Debamestrocel multimodal effects on biomarker pathways in amyotrophic lateral sclerosis are linked to clinical outcomes.

INTRODUCTION/AIMS: Biomarkers have shown promise in amyotrophic lateral sclerosis (ALS) research, but the quest for reliable biomarkers remains active. This study evaluates the effect of debamestrocel on cerebrospinal fluid (CSF) biomarkers, an exploratory endpoint. METHODS: A total of 196 participants randomly received debamestrocel or placebo. Seven CSF samples were to be collected from all participants. Forty-five biomarkers were analyzed in the overall study and by two subgroups characterized by the ALS Functional Rating Scale-Revised (ALSFRS-R). A prespecified model was employed to predict clinical outcomes leveraging biomarkers and disease characteristics. Causal inference was used to analyze relationships between neurofilament light chain (NfL) and ALSFRS-R. RESULTS: We observed significant changes with debamestrocel in 64% of the biomarkers studied, spanning pathways implicated in ALS pathology (63% neuroinflammation, 50% neurodegeneration, and 89% neuroprotection). Biomarker changes with debamestrocel show biological activity in trial participants, including those with advanced ALS. CSF biomarkers were predictive of clinical outcomes in debamestrocel-treated participants (baseline NfL, baseline latency-associated peptide/transforming growth factor beta1 [LAP/TGFß1], change galectin-1, all p < .01), with baseline NfL and LAP/TGFß1 remaining (p < .05) when disease characteristics (p < .005) were incorporated. Change from baseline to the last measurement showed debamestrocel-driven reductions in NfL were associated with less decline in ALSFRS-R. Debamestrocel significantly reduced NfL from baseline compared with placebo (11% vs. 1.6%, p = .037). DISCUSSION: Following debamestrocel treatment, many biomarkers showed increases (anti-inflammatory/neuroprotective) or decreases (inflammatory/neurodegenerative) suggesting a possible treatment effect. Neuroinflammatory and neuroprotective biomarkers were predictive of clinical response, suggesting a potential multimodal mechanism of action. These results offer preliminary insights that need to be confirmed.

The Impact of Injury on Career Progression in Elite Youth Football-Findings at 10 Years.

Background: There is a lack of evidence regarding the impact of time loss, match exposure, and age at injury on career progression in elite football. Therefore, the aim of this study was to identify injury characteristics and their influence on career progression in a German youth academy. Methods: During the 2012/2013 season, a prospective cohort study reported 107 time-loss injuries among 130 young athletes from an elite German soccer academy. Individual career progression was analyzed using 10-year data. Results: Injuries and time loss were not associated with career progression (p > 0.05) in the overall cohort. In the U17 and U19 groups, 24% were able to reach the professional level, with injuries significantly decreasing this probability (p = 0.002). Injuries lasting more than 28 days had a negative impact on career progression compared to minor injuries (30% vs. 10%; p = 0.02). Conclusions: Not only the characteristics of injuries, but also their impact on career development, vary with age. In the U17 and U19 age groups, serious injuries resulting in more than 28 days of absence have a negative impact on career progression. It is important to be aware of these effects in order to focus on the prevention of long-term injuries to ensure the optimal development of young athletes.

Safety, tolerability, and efficacy estimate of evoked gamma oscillation in mild to moderate Alzheimer's disease.

Background: Alzheimer's Disease (AD) is a multifactorial, progressive neurodegenerative disease that disrupts synaptic and neuronal activity and network oscillations. It is characterized by neuronal loss, brain atrophy and a decline in cognitive and functional abilities. Cognito's Evoked Gamma Therapy System provides an innovative approach for AD by inducing EEG-verified gamma oscillations through sensory stimulation. Prior research has shown promising disease-modifying effects in experimental AD models. The present study (NCT03556280: OVERTURE) evaluated the feasibly, safety and efficacy of evoked gamma oscillation treatment using Cognito's medical device (CogTx-001) in participants with mild to moderate AD. Methods: The present study was a randomized, double blind, sham-controlled, 6-months clinical trial in participants with mild to moderate AD. The trial enrolled 76 participants, aged 50 or older, who met the clinical criteria for AD with baseline MMSE scores between 14 and 26. Participants were randomly assigned 2:1 to receive self-administered daily, one-hour, therapy, evoking EEG-verified gamma oscillations or sham treatment. The CogTx-001 device was use at home with the help of a care partner, over 6 months. The primary outcome measures were safety, evaluated by physical and neurological exams and monthly assessments of adverse events (AEs) and MRI, and tolerability, measured by device use. Although the trial was not statistically powered to evaluate potential efficacy outcomes, primary and secondary clinical outcome measures included several cognitive and functional endpoints. Results: Total AEs were similar between groups, there were no unexpected serious treatment related AEs, and no serious treatment-emergent AEs that led to study discontinuation. MRI did not show Amyloid-Related Imaging Abnormalities (ARIA) in any study participant. High adherence rates (85-90%) were observed in sham and treatment participants. There was no statistical separation between active and sham arm participants in primary outcome measure of MADCOMS or secondary outcome measure of CDR-SB or ADAS-Cog14. However, some secondary outcome measures including ADCS-ADL, MMSE, and MRI whole brain volume demonstrated reduced progression in active compared to sham treated participants, that achieved nominal significance. Conclusion: Our results demonstrate that 1-h daily treatment with Cognito's Evoked Gamma Therapy System (CogTx-001) was safe and well-tolerated and demonstrated potential clinical benefits in mild to moderate AD.Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03556280.

Noninvasive Gamma Sensory Stimulation May Reduce White Matter and Myelin Loss in Alzheimer's Disease.

BACKGROUND: Patients with Alzheimer's disease (AD) demonstrate progressive white matter atrophy and myelin loss. Restoring myelin content or preventing demyelination has been suggested as a therapeutic approach for AD. OBJECTIVE: Herein, we investigate the effects of non-invasive, combined visual and auditory gamma-sensory stimulation on white matter atrophy and myelin content loss in patients with AD. METHODS: In this study, we used the magnetic resonance imaging (MRI) data from the OVERTURE study (NCT03556280), a randomized, controlled, clinical trial in which active treatment participants received daily, non-invasive, combined visual and auditory, 40 Hz stimulation for six months. A subset of OVERTURE participants who meet the inclusion criteria for detailed white matter (N = 38) and myelin content (N = 36) assessments are included in the analysis. White matter volume assessments were performed using T1-weighted MRI, and myelin content assessments were performed using T1-weighted/T2-weighted MRI. Treatment effects on white matter atrophy and myelin content loss were assessed. RESULTS: Combined visual and auditory gamma-sensory stimulation treatment is associated with reduced total and regional white matter atrophy and myelin content loss in active treatment participants compared to sham treatment participants. Across white matter structures evaluated, the most significant changes were observed in the entorhinal region. CONCLUSIONS: The study results suggest that combined visual and auditory gamma-sensory stimulation may modulate neuronal network function in AD in part by reducing white matter atrophy and myelin content loss. Furthermore, the entorhinal region MRI outcomes may have significant implications for early disease intervention, considering the crucial afferent connections to the hippocampus and entorhinal cortex.

How Does Age Affect Injury Characteristics in Young Elite Footballers?-A Prospective Cohort Study of a German Youth Academy.

BACKGROUND: Little is known about age-related changes in injury characteristics and burden, and existing data are inconsistent, highlighting the need for new studies on this topic. This study aimed to describe age-related injury risk, severity and burden in a German elite youth football academy. METHODS: A prospective cohort study was conducted in the 2012/2013 season, reporting 109 time-loss injuries among 138 young athletes playing at an elite football academy in Germany. For the most severe injuries, the injury burden in the different age groups was considered separately. RESULTS: Athletes missed a total of 2536 days of exposure, resulting in an overall incidence of 2.6 per 1000 h (1.7-3.0; 95% CI) and a burden of 60.6 days lost per 1000 h (40.8-80.3; 95% CI). The incidence and burden of joint sprains and muscle injuries were higher in the older age groups. Physeal injuries peaked in the U14 age group during the pubertal growth spurt. Bone injuries and contusions showed no age trend. CONCLUSION: Injury characteristics vary with age. The overall incidence, severity and burden of injuries increased with the age of the athletes. To ensure the optimal development of young athletes, it is important to be aware of the differences in injury susceptibility between age groups in order to implement tailored prevention programmes.

Evaluation of neurotrophic factor secreting mesenchymal stem cells in progressive multiple sclerosis.

BACKGROUND: Autologous mesenchymal stem cell neurotrophic factor-secreting cells (NurOwn®) have the potential to modify underlying disease mechanisms in progressive multiple sclerosis (PMS). OBJECTIVE: This open-label phase II study was conducted to evaluate safety/efficacy of three intrathecal cell treatments. METHODS: Eighteen participants with non-relapsing PMS were treated. The primary endpoint was safety. Secondary endpoints included: cerebrospinal fluid (CSF) biomarkers; timed 25-foot walk speed, nine-hole peg test (9-HPT), low-contrast letter acuity, symbol digit modalities test, and 12-item multiple sclerosis (MS) walking scale. Seventeen participants received all treatments. RESULTS: No deaths/adverse events related to worsening of MS, clinical/magnetic resonance imaging (MRI) evidence of disease activation, and clinically significant changes in safety lab results were reported. Two participants developed symptoms of low back and leg pain, consistent with a diagnosis of arachnoiditis, occurring in one of three intrathecal treatments in both participants. Nineteen percent of treated participants achieved pre-specified ⩾ 25% improvements in timed 25-foot walk speed/nine-HPT at 28 weeks compared to baseline, along with consistent efficacy signals for pre-specified response criteria across other secondary efficacy outcomes. CSF neuroprotective factors increased, and inflammatory biomarkers decreased after treatment, consistent with the proposed mechanism of action. CONCLUSION: Based on these encouraging preliminary findings, further confirmation in a randomized study is warranted.

A randomized placebo-controlled phase 3 study of mesenchymal stem cells induced to secrete high levels of neurotrophic factors in amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative illness with great unmet patient need. We aimed to evaluate whether mesenchymal stem cells induced to secrete high levels of neurotrophic factors (MSC-NTF), a novel autologous cell-therapy capable of targeting multiple pathways, could safely slow ALS disease progression. METHODS: This randomized, double-blind, placebo-controlled study enrolled ALS participants meeting revised El Escorial criteria, revised ALS Functional Rating Scale (ALSFRS-R) ≥25 (screening) and ≥3 ALSFRS-R points decline prior to randomization. Participants received three treatments of MSC-NTF or placebo intrathecally. The primary endpoint evaluated efficacy of MSC-NTF through a responder analysis and safety. A change in disease progression post-treatment of ≥1.25 points/mo defines a clinical response. A pre-specified analysis leveraged baseline ALSFRS-R of 35 as a subgroup threshold. RESULTS: Overall, MSC-NTF treatment was well tolerated; there were no safety concerns. Thirty-three percent of MSC-NTF and 28% of placebo participants met clinical response criteria at 28 wk (odds ratio [OR] = 1.33, P = .45); thus, the primary endpoint was not met. A pre-specified analysis of participants with baseline ALSFRS-R ≥ 35 (n = 58) showed a clinical response rate at 28 wk of 35% MSC-NTF and 16% placebo (OR = 2.6, P = .29). Significant improvements in cerebrospinal biomarkers of neuroinflammation, neurodegeneration, and neurotrophic factor support were observed with MSC-NTF, with placebo unchanged. DISCUSSION: The study did not reach statistical significance on the primary endpoint. However, a pre-specified subgroup suggests that MSC-NTF participants with less severe disease may have retained more function compared to placebo. Given the unmet patient need, the results of this trial warrant further investigation.

MSC-NTF (NurOwn®) exosomes: a novel therapeutic modality in the mouse LPS-induced ARDS model.

BACKGROUND: One of the most severe complications of the current COVID-19 pandemic is acute respiratory distress syndrome (ARDS). ARDS is caused by increased amounts of pro-inflammatory cytokines, leading to lung damage and loss of lung function. There are currently no effective therapies for combatting ARDS. Mesenchymal stem cells (MSCs) have been suggested as a potential treatment for ARDS due to their significant immunomodulatory properties. MSC small extracellular vesicles (sEVs), including exosomes, modulate the immune response as effectively as MSCs themselves, with the added advantages of increased safety and tissue penetration. METHODS: We isolated sEVs from MSCs induced to secrete increased levels of neurotrophic and immunomodulatory factors, termed Exo MSC-NTF, and compared their ability to treat ARDS, in a lung injury LPS mouse model, to sEVs isolated from naïve MSCs (Exo MSC). Measurments of lung histopathological changes and neutrophil infiltration, blood oxygen saturation, and bronchoalveolar lavge fluid (BALF) proinflammatory cytokines and coagulation related factors were performed. RESULTS: We found that Exo MSC-NTF was superior to Exo MSC in reducing LPS-induced ARDS markers, including physiological lung damage such as alveolar wall thickness, fibrin presence, and neutrophil accumulation, as well as increasing oxygenation levels. Furthermore, Exo MSC-NTF reversed the imbalance in the host immune response, seen as decreased IFN-γ, IL-6, TNF-α, and RANTES levels in the bronchoalveolar lavage fluid. CONCLUSIONS: These positive preclinical results suggest that Exo MSC-NTF may be suitable as a therapy for COVID-19-induced ARDS and are more effective at combatting ARDS physiological, pathological, and biochemical symptoms than sEVs isolated from non-induced MSCs.

Addressing heterogeneity in amyotrophic lateral sclerosis CLINICAL TRIALS.

Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder with complex biology and significant clinical heterogeneity. Many preclinical and early phase ALS clinical trials have yielded promising results that could not be replicated in larger phase 3 confirmatory trials. One reason for the lack of reproducibility may be ALS biological and clinical heterogeneity. Therefore, in this review, we explore sources of ALS heterogeneity that may reduce statistical power to evaluate efficacy in ALS trials. We also review efforts to manage clinical heterogeneity, including use of validated disease outcome measures, predictive biomarkers of disease progression, and individual clinical risk stratification. We propose that personalized prognostic models with use of predictive biomarkers may identify patients with ALS for whom a specific therapeutic strategy may be expected to be more successful. Finally, the rapid application of emerging clinical and biomarker strategies may reduce heterogeneity, increase trial efficiency, and, in turn, accelerate ALS drug development.

Biogen's portfolio and research efforts in multiple sclerosis: an interview with Dr Ralph Kern.

Ralph Kern speaks to Laura Dormer, Commissioning Editor: Dr Ralph Kern is Senior Vice President and Head of Worldwide Medical at Biogen in Cambridge, MA, USA. In this role, he oversees Biogen's global therapeutic, regional and country medical teams, global medical operations, as well as medical research and scientific communications functions. Prior to joining Biogen, he was head of the Neuroscience Medical Unit at Novartis Pharmaceuticals Corporation and held various medical and commercial leadership roles at Genzyme Corporation. Prior to joining industry, he was a consultant neurologist at Mount Sinai Hospital and the University Health Network in Toronto, Ontario and was head of the neurology postgraduate academic program at the University of Toronto. Ralph completed neurology postgraduate training at McGill University and completed a masters of health administration from the Institute for Health Policy, Management and Evaluation at the University of Toronto. He is a member of the College of Physicians and Surgeons of Ontario and the Royal College of Physicians and Surgeons of Canada.

Telemedicine in the management of chronic pain: a cost analysis study.

PURPOSE: Telemedicine provides patients with easy and remote access to consultant expertise irrespective of geographic location. In a randomized controlled trial, this study has applied a rigorous costing methodology to the use of telemedicine in chronic pain management. METHODS: We performed a randomized two-period crossover trial comparing in-person (IP) consultation with telemedicine (TM) consultation in the management of chronic pain. Over an 18-month period, 26 patients each completed two diaries capturing their direct and indirect travel costs, daily pain scores, and satisfaction with physician consultation. Costing models were developed to account for direct, indirect, fixed, and variable costs in order to perform break-even analyses. Sensitivity analysis was performed over a broad range of assumptions. RESULTS: Direct patient costs were significantly lower in the TM group than in the IP group, with median cost and interquartile range 133 dollars (28-377) vs 443 dollars (292-1075), respectively (P = 0.001). More patients were highly satisfied with the TM consultation than with the IP consultation (56 and 24%, respectively; P < 0.05). Break-even annual patient volume was estimated at 57 patients. A two-way sensitivity analysis controlling for annual patient volume and round-trip distance indicated that TM remains cost-effective at volumes >50 patients/year or at round-trip distances >200 km. CONCLUSION: Telemedicine is cost-effective over a broad range of assumptions, including annual patient volumes, travel distance, fuel costs, amortization, and discount rates. This study provides data from a real-world setting to determine relevant thresholds and targets for establishing a TM program for patients who are undergoing chronic pain therapy.

Reversible cerebral vasoconstriction syndrome: a thunderclap headache-associated condition.

Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by a sudden, severe headache at onset, vascular narrowing involving the circle of Willis and its immediate branches, and angiographic evidence of vasoconstriction reversibility within minutes to weeks of onset. RCVS is underrecognized and often misdiagnosed; it can defy clinical detection because it can mimic common conditions such as migraine and ischemic stroke. A lack of shared nosology has hampered awareness and understanding of the syndrome. Clinicians must consider primary angiitis of the central nervous system because of its high rates of morbidity and mortality if left untreated. RCVS has a number of primary and secondary associations (cerebral hemorrhage, vasoactive substances, the peripartum period, bathing, and physical exertion) but also occurs in isolation. RCVS can present in conjunction with hypertensive encephalopathy, preeclampsia, and reversible posterior leukoencephalopathy. This review provides an up-to-date account of RCVS.

Reversible cerebral vasoconstriction syndrome or primary angiitis of the central nervous system?

BACKGROUND: Reversible Cerebral Vasoconstriction Syndrome (RCVS) may present as thunderclap headache (TCH), accompanied by reversible cerebral vasospasm and focal neurological deficits, often without a clear precipitant. RCVS may be mistaken for Primary Angiitis of the Central Nervous System (PACNS) due to the presence of similar angiographic features of segmental narrowing of cerebral arteries. We discuss the clinical features of a young female migraine patient who developed TCH and was found to have RCVS following initial treatment with corticosteroids for PACNS, in the context of a systematic review of the available medical literature. METHODS: A Medline search was performed to identify all case reports since 1966 describing RCVS and PACNS that provide sufficient clinical detail to permit diagnostic classification according to published criteria. RCVS included case studies in which there was angiographic or transcranial Doppler ultrasound evidence of near-to-complete resolution of cerebral vasoconstriction in the absence of a well-recognized secondary cause. PACNS included reports of histologically confirmed PACNS either through biopsy or necropsy. RESULTS: Reversible Cerebral Vasoconstriction Syndrome occurs primarily in females and is characterized by sudden, severe headache at onset, normal CSF analysis, vasoconstriction involving the Circle of Willis and its immediate branches, and angiographic or TCD ultrasound evidence of near-to-complete vasospastic resolution within 1-4 weeks. It occurs typically in the context of vasoconstrictive drug use, the peripartum period, bathing, and physical exertion. CONCLUSION: Initial and follow-up (within 4 weeks) non-invasive angiographic studies are indicated in patients who present with TCH or who have clinical presentations that could be consistent with RCVS or PACNS in the absence of a well-recognized secondary cause, such as subarachnoid haemorrhage. Early reversibility of cerebral vasospasm is the key neuroradiological feature that supports the clinical diagnosis of RCVS.

The incidence and etiology of postpartum headaches: a prospective cohort study.

PURPOSE: We sought to determine the incidence, etiology, characteristics and risk factors for all headaches in the first week postpartum. METHODS: This was a prospective cohort study of 985 women delivering over a three-month period in a single tertiary-care institution. These women underwent a structured interview and follow-up to collect demographic data and to assess for the presence and characteristics of postpartum headache (PPHa) or neck/shoulder pain. All headaches were diagnosed using an algorithm based on the diagnostic criteria of the International Headache Society. Multivariate analysis was used to examine possible risk factors. RESULTS: Three hundred eighty-one of the 985 study participants (39%) reported headaches or neck/shoulder pain during the study period. The median time to onset of the PPHa was two days (0, 6; 1st and 3rd quartiles) and duration was four hours (2, 24; 1st and 3rd quartiles). Primary headaches accounted for > 75% of PPHa. Only a small number of headaches (4%) were incapacitating. Postdural puncture headache accounted for 4.7% of all PPHa. Significant risk factors for the development of PPHa were: known inadvertent dural puncture [odds ratio (OR)adj = 6.36; 95% confidence interval (CI) 1.29, 31.24]; previous headache history (1-12/yr-OR(adj) = 1.57; 95% CI 1.01, 2.44; > 12/yr-OR(adj) = 2.25; 95% CI 1.63, 3.11); multiparity (OR(adj) = 1.37; 95% CI 1.03, 1.82) and increasing age (OR(adj) = 1.03/yr; 95% CI 1.00, 1.06). CONCLUSIONS: Postpartum headaches are common, often first noted after discharge from hospital. The majority are related to primary headache disorders. Increased awareness of this epidemiological relationship and improved diagnosis of primary headache conditions may lead to improved headache-specific therapy and avoidance of unnecessary investigations or read-mission to hospital.

Progress in clinical neurosciences: Migraine-stroke: a causal relationship, but which direction?

A significant association between migraine and ischemic stroke has been demonstrated in population and case-control studies. The risk of ischemic stroke appears to be higher in migraine with aura (MWA) than migraine without aura (MwoA). Migraine-stroke comprises a number of distinct entities, including migrainous infarction, in which ischemic stroke occurs during an attack of MWA and migraine-related stroke, in which the causal link is less clear. Migrainous infarction accounts for only one-third of migraine-stroke, strokes may occur during attacks of MwoA, and a number of cerebrovascular disorders may present as MWA or MwoA. Migraine may occur as a consequence of conditions that are known to cause stroke; therefore it remains to be determined whether migraine predisposes to stroke in the absence of any known disease associations, if it is an epiphenomenon of an underlying stroke diathesis, or if it requires the presence of another stroke risk factor to produce cerebral ischemia. Furthermore, it is unclear if ischemia results in migraine more often than migraine results in ischemia. Careful clinical studies that evaluate this bidirectional relationship are needed to determine why migraine patients are subject to a higher risk of ischemic stroke.

Disease adaptation may have decreased quality-of-life responsiveness in patients with chronic progressive neurological disorders.

OBJECTIVE: We hypothesized that disease adaptation could be measured in chronic progressive neurological disorders (CPND) through paired longitudinal comparisons of quality of life (QOL) and health status (HS) and of the mental health (MH) and physical health (PH) domains of QOL instruments. STUDY DESIGN AND SETTING: We identified 193 quantitative studies of QOL and HS in a systematic review of episodic (END) and chronic progressive (CPND) neurological disorders. Effect size or other responsiveness measures were analyzed in 31 studies that included paired longitudinal comparisons of QOL-HS, MH-PH, or both. Responsiveness means were compared using the paired-sample t-test or sign test. RESULTS: In 12 paired comparisons, QOL responsiveness was significantly lower than HS (P=.05, sign test). In 53 paired MH-PH effect-size comparisons, MH responsiveness was lower than PH (P=.02, t=2.48, paired sample). Significantly lower MH responsiveness was observed in 28 paired CPND comparisons (P < .01, t=3.86, paired sample) but not in 25 paired END comparisons (P=.50, t=0.68, paired sample). CONCLUSION: Lower responsiveness of QOL in CPND may be related to disease adaptation. Further prospective studies are needed to confirm our findings and to investigate the importance of disease adaptation in the evaluation of neurological disease and in health resource allocation.

Migraine is associated with magnetic resonance imaging white matter abnormalities: a meta-analysis.

BACKGROUND: There is controversy as to whether migraine is associated with white matter abnormalities (WMAs) on magnetic resonance images. These abnormalities may be important as a risk factor for future stroke. Further, it is controversial whether any increased risk of WMAs is attributable to comorbidities such as vascular disease. METHODS: A meta-analysis of published case-control studies was undertaken to address the relationship between migraine and magnetic resonance imaging WMAs. Seven studies were identified. Data from studies reporting the incidence of magnetic resonance imaging WMAs in those with migraine and appropriate control populations were used to calculate odds ratios for WMAs in migraine for each study. A stratified meta-analysis was performed using studies that did and did not exclude subjects with disease comorbidities. RESULTS: The summary odds ratio shows that those with migraine are at increased risk for WMAs (odds ratio, 3.9 [95% confidence interval, 2.26-6.72]). The risk does not differ between studies that included subjects with comorbidities and those that did not. CONCLUSION: This meta-analysis demonstrates that subjects with migraine are at higher risk of having WMAs on magnetic resonance images than those without migraine. This increased risk is present even in younger individuals who do not have co-occurring cerebrovascular disease risk factors. Prospective studies are needed to determine whether the increased risk of stroke in migraine is mediated or foreshadowed by the presence of WMAs.