Treatment with Cerebrolysin Prolongs Lifespan in a Mouse Model of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare familial neurological disorder caused by mutations in the NOTCH3 gene and characterized by migraine attacks, depressive episodes, lacunar strokes, dementia, and premature death. Since there is no therapy for CADASIL the authors investigate whether the multi-modal neuropeptide drug Cerebrolysin may improve outcome in a murine CADASIL model. Twelve-month-old NOTCH3R169C mutant mice (n=176) are treated for nine weeks with Cerebrolysin or Vehicle and histopathological and functional outcomes are evaluated within the subsequent ten months. Cerebrolysin treatment improves spatial memory and overall health, reduces epigenetic aging, and prolongs lifespan, however, CADASIL-specific white matter vacuolization is not affected. On the molecular level Cerebrolysin treatment increases expression of Calcitonin Gene-Related Peptide (CGRP) and Silent Information Regulator Two (Sir2)-like protein 6 (SIRT6), decreases expression of Insulin-like Growth Factor 1 (IGF-1), and normalizes the expression of neurovascular laminin. In summary, Cerebrolysin fosters longevity and healthy aging without specifically affecting CADASIL pathology. Hence, Cerebrolysin may serve a therapeutic option for CADASIL and other disorders characterized by accelerated aging.

Effect of blood pressure-lowering agents on microvascular function in people with small vessel diseases (TREAT-SVDs): a multicentre, open-label, randomised, crossover trial.

BACKGROUND: Hypertension is the leading risk factor for cerebral small vessel disease. We aimed to determine whether antihypertensive drug classes differentially affect microvascular function in people with small vessel disease. METHODS: We did a multicentre, open-label, randomised crossover trial with blinded endpoint assessment at five specialist centres in Europe. We included participants aged 18 years or older with symptomatic sporadic small vessel disease or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and an indication for antihypertensive treatment. Participants were randomly assigned (1:1:1) to one of three sequences of antihypertensive treatment using a computer-generated multiblock randomisation, stratified by study site and patient group. A 2-week washout period was followed by three 4-week periods of oral monotherapy with amlodipine, losartan, or atenolol at approved doses. The primary endpoint was change in cerebrovascular reactivity (CVR) determined by blood oxygen level-dependent MRI response to hypercapnic challenge in normal-appearing white matter from the end of washout to the end of each treatment period. Efficacy analyses were done by intention-to-treat principles in all randomly assigned participants who had at least one valid assessment for the primary endpoint, and analyses were done separately for participants with sporadic small vessel disease and CADASIL. This trial is registered at ClinicalTrials.gov, NCT03082014, and EudraCT, 2016-002920-10, and is terminated. FINDINGS: Between Feb 22, 2018, and April 28, 2022, 75 participants with sporadic small vessel disease (mean age 64·9 years [SD 9·9]) and 26 with CADASIL (53·1 years [7·0]) were enrolled and randomly assigned to treatment. 79 participants (62 with sporadic small vessel disease and 17 with CADASIL) entered the primary efficacy analysis. Change in CVR did not differ between study drugs in participants with sporadic small vessel disease (mean change in CVR 1·8 × 10-4%/mm Hg [SE 20·1; 95% CI -37·6 to 41·2] for amlodipine; 16·7 × 10-4%/mm Hg [20·0; -22·3 to 55·8] for losartan; -7·1 × 10-4%/mm Hg [19·6; -45·5 to 31·1] for atenolol; poverall=0·39) but did differ in patients with CADASIL (15·7 × 10-4%/mm Hg [SE 27·5; 95% CI -38·3 to 69·7] for amlodipine; 19·4 × 10-4%/mm Hg [27·9; -35·3 to 74·2] for losartan; -23·9 × 10-4%/mm Hg [27·5; -77·7 to 30·0] for atenolol; poverall=0·019). In patients with CADASIL, pairwise comparisons showed that CVR improved with amlodipine compared with atenolol (-39·6 × 10-4%/mm Hg [95% CI -72·5 to -6·6; p=0·019) and with losartan compared with atenolol (-43·3 × 10-4%/mm Hg [-74·3 to -12·3]; p=0·0061). No deaths occurred. Two serious adverse events were recorded, one while taking amlodipine (diarrhoea with dehydration) and one while taking atenolol (fall with fracture), neither of which was related to study drug intake. INTERPRETATION: 4 weeks of treatment with amlodipine, losartan, or atenolol did not differ in their effects on cerebrovascular reactivity in people with sporadic small vessel disease but did result in differential treatment effects in patients with CADASIL. Whether antihypertensive drug classes differentially affect clinical outcomes in people with small vessel diseases requires further research. FUNDING: EU Horizon 2020 programme.

Antiplatelet use and CADASIL: a retrospective observational analysis.

OBJECTIVES: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is hallmarked by age-dependent accumulation of microangiopathy with antiplatelet medications commonly used for stroke prevention though without known therapeutic benefit. Our objective was to identify whether antiplatelet therapy impacted the incidence of acute ischemic stroke (AIS) or intracerebral hemorrhage (ICH) in those with reported CADASIL. MATERIALS AND METHODS: Owing to the rarity of the disease, we performed a retrospective study of anonymized data from the international TriNetX Research Network (Oct 2015 through January 2021). Individuals had an ICD-10 code (I67.850) for CADASIL. The primary outcome was incidence of validated ICD-10 codes for AIS (I63) and ICH (I61) linked with unique hospital admission encounters. The primary exposure was use of an antiplatelet medication for at least 1 month prior to the primary outcome. Age-adjusted logistic regression was used for likelihood ratios. RESULTS: We identified 455 individuals: 36% female, 40 (8.8%) antiplatelet exposed. Those with antiplatelet use were older (antiplatelet: 61±12 years vs. unexposed: 57±14 years, p = 0.034) with similar rates of AIS [antiplatelet: 23%(9/40) vs. unexposed: 14%(60/415); p=0.18] and ICH [antiplatelet: 3%(1/40) vs. unexposed: 5%(19/415); p = 0.54) and without significant impact on age-adjusted AIS likelihood (OR 1.62, 95%CI 0.73-3.60, p=0.23). Sample size precluded ICH regression analyses. CONCLUSIONS: Our data suggests that antiplatelet use did not significantly impact incidence of AIS or ICH within a group of individuals with suspected CADASIL This study highlights the need for further understanding of the pathophysiology of CADASIL to lead to disease modifying treatments.

Intravenous thrombolysis in CADASIL: report of two cases and a systematic review.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic small vessel disease responsible for recurrent ischemic strokes, often with a progressive course leading to dementia and disability. On MRI, lacunes, microbleeds, and severe white matter alterations are typical features of the disease. In case of acute stroke, because of the bleeding risk associated with the disease and the doubtful efficacy of fibrinolytic treatment in a disease with poor evidence of thrombosis, the efficacy of intravenous thrombolysis remains unproven. Nevertheless, stroke is a frequent occurrence in CADASIL patients, and clinicians not unlikely may face in the emergency room the situation of a CADASIL patient with an acute stroke within the time window for thrombolysis. OBJECTIVE: We report on two CADASIL patients treated with intravenous alteplase for acute ischemic stroke, and we present a review of literature aimed to report epidemiological data, efficacy and safety of intravenous thrombolysis in CADASIL patients. METHODS: We performed a systematic review of medical literature published until August 2, 2022. Case reports and series in English language reporting on CADASIL patients and acute stroke were included. RESULTS: Both patients were treated with intravenous thrombolysis without complications and had a good clinical outcome. The systematic review identified three case reports of CADASIL patients who were treated with intravenous alteplase for acute ischemic stroke; no bleedings complications were described. CONCLUSIONS: Available data on intravenous thrombolysis in CADASIL patients are scarce but suggest that this treatment can be taken into consideration for these patients.

CADASIL from Bench to Bedside: Disease Models and Novel Therapeutic Approaches.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic disease caused by NOTCH3 mutations and characterized by typical clinical, neuroradiological, and pathological features. NOTCH3 belongs to a family of highly conserved transmembrane receptors rich of epidermal growth factor repeats, mostly expressed in vascular smooth muscle cells and pericytes, which perform essential developmental functions and are involved in tissues maintenance and renewal. To date, no therapeutic option for CADASIL is available except for few symptomatic treatments. Novel in vitro and in vivo models are continuously explored with the aim to investigate underlying pathogenic mechanisms and to test novel therapeutic approaches. In this scenario, knock-out, knock-in, and transgenic mice studies have generated a large amount of information on molecular and biological aspects of CADASIL, despite that they incompletely reproduce the human phenotype. Moreover, the field of in vitro models has been revolutionized in the last two decades by the introduction of induced pluripotent stem cells (iPSCs) technology. As a consequence, novel therapeutic approaches, including immunotherapy, growth factors administration, and antisense oligonucleotides, are currently under investigation. While waiting that further studies confirm the promising results obtained, the data reviewed suggest that our therapeutic approach to the disease could be transformed, generating new hope for the future.

Two cases of NMOSD with MRI findings mimicking CADASIL.

PURPOSE: The purpose of this study is to increase awareness of the importance of considering neuromyelitis optica spectrum disorder (NMOSD) as a differential diagnosis for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). METHODS: We report two NMOSD patients demonstrating magnetic resonance imaging (MRI) abnormalities resembling those of CADASIL. RESULTS: Brain MRIs of both patients showed symmetrical hyperintense signals in the temporal poles and cerebral hemispheres on T2 weighted images. One case also involved the bilateral external capsule. The chief complaint of both patients was loss of visual acuity, and neurologic examination showed no other apparent neurological signs or symptoms. Anti-aquaporin-4 antibodies were detected on serological examination, and NMOSD was subsequently diagnosed. Visual acuity improved following intravenous methylprednisolone therapy. One patient refused further immunological treatment. Although she remained clinically stable, gradual radiographic deterioration was observed. This deterioration then stabilized after the patient commenced oral prednisolone therapy. The other patient was treated with prednisolone and azathioprine. She is clinically stable, but we have observed gradual radiographic deterioration over the past 5 years. CONCLUSION: MRI findings in patients with NMOSD may resemble those of CADASIL, namely symmetrical hyperintensities in the temporal poles, external capsules and cerebral hemispheres. NMOSD is a differential diagnosis for CADASIL, and testing for anti-AQP4 antibodies should be considered.

Effect of Lomerizine Hydrochloride on Preventing Strokes in Patients With Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an orphan disease clinically characterized by migraine, recurrent strokes, and dementia. Currently, there are no disease-modifying therapies, and it is difficult to prevent cerebral ischemic events in CADASIL patients by conventional antithrombotic medication. We hypothesized that an antimigraine agent, lomerizine hydrochloride, may prevent strokes in CADASIL patients, based on its effect on increasing cerebral blood flow. SUBJECTS AND METHODS: This was an open-labeled clinical trial in which 30 adult CADASIL patients received lomerizine at 10 mg/d. Numbers of symptomatic strokes during the 2 years after the start of lomerizine administration were compared with those in the 2 years before its initiation. The effect of lomerizine on preventing strokes was evaluated based on the incidence rate ratio (IR) calculated with the Mantel-Haenszel method. RESULTS: When including all 30 patients (analysis 1), the IR was less than 1 (0.46; 95% confidence interval [CI], 0.19-1.12) but did not reach significance. To evaluate the effect of lomerizine on secondary prevention, subgroups of 15 patients with stroke episodes occurring any time before lomerizine administration (analysis 2) and 10 patients with stroke episodes during the 2 years before lomerizine administration (analysis 3) were analyzed. The IR values were 0.33 (95% CI, 0.12-0.94) in analysis 2 and 0.17 (95% CI, 0.04-0.67) in analysis 3. CONCLUSIONS: Our results suggest the effect of lomerizine on preventing secondary stroke in CADASIL patients.

The potential danger of blocking CGRP for treating migraine in CADASIL patients.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease characterised by recurrent ischemic stroke, cognitive decline progressing to dementia, psychiatric disturbances and apathy. More than half of mutation carriers suffer from migraine, most often migraine with aura. Recently, a CADASIL patient was treated with a monoclonal antibody targeting the calcitonin gene-related peptide (CGRP) receptor. Monoclonal antibodies targeting the CGRP system have been demonstrated to be safe, well tolerated, and effective in reducing migraine attacks. There is, however, abundant evidence that CGRP is important in maintaining cardiovascular homeostasis under (patho)physiological conditions. CGRP may act as a vasodilatory safeguard during cerebral and cardiac ischemia and blockage of the system could, therefore, potentially worsen ischemic events. Therefore, we caution against treating patients with small vessel diseases, such as the monogenic disorder CADASIL, with these drugs until relevant safety data and long term follow up results are available. Alternative preventive migraine treatments in CADASIL may be acetazolamide, sodium valproate, lamotrigine, topiramate, verapamil, or flunarizine.

Arteriopatía cerebral autosómica dominante con infartos subcorticales yleucoencefalopatía / Autosomal dominant cerebral arteriopathy with subcortical infarctions and leukoencephalopathy

Objetivo: Describir la obtención del diagnóstico de la arteriopatía cerebral autosómica dominante con infartos subcorticales y leucoencefalopatía, así como el tratamiento dado y la evolución de un paciente.Caso clínico: Paciente femenina de 44 años, con antecedentes de migraña, con aura típica desde los 25 años. Tenía antecedentes familiares de migraña, infartos cerebrales, muerte y discapacidad de origen neurológico en adultos jóvenes. Acudió con un cuadro clínico de encefalopatía aguda, que comenzó con cefalea migrañosa acompañada de vómitos, fotofobia, escotomas y, posteriormente, fiebre yalucinaciones. La imagen de resonancia magnética de cráneo mostró infartos lacunares e hiperintensidades en T2 en la sustancia blanca del polo temporal izquierdo. El electroencefalogramamostró actividad de base lenta. Se diagnosticó una arteriopatía cerebral autosómica dominante con infartos subcorticales y leucoencefalopatía a través de la clínica, signos característicos en la neuroimagen, y la biopsia de piel. Se le indicó tratamiento con aspirina y acetazolamida. La paciente ha tenido una evolución favorable.Conclusiones: El análisis de las características clínicas, los hallazgos de neuroimagen y el examen pormicroscopia electrónica de la biopsia de piel permitieron el diagnóstico en la paciente de una arteriopatía cerebral autosómica dominante con infartos subcorticales y leucoencefalopatía. Se le indicó tratamiento farmacológico con el que la paciente ha tenido una evolución favorable(AU)

ABSTRACTIntroduction: CADASIL (Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is an autosomal dominant neurovascular disorder that causes ischemic subcortical stroke, migraine with aura, depression, apathy, and dementia. It have a variable prevalence(at least 2-10.7 per 100,000 adults) and is the most common cause of inherited stroke and vascular dementia in adults.Clinical case: Female patient aged 44 with a history of migraine with aura since age 25. Also, family history of migraine, stroke, death and disability in youngsters. She arrives with clinical picture of acute encephalopathy that begins with a migraine headache accompanied by vomiting, photophobia, scotoma and later fever and hallucinations. Brain MRI shows abnormalities such as several lacunar infarcts and T2 hyperintensities involving the white matter of the left anterior temporal pole. The EEG shows slow background. Diagnosis was confirmed with detection of eosinophilic inclusions in smooth muscle cell of dermic capillary of skin biopsy (osmophilic in transmission electronic microscopy).Conclusions: The patient showed is the first confirmed case in Cuba with CADASIL. Unfortunately, because of similarities in clinical presentation and neuroimaging, this disorder is often misdiagnosed as multiple sclerosis and treated with immunomodulatory medications that confer risk without benefit(AU)

Stem cell factor and granulocyte colony-stimulating factor promote brain repair and improve cognitive function through VEGF-A in a mouse model of CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) is a cerebral small vascular disease caused by NOTCH3 gene mutation in vascular smooth muscle cells (VSMCs), leading to ischemic stroke and vascular dementia. To date, the pathogenesis of CADASIL remains poorly understood, and there is no treatment that can slow the progression of CADASIL. Using a transgenic mouse model of CADASIL (TgNotch3R90C), this study reveals novel findings for understanding CADASIL pathogenesis that decreased cerebral vascular endothelial growth factor (VEGF/VEGF-A) is linked to reduced cerebral blood vessel density. Reduced endothelial cell (EC) proliferation and angiogenesis are seen in TgNotch3R90C mouse brain-isolated ECs. Decreased dendrites, axons, and synapses in the somatosensory and motor cortex layer 2/3 and in the hippocampal CA1, and reduced neurogenesis in both the subventricular zone and subgranular zone occur in 15-month-old TgNotch3R90C mice. These reductions in neuron structures, synapses, and neurogenesis are significantly correlated to decreased cerebral vasculature in the corresponding areas. Impaired spatial learning and memory in TgNotch3R90C mice are significantly correlated with the reduced cerebral vasculature, neuron structures, and synapses. Repeated treatment of stem cell factor and granulocyte colony-stimulating factor (SCF+G-CSF) at 9 and 10 months of age improves cognitive function, increases cerebral VEGF/VEGF-A, restores cerebral vasculature, and enhances regeneration of neuronal structures, synaptogenesis and neurogenesis in TgNotch3R90C mice. Pretreatment with Avastin, an angiogenesis inhibitor by neutralizing VEGF-A, completely eliminates the SCF+G-CSF-enhanced cognitive function, vascular and neuronal structure regeneration, synaptogenesis and neurogenesis in TgNotch3R90C mice. SCF+G-CSF-enhanced EC proliferation and angiogenesis in TgNotch3R90C mouse brain-isolated ECs are also blocked by Avastin pretreatment. These data suggest that SCF+G-CSF treatment may repair Notch3R90C mutation-damaged brain through the VEGF-A-mediated angiogenesis. This study provides novel insight into the involvement of VEGF/VEGF-A in the pathogenesis of CADASIL and sheds light on the mechanism underlying the SCF+G-CSF-enhanced brain repair in CADASIL.

CNS small vessel disease: A clinical review.

CNS small vessel disease (CSVD) causes 25% of strokes and contributes to 45% of dementia cases. Prevalence increases with age, affecting about 5% of people aged 50 years to almost 100% of people older than 90 years. Known causes and risk factors include age, hypertension, branch atheromatous disease, cerebral amyloid angiopathy, radiation exposure, immune-mediated vasculitides, certain infections, and several genetic diseases. CSVD can be asymptomatic; however, depending on location, lesions can cause mild cognitive dysfunction, dementia, mood disorders, motor and gait dysfunction, and urinary incontinence. CSVD is diagnosed on the basis of brain imaging biomarkers, including recent small subcortical infarcts, white matter hyperintensities, lacunes, cerebral microbleeds, enlarged perivascular spaces, and cerebral atrophy. Advanced imaging modalities can detect signs of disease even earlier than current standard imaging techniques. Diffusion tensor imaging can identify altered white matter connectivity, and blood oxygenation level-dependent imaging can identify decreased vascular reactivity. Pathogenesis is thought to begin with an etiologically specific insult, with or without genetic predisposition, which results in dysfunction of the neurovascular unit. Uncertainties regarding pathogenesis have delayed development of effective treatment. The most widely accepted approach to treatment is to intensively control well-established vascular risk factors, of which hypertension is the most important. With better understanding of pathogenesis, specific therapies may emerge. Early identification of pathologic characteristics with advanced imaging provides an opportunity to forestall progression before emergence of symptoms.

Nucleic Acid Therapies for Ischemic Stroke.

Stroke remains a leading cause of disability and death worldwide despite significant scientific and therapeutic advances. Therefore, there is a critical need to improve stroke prevention and treatment. In this review, we describe several examples that leverage nucleic acid therapeutics to improve stroke care through prevention, acute treatment, and recovery. Aptamer systems are under development to increase the safety and efficacy of antithrombotic and thrombolytic treatment, which represent the mainstay of medical stroke therapy. Antisense oligonucleotide therapy has shown some promise in treating stroke causes that are genetically determined and resistant to classic prevention approaches such as elevated lipoprotein (a) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Targeting microRNAs may be attractive because they regulate factors involved in neuronal cell death and reperfusion-associated injury, as well as neurorestorative pathways. Lastly, microRNAs may aid reliable etiologic classification of stroke subtypes, which is important for effective secondary stroke prevention.

Stem Cell Factor in Combination with Granulocyte Colony-Stimulating Factor reduces Cerebral Capillary Thrombosis in a Mouse Model of CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a cerebral small vascular disease caused by NOTCH3 mutation-induced vascular smooth muscle cell (VSMC) degeneration, leading to ischemic stroke and vascular dementia. Our previous study has demonstrated that repeated treatment with a combination of stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) reduces VSMC degeneration and cerebral endothelial cell (EC) damage and improves cognitive function in a mouse model of CADASIL (TgNotch3R90C). This study aimed to determine whether cerebral thrombosis occurs in TgNotch3R90C mice and whether repeated SCF+G-CSF treatment reduces cerebral thrombosis in TgNotch3R90C mice. Using the approaches of bone marrow transplantation to track bone marrow-derived cells and confocal imaging, we observed bone marrow-derived blood cell occlusion in cerebral small vessels and capillaries (thrombosis). Most thrombosis occurred in the cerebral capillaries (93% of total occluded vessels), and the thrombosis showed an increased frequency in the regions of capillary bifurcation. Degenerated capillary ECs were seen inside and surrounding the thrombosis, and the bone marrow-derived ECs were also found next to the thrombosis. IgG extravasation was seen in and next to the areas of thrombosis. SCF+G-CSF treatment significantly reduced cerebral capillary thrombosis and IgG extravasation. These data suggest that the EC damage is associated with thrombosis and blood-brain barrier leakage in the cerebral capillaries under the CADASIL-like condition, whereas SCF+G-CSF treatment diminishes these pathological alterations. This study provides new insight into the involvement of cerebral capillary thrombosis in the development of CADASIL and potential approaches to reduce the thrombosis, which may restrict the pathological progression of CADASIL.

Location, number and factors associated with cerebral microbleeds in an Italian-British cohort of CADASIL patients.

BACKGROUND AND PURPOSE: The frequency, clinical correlates, and risk factors of cerebral microbleeds (CMB) in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) are still poorly known. We aimed at determining the location and number of CMB and their relationship with clinical manifestations, vascular risk factors, drugs, and other neuroimaging features in CADASIL patients. METHODS: We collected clinical data by means of a structured proforma and centrally evaluated CMB on magnetic resonance gradient echo sequences applying the Microbleed Anatomical Rating Scale in CADASIL patients seen in 2 referral centers in Italy and United Kingdom. RESULTS: We evaluated 125 patients. CMB were present in 34% of patients and their presence was strongly influenced by the age. Twenty-nine percent of the patients had CMB in deep subcortical location, 22% in a lobar location, and 18% in infratentorial regions. After adjustment for age, factors significantly associated with a higher total number of CMB were hemorrhagic stroke, dementia, urge incontinence, and statins use (this latter not confirmed by multivariate analysis). Infratentorial and deep CMB were associated with dementia and urge incontinence, lobar CMB with hemorrhagic stroke, dementia, and statins use. Unexpectedly, patients with migraine, with or without aura, had a lower total, deep, and lobar number of CMB than patients without migraine. DISCUSSION: CMB formation in CADASIL seems to increase with age. History of hemorrhagic stroke, dementia, urge incontinence, and statins use are associated with a higher number of CMB. However, these findings need to be confirmed by longitudinal studies.

CADASIL: Migraine, Encephalopathy, Stroke and Their Inter-Relationships.

BACKGROUND: Migraine is common in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) but its treatment responses are not well described, and its relationship to stroke risk unknown. Encephalopathy is a less common presentation; it has been suggested it is related to migraine. We characterised migraine patterns and treatment responses in CADASIL, and examined associations between migraine and both stroke risk and encephalopathy. METHODS: 300 symptomatic CADASIL patients were prospectively recruited from a national referral clinic over a nineteen year period, from 1996 to 2015. Data was collected using a standardised questionnaire. Migraine was classified according to the International Classification of Headache Disorders, 3rd edition (beta version). A cross-sectional analysis was carried out on the data collected. RESULTS: Migraine was present in 226 (75.3%), and the presenting feature in 203 (67.7%). It was usually accompanied by aura (89.8%). Patients showed variable responses to a variety of drugs for migraine. Of 24 given triptans, 45.5% had consistent or partial responses. None had complications following triptans. Thirty-three (11.0%) patients experienced encephalopathy lasting on average 8.1 ± 3.4 days. Patients with migraine with aura had higher odds of encephalopathy (OR = 5.4; 95%CI 1.6-28.4; p = 0.002). Patients with confusional aura had higher odds of encephalopathy than those with other aura types (OR = 2.5, 95%CI = 1.0-5.8, p = 0.04). There was also no increase in risk of encephalopathy with sex or age at onset of migraine. Migraineurs had a lower stroke risk than non-migraineurs (HR = 0.46, 95%CI 0.3-0.6, p = 2.1x10-6). CONCLUSIONS: Migraine with aura is a prominent feature of CADASIL. Treatment responses are similar to those seen in the general migraine population and no complications were observed with triptans. Migraine with aura was associated with increased risk of encephalopathy suggesting they may share pathophysiological mechanisms. There was no increased stroke risk associated with migraine, but risk appeared to be reduced although this finding needs confirming.

Notch -- a goldilocks signaling pathway in disease and cancer therapy.

The Notch signaling pathway is a fundamental signaling mechanism operating in most, if not all, multicellular organisms and in most cell types in the body. Like other "ivy league" pathways such as Wnt, PI3K, Sonic Hedgehog, Receptor Tyrosine Kinases (RTKs), and JAK/STAT signaling, the Notch pathway is a linear signaling mechanism, i.e., an extracellular ligand activates a receptor, which ultimately leads to transcriptional alterations in the cell nucleus, but Notch signaling is a strict cell-cell communication mechanism and lacks built-in amplification steps in the signaling pathway. Dysregulated Notch signaling, either by direct mutations in the pathway or by altered signaling output, is increasingly linked to disease, and Notch can act as an oncogene or tumor suppressor depending on the cellular context. This underscores that appropriate level of Notch signaling is important for differentiation and tissue homeostasis, a notion supported also by genetic data indicating that Notch signaling is very gene dosage-sensitive. Thus, too much or too little signaling can lead to disease and Notch can therefore be considered a Goldilocks signaling pathway. Given the emerging role of dysregulated Notch signaling in disease, there is increasing interest in developing therapeutic approaches to modulate Notch signaling. In this review we discuss recent findings on how signal transduction is tuned in the Notch pathway and how Notch signaling is dysregulated in disease. We also discuss different strategies to modulate Notch signaling for clinical use, for example by novel antibody-based tools and by taking advantage of the cross-talk between Notch and other signaling mechanisms.

Successful Use of Intravenous Tissue Plasminogen Activator as Treatment for a Patient with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy: A Case Report and Review of Literature.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is considered a common cause of hereditary stroke caused by mutation of the NOTCH3 gene. Evidence against the use of intravenous tissue plasminogen activator (IV tPA) has been suggested due to possibility of hemorrhage. We present a case of a patient with CADASIL who was successfully treated using IV tPA. METHODS: A case description of a female patient who presented with stroke-like symptoms was a previously known case of CADASIL. Review of literature was done using search terms such as CADASIL, NOTCH3, and intracranial hemorrhage or brain hemorrhage. RESULTS: A 35-year-old female patient presented to the emergency department with acute onset hemiparesis, hemiparesthesia, and motor aphasia with a National Institutes of Health Stroke Scale score of 8. The patient was a previously diagnosed case of CADASIL with a positive NOTCH3 mutation. Computed tomography scan showed no large vessel occlusion with no perfusion deficient. Patient was within window for IV tPA treatment which was administered, and she subsequently had marked improvement of all symptoms. CONCLUSION: There is slight evidence against the use of IV tPA for CADASIL patients who present with stroke-like symptoms but nothing is concrete. It has also been suggested that some patients who are undiagnosed have been treated with IV tPA with favorable results but unfortunately are not reported. Further studies and or large clinical trials could be beneficial for those patients who may benefit from IV tPA and who have previously been diagnosed with CADASIL.