, 62].”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [26] Ge W, Kuang H, Wei B, Bo L, Xu Z, Xu X, Geng D, Sun M, A novel cysteine-sparing NOTCH3 mutation in a Chinese family with CADASIL, PloS one 9 (2014) e104533. 25098330 PMC4123979 source

      Not checked in the free run.

    • cites [35] Kim Y, Choi E, Choi C, Kim G, Choi J, Yoo H, Kim J, Characteristics of CADASIL in Korea A novel cysteine-sparing Notch3 mutation, Neurology 66 (2006) 1511– 1516. 16717210 source

      Not checked in the free run.

    • cites [44] Matsushima T, Conedera S, Tanaka R, Li Y, Yoshino H, Funayama M, Ikeda A, Hosaka Y, Okuzumi A, Shimada Y, Genotype–phenotype correlations of cysteine replacement in CADASIL, Neurobiology of aging 50 (2017) 169. e167– 169. e114. 27890607 source

      Not checked in the free run.

    • cites [45] Mazzei R, Conforti F, Lanza P, Sprovieri T, Lupo M, Gallo O, Patitucci A, Magariello A, Caracciolo M, Gabriele A, A novel Notch3 gene mutation not involving a cysteine residue in an Italian family with CADASIL, Neurology 63 (2004) 561– 564. 15304596 source

      Not checked in the free run.

    • cites [46] Mizuno T, Muranishi M, Torugun T, Tango H, Nagakane Y, Kudeken T, Kawase Y, Kawabe K, Oshima F, Yaoi T, Two Japanese CADASIL families exhibiting Notch3 mutation R75P not involving cysteine residue, Internal Medicine 47 (2008) 2067– 2072. 19043263 source

      Not checked in the free run.

    • cites [62] Scheid R, Heinritz W, Leyhe T, Thal D, Schober R, Strenge S, von Cramon DY, Froster U, Cysteine-sparing notch3 mutations: cadasil or cadasil variants?, Neurology 71 (2008) 774– 776. 18765654 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A study of members of a single family carrying a CADASIL mutation concluded that atrophy was rather rare.

    “In contrast, a previous study on members of a single family carrying a CADASIL mutation concluded that atrophy was rather rare [12].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Coulthard A, Blank S, Bushby K, Kalaria R, Burn D, Distribution of cranial MRI abnormalities in patients with symptomatic and subclinical CADASIL, The British journal of radiology 73 (2000) 256– 265. 10817040 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The severity of apoptosis was related to normalized brain volumes, suggesting that apoptosis likely contributes to cerebral atrophy in CADASIL.

    “The severity of the apoptosis was related to normalized brain volumes, suggesting that it likely contributes to cerebral atrophy in CADASIL.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [72] Viswanathan A, Gray F, Bousser M-G, Baudrimont M, Chabriat H, Cortical neuronal apoptosis in CADASIL, Stroke 37 (2006) 2690– 2695. 17008611 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MRI differences between CADASIL patients and non-carriers are overall limited and are not consistently found across studies.

    “Despite the identification of MRI differences between CADASIL patients and non-carriers, these differences are overall limited and not consistently found across studies.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [51] Nannucci S, Pescini F, Bertaccini B, Bianchi S, Ciolli L, Valenti R, Dotti M, Federico A, Inzitari D, Pantoni L, Clinical, familial, and neuroimaging features of CADASIL-like patients, Acta Neurologica Scandinavica 131 (2015) 30– 36. 25109394 source

      Not checked in the free run.

    • cites [58] Pantoni L, Pescini F, Nannucci S, Sarti C, Bianchi S, Dotti M, Federico A, Inzitari D, Comparison of clinical, familial, and MRI features of CADASIL and NOTCH3-negative patients, Neurology 74 (2010) 57– 63. 20038773 source

      Not checked in the free run.

    • cites [63] Schmidt H, Zeginigg M, Wiltgen M, Freudenberger P, Petrovic K, Cavalieri M, Gider P, Enzinger C, Fornage M, Debette S, Genetic variants of the NOTCH3 gene in the elderly and magnetic resonance imaging correlates of age-related cerebral small vessel disease, Brain 134 (2011) 3384– 3397. 22006983 PMC3212720 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Whole-brain diffusion trace histograms differ significantly between CADASIL patients and age-matched controls, indicating widespread microstructural tissue damage.

    “Significant differences in histograms representing the whole-brain trace of the diffusion have been observed between CADASIL patients and age-matched controls, pointing to the presence of widespread microstructural tissue damage in this disease [48].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Molko N, Pappata S, Mangin J-F, Poupon F, LeBihan D, Bousser M-G, Chabriat H, Monitoring disease progression in CADASIL with diffusion magnetic resonance imaging: a study with whole brain histogram analysis, Stroke 33 (2002) 2902– 2908. 12468789 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    External capsule lesions have been proposed as a potential diagnostic feature of CADASIL, but they occur in a lower proportion of patients and have lower diagnostic specificity.

    “The presence of lesions in the external capsule has also been proposed as a potential diagnostic feature of CADASIL [1, 3, 9, 10, 43, 52, 54, 58, 64, 65, 76], although it has been reported in a lower proportion of patients and has been associated with a lower diagnostic specificity [69].”
    Quote in the paperNot a substantial claim0 of 10 sources checked
    • cites [1] Abramycheva N, Stepanova M, Kalashnikova L, Zakharova M, Maximova M, Tanashyan M, Lagoda O, Fedotova E, Klyushnikov S, Konovalov R, New mutations in the Notch3 gene in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), Journal of the neurological sciences 349 (2015) 196– 201. 25623805 source

      Not checked in the free run.

    • cites [3] Ayrignac X, Carra-Dalliere C, Menjot de Champfleur N, Denier C, Aubourg P, Bellesme C, Castelnovo G, Pelletier J, Audoin B, Kaphan E, Adult-onset genetic leukoencephalopathies: a MRI pattern-based approach in a comprehensive study of 154 patients, Brain 138 (2014) 284– 292. 25527826 source

      Not checked in the free run.

    • cites [9] Chabriat H, Vahedi K, Bousser M, Iba-Zizen M, Joutel A, Nibbio A, Nagy T, Lasserve ET, Krebs M, Julien J, Clinical spectrum of CADASIL: a study of 7 families, The Lancet 346 (1995) 934– 939. 7564728 source

      Not checked in the free run.

    • cites [10] Chawda S, De Lange R, Hourihan M, Halpin S, Clair DS, Diagnosing CADASIL using MRI: evidence from families with known mutations of Notch 3 gene, Neuroradiology 42 (2000) 249– 255. 10872167 source

      Not checked in the free run.

    • cites [43] Markus H, Martin R, Simpson M, Dong Y, Ali N, Crosby A, Powell J, Diagnostic strategies in CADASIL, Neurology 59 (2002) 1134– 1138. 12395806 source

      Not checked in the free run.

    • cites [52] O’Riordan S, Nor A, Hutchinson M, CADASIL imitating multiple sclerosis: the importance of MRI markers, Multiple Sclerosis Journal 8 (2002) 430– 432. 12356211 source

      Not checked in the free run.

    • cites [54] O’Sullivan M, Jarosz J, Martin R, Deasy N, Powell J, Markus H, MRI hyperintensities of the temporal lobe and external capsule in patients with CADASIL, Neurology 56 (2001) 628– 634. 11245715 source

      Not checked in the free run.

    • cites [58] Pantoni L, Pescini F, Nannucci S, Sarti C, Bianchi S, Dotti M, Federico A, Inzitari D, Comparison of clinical, familial, and MRI features of CADASIL and NOTCH3-negative patients, Neurology 74 (2010) 57– 63. 20038773 source

      Not checked in the free run.

    • cites [64] Singhal S, Rich P, Markus HS, The spatial distribution of MR imaging abnormalities in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and their relationship to age and clinical features, American Journal of Neuroradiology 26 (2005) 2481– 2487. 16286388 PMC7976180

      Not checked in the free run.

    • cites [65] Skehan SJ, Hutchinson M, MacErlaine DP, Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: MR findings, American journal of neuroradiology 16 (1995) 2115– 2119. 8585503 PMC8337226

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Anterior temporal lobe involvement on MRI is highly specific and can distinguish CADASIL from other conditions.

    “Previous evidence suggests that anterior temporal lobe involvement on MR images is highly specific and allows for distinguishing CADASIL from other conditions [1, 2, 10, 27, 43, 52, 54, 64, 68–70, 76].”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [1] Abramycheva N, Stepanova M, Kalashnikova L, Zakharova M, Maximova M, Tanashyan M, Lagoda O, Fedotova E, Klyushnikov S, Konovalov R, New mutations in the Notch3 gene in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), Journal of the neurological sciences 349 (2015) 196– 201. 25623805 source

      Not checked in the free run.

    • cites [2] Auer DP, Putz B, Gossl C, Elbel G-K, Gasser T, Dichgans M, Differential lesion patterns in CADASIL and sporadic subcortical arteriosclerotic encephalopathy: MR imaging study with statistical parametric group comparison, Radiology 218 (2001) 443– 451. 11161160 source

      Not checked in the free run.

    • cites [10] Chawda S, De Lange R, Hourihan M, Halpin S, Clair DS, Diagnosing CADASIL using MRI: evidence from families with known mutations of Notch 3 gene, Neuroradiology 42 (2000) 249– 255. 10872167 source

      Not checked in the free run.

    • cites [27] He D, Chen D, Li X, Hu Z, Yu Z, Wang W, The comparisons of phenotype and genotype between CADASIL and CADASIL-like patients and population-specific evaluation of CADASIL scale in China, The journal of headache and pain 17 (2016) 55. 27206574 PMC4875019 source

      Not checked in the free run.

    • cites [43] Markus H, Martin R, Simpson M, Dong Y, Ali N, Crosby A, Powell J, Diagnostic strategies in CADASIL, Neurology 59 (2002) 1134– 1138. 12395806 source

      Not checked in the free run.

    • cites [52] O’Riordan S, Nor A, Hutchinson M, CADASIL imitating multiple sclerosis: the importance of MRI markers, Multiple Sclerosis Journal 8 (2002) 430– 432. 12356211 source

      Not checked in the free run.

    • cites [54] O’Sullivan M, Jarosz J, Martin R, Deasy N, Powell J, Markus H, MRI hyperintensities of the temporal lobe and external capsule in patients with CADASIL, Neurology 56 (2001) 628– 634. 11245715 source

      Not checked in the free run.

    • cites [64] Singhal S, Rich P, Markus HS, The spatial distribution of MR imaging abnormalities in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and their relationship to age and clinical features, American Journal of Neuroradiology 26 (2005) 2481– 2487. 16286388 PMC7976180

      Not checked in the free run.

    • cites [68] Tomimoto H, Ohtani R, Wakita H, Lin J-X, Ihara M, Miki Y, Oshima F, Murata T, Ishibashi K, Suenaga T, Small artery dementia in Japan: radiological differences between CADASIL, leukoaraiosis and Binswanger’s disease, Dementia and geriatric cognitive disorders 21 (2006) 162– 169. 16391479 source

      Not checked in the free run.

    • cites [69] van den Boom R, Lesnik Oberstein SA, Ferrari MD, Haan J, van Buchem MA, Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: MR imaging findings at different ages—3rd–6th decades, Radiology 229 (2003) 683– 690. 14593195 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Anterior temporal pole and external capsule involvement may suggest CADASIL but are not sufficient to confirm its diagnosis.

    “While the involvement of the anterior temporal pole and external capsule may hint the presence of CADASIL, these features are not sufficient to confirm its diagnosis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Other studies have failed to find an independent influence of cerebral microbleeds on cognition or depressive symptoms.

    “In opposition, other studies have failed to find an independent influence of CM on cognition [56, 73] or depressive symptoms [59].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [56] Oberstein SL, Van den Boom R, Van Buchem M, Van Houwelingen H, Bakker E, Vollebregt E, Ferrari M, Breuning M, Haan J, Cerebral microbleeds in CADASIL, Neurology 57 (2001) 1066– 1070. 11571335 source

      Not checked in the free run.

    • cites [73] Viswanathan A, Gschwendtner A, Guichard J-P, Buffon F, Cumurciuc R, O’Sullivan M, Holtmannspötter M, Pachai C, Bousser M-G, Dichgans M, Lacunar lesions are independently associated with disability and cognitive impairment in CADASIL, Neurology 69 (2007) 172– 179. 17620550 source

      Not checked in the free run.

    • cites [59] Park JH, Jeon B-H, Lee JS, Newhouse PA, Taylor WD, Boyd BD, Kim KW, Kim M-D, CADASIL as a useful medical model and genetic form of vascular depression, The American Journal of Geriatric Psychiatry 25 (2017) 719– 727. 28434675 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Yamamoto et al. (2009) proposed that MRI temporal pole hyperintensities in CADASIL reflect enlarged perivascular spaces together with myelin depletion and axonal damage.

    “They proposed that MRI temporal pole hyperintensities in CADASIL patients reflect enlarged PVS, together with myelin depletion and axonal damage.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [74] Yamamoto Y, Ihara M, Tham C, Low RW, Slade JY, Moss T, Oakley AE, Polvikoski T, Kalaria RN, Neuropathological correlates of temporal pole white matter hyperintensities in CADASIL, Stroke 40 (2009) 2004– 2011. 19359623 PMC2724668 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    No associations were found between lenticulostriate artery luminal diameters and basal ganglia lacunes, suggesting that these lesions were not caused by narrowing of lenticulostriate arteries.

    “The authors found no associations between luminal diameters and lacunes in the basal ganglia, suggesting that these lesions were not caused by a narrowing of lenticulostriate arteries.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Liem MK, van der Grond J, Versluis MJ, Haan J, Webb AG, Ferrari MD, van Buchem MA, Lesnik Oberstein SA, Lenticulostriate arterial lumina are normal in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy: a high-field in vivo MRI study, Stroke 41 (2010) 2812– 2816. 20966419 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing). May combine two claims.

    Premisecitation

    It has been proposed that cerebral microbleeds may not have a direct effect on disability in CADASIL but may instead represent a consequence of the severity of other lesions.

    “Potentially contributing to discrepancies in findings across studies, it has been proposed that CM may not have a direct effect on disability in CADASIL but rather represent a consequence of the severity of other lesions [72].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [72] Viswanathan A, Gray F, Bousser M-G, Baudrimont M, Chabriat H, Cortical neuronal apoptosis in CADASIL, Stroke 37 (2006) 2690– 2695. 17008611 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The divergence in findings on brain parenchymal fraction and cognition may be due to Benisty et al. studying a specific CADASIL subpopulation without lacunes.

    “However, this group studied a specific CADASIL subpopulation presenting without lacunes, potentially contributing to this divergence in findings.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Benisty S, Reyes S, Godin O, Hervé D, Zieren N, Jouvent E, Zhu Y, During M, Dichgans M, Chabriat H, White-matter lesions without lacunar infarcts in CADASIL, Journal of Alzheimer’s Disease 29 (2012) 903– 911. 22330818 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Considering regional white matter hyperintensity burden rather than adopting a whole-brain approach allowed superior prediction of clinical outcomes.

    “According to the authors, considering regional WMH burden, rather than adopting a whole-brain approach, allowed a superior prediction of clinical outcomes.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Duchesnay E, Selem FH, De Guio F, Dubois M, Mangin J-F, Duering M, Ropele S, Schmidt R, Dichgans M, Chabriat H, Different Types of White Matter Hyperintensities in CADASIL, Frontiers in neurology 9 (2018). PMC6048276 30042721 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    An increase in the number of cerebral microbleeds over time is linked with a decrease in global cognitive functioning, memory, and executive function.

    “The increase in the number of CM over time has further been linked with a decrease in global cognitive functioning, memory and executive function [37].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Liem M, Oberstein SL, Haan J, Van der Neut I, Ferrari M, Van Buchem M, Middelkoop H, Van der Grond J, MRI correlates of cognitive decline in CADASIL A 7-year follow-up study, Neurology 72 (2009) 143– 148. 19139365 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Overall lesion load on T1-weighted MRI is associated with global disability, often measured by the modified Rankin Scale, and with performance on different cognitive domains in CADASIL.

    “The overall lesion load observed on T1-weighted MR images has been associated with the degree of global disability, often quantified using the modified Rankin Scale [4], and with performance on different cognitive domains [18, 76].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [4] Banks JL, Marotta CA, Outcomes validity and reliability of the modified Rankin scale: implications for stroke clinical trials: a literature review and synthesis, Stroke 38 (2007) 1091– 1096. 17272767 source

      Not checked in the free run.

    • cites [18] Dichgans M, Filippi M, Brüning R, Iannucci G, Berchtenbreiter C, Minicucci L, Uttner I, Crispin A, Ludwig H, Gasser T, Quantitative MRI in CADASIL correlation with disability and cognitive performance, Neurology 52 (1999) 1361– 1361. 10227618 source

      Not checked in the free run.

    • cites [76] Yousry TA, Seelos K, Mayer M, Brüning R, Uttner I, Dichgans M, Mammi S, Straube A, Mai N, Filippi M, Characteristic MR lesion pattern and correlation of T1 and T2 lesion volume with neurologic and neuropsychological findings in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), American journal of neuroradiology 20 (1999) 91– 100. 9974062

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The regional distribution pattern of MRI lesions is an important factor in explaining observed deficits in CADASIL.

    “For example, in two articles, Duering et al. proposed that the regional pattern of distribution of MRI lesions is an important factor in the explanation of observed deficits [21, 23].”
    • Also stated in: § Conclusion · hedged
      “However, associations between clinical and imaging variables appear to fluctuate depending on the type of symptoms examined as well as other modulating factors, such as the cognitive reserve or the regional distribution of brain lesions.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [21] Duering M, Gonik M, Malik R, Zieren N, Reyes S, Jouvent E, Hervé D, Gschwendtner A, Opherk C, Chabriat H, Identification of a strategic brain network underlying processing speed deficits in vascular cognitive impairment, Neuroimage 66 (2013) 177– 183. 23153965 source

      Not checked in the free run.

    • cites [23] Duering M, Zieren N, Hervé D, Jouvent E, Reyes S, Peters N, Pachai C, Opherk C, Chabriat H, Dichgans M, Strategic role of frontal white matter tracts in vascular cognitive impairment: a voxel-based lesion-symptom mapping study in CADASIL, Brain 134 (2011) 2366– 2375. 21764819 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Yao et al. (2014) demonstrated that the severity of perivascular space dilatation was worsened in demented CADASIL patients and was associated with global cognitive functioning regardless of age.

    “For example, Yao et al. (2014) demonstrated that the severity of PVS dilatation was worsened in demented CADASIL patients and was associated with global cognitive functioning, regardless of the age [75].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [75] Yao M, Hervé D, Jouvent E, Duering M, Reyes S, Godin O, Guichard JP, Dichgans M, Chabriat H, Dilated perivascular spaces in small-vessel disease: a study in CADASIL, Cerebrovascular Diseases 37 (2014) 155– 163. 24503815 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In CADASIL, the link between clinical and imaging measures seems to vary with the symptom type and with modulators such as cognitive reserve or lesion distribution.

    “However, associations between clinical and imaging variables appear to fluctuate depending on the type of symptoms examined as well as other modulating factors, such as the cognitive reserve or the regional distribution of brain lesions.”
    Quote in the paperSubstantial claim
33 of 33

  • The paper relies on this without support.

    Genetic testing is the gold standard for the clinical diagnosis of CADASIL.

    “Genetic testing is the gold standard for the clinical diagnosis of CADASIL.”

  • The paper relies on this without support.

    CADASIL is the most prevalent monogenic cause of stroke and vascular dementia.

    “It is recognized as the most prevalent monogenic cause of stroke and vascular dementia.”
2 of 2

Cites

Flagged first, then by citations

6 of the 86 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Stromillo, 2008, Structural and metabolic brain abnormalities in preclinical CADASIL, J. Neurol. Neurosurg. Psychiatry

Cited by

Sorted by citations

Related

Authors
Schoemaker, D., Quiroz, Y. T., Torrico-Teave, H., & Arboleda-Velasquez, J. F.
Affiliations
Harvard University (US)
ORCID
Quiroz, Yakeel T.
Venue
Neuroscience Letters
Publisher
Elsevier BV
Published
2019-04
Volume
698
Pages
173-179
ISSN
0304-3940 (ISSN-L)
DOI
10.1016/j.neulet.2019.01.014
PMC
PMC6661177
OpenAlex
W2909830543
Cited by
36
References
86
Citations by year
2026: 1 · 2025: 2 · 2024: 8 · 2023: 7 · 2022: 6 · 2021: 6 · 2020: 4 · 2019: 2
FWCI
0.60
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuroscience Letters (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Fonds de Recherche Santé Québec (Canada)
  • National Institute of Neurological Disorders and Stroke (UH3 NS100121, RF1 NS110048)
  • Massachusetts General Hospital Executive Committee on Research (ECOR)
Topics
  • Health Sciences › Medicine › Neurology › Cerebrovascular and genetic disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Health Sciences › Medicine › Neurology › Intracerebral and Subarachnoid Hemorrhage Research
Keywords
CADASIL, magnetic resonance imaging, MRI markers, cerebral small vessel disease, clinical symptoms, disease diagnosis and monitoring
MeSH terms
Brain, Humans, Magnetic Resonance Imaging, Biomarkers, Stroke, CADASIL, Neuroimaging

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-01.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-01.

Statistics and arithmetic are recomputed, not judged.

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