Background and Purpose—This scientific statement provides an overview of the evidence on vascular contributions to cognitive impairment and dementia. Vascular contributions to cognitive impairment ...

Vascular Contributions to Cognitive Impairment and Dementia A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association

Objectives: This is the first of a pair of studies designed to assess efficacy, safety and tolerability of onabotulinumtoxinA (BOTOX®) as headache prophylaxis in adults with chronic migraine.Methods: The Phase III REsearch Evaluating Migraine Prophylaxis Therapy 1 (PREEMPT 1) is a phase 3 study, with a 24-week, double-blind, parallel-group, placebo-controlled phase followed by a 32-week, open-label phase. Subjects were randomized (1:1) to injections every 12 weeks of onabotulinumtoxinA (155 U–195 U; n = 341) or placebo (n = 338) (two cycles). The primary endpoint was mean change from baseline in headache episode frequency at week 24.Results: No significant between-group difference for onabotulinumtoxinA versus placebo was observed for the primary endpoint, headache episodes (−5.2 vs. −5.3; p = 0.344). Large within-group decreases from baseline were observed for all efficacy variables. Significant between-group differences for onabotulinumtoxinA were observed for the secondary endpoints, headache days (p =...

/pdf/onabotulinumtoxina-for-treatment-of-chronic-migraine-results-38mv2m8yss.pdf

OnabotulinumtoxinA for treatment of chronic migraine: Results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial

ContextSmall open-label and controlled trials suggest that the antiepileptic
drug topiramate is effective for migraine prevention.ObjectiveTo assess the efficacy and safety of topiramate for migraine prevention
in a large controlled trial.Design, Setting, and PatientsA 26-week, randomized, double-blind, placebo-controlled study was conducted
during outpatient treatment at 52 North American clinical centers. Patients
were aged 12 to 65 years and had a 6-month history of migraine (International
Headache Society criteria) and 3 to 12 migraines a month but no more than
15 headache days a month during a 28-day prospective baseline phase.InterventionsAfter a washout period, patients meeting entry criteria were randomized
to topiramate (50, 100, or 200 mg/d) or placebo. Topiramate was titrated by
25 mg/wk for 8 weeks to the assigned or maximum tolerated dose, whichever
was less. Patients continued receiving that dose for 18 weeks.Main Outcome MeasuresThe primary efficacy measure was change from baseline in mean monthly
migraine frequency. Secondary efficacy measures included responder rate (proportion
of patients with ≥50% reduction in monthly migraine frequency), reductions
in mean number of monthly migraine days, severity, duration, and days a month
requiring rescue medication, and adverse events. The month of onset of preventive
treatment action was assessed.ResultsOf 483 patients randomized, 468 provided at least 1 postbaseline efficacy
assessment and comprised the intent-to-treat population. Mean monthly migraine
frequency decreased significantly for patients receiving topiramate at 100
mg/d (−2.1, P = .008) and topiramate at 200
mg/d (−2.4, P<.001) vs placebo (−1.1).
Statistically significant reductions (P<.05) occurred
within the first month with topiramate at 100 and 200 mg/d. The responder
rate was significantly greater with topiramate at 50 mg/d (39%, P = .01), 100 mg/d (49%, P<.001), and 200
mg/d (47%, P<.001) vs placebo (23%). Reductions
in migraine days were significant for the 100-mg/d (P =
.003) and 200-mg/d (P<.001) topiramate groups.
Rescue medication use was reduced in the 100-mg/d (P =
.01) and 200-mg/d (P = .005) topiramate groups. Adverse
events resulting in discontinuation in the topiramate groups included paresthesia,
fatigue, and nausea.ConclusionTopiramate showed significant efficacy in migraine prevention within
the first month of treatment, an effect maintained for the duration of the
double-blind phase.

https://jamanetwork.com/journals/jama/articlepdf/198261/joc31588.pdf

Topiramate for migraine prevention: a randomized controlled trial.

Background: Obstructive sleep apnea (OSA) is associated with several cardiovascular diseases. However, the mechanisms are not completely understood. Recent studies have shown that OSA is associated with multiple markers of endothelial damage. We hypothesized that OSA affects functional and structural properties of large arteries, contributing to atherosclerosis progression. Methods and Measurements: Twelve healthy volunteers, 15 patients with mild to moderate OSA, and 15 with severe OSA matched for age, sex, and body mass index were studied by using (1) full standard overnight polysomnography; (2) carotid-femoral pulse wave velocity with a noninvasive automatic device; and (3) a high-definition echo-tracking device to measure intima-media thickness, diameter, and distensibility. All participants were free of hypertension, diabetes, and smoking, and were not on any medications. Patients with OSA were naive to treatment. Main Results: Significant differences existed between control subjects and patients wit...

https://www.atsjournals.org/doi/pdf/10.1164/rccm.200503-340OC

Early Signs of Atherosclerosis in Obstructive Sleep Apnea

There is increasing evidence that cerebrovascular dysfunction plays a role not only in vascular causes of cognitive impairment but also in Alzheimer’s disease (AD). Vascular risk factors and AD impair the structure and function of cerebral blood vessels and associated cells (neurovascular unit), effects mediated by vascular oxidative stress and inflammation. Injury to the neurovascular unit alters cerebral blood flow regulation, depletes vascular reserves, disrupts the blood–brain barrier, and reduces the brain’s repair potential, effects that amplify the brain dysfunction and damage exerted by incident ischemia and coexisting neurodegeneration. Clinical-pathological studies support the notion that vascular lesions aggravate the deleterious effects of AD pathology by reducing the threshold for cognitive impairment and accelerating the pace of the dementia. In the absence of mechanism-based approaches to counteract cognitive dysfunction, targeting vascular risk factors and improving cerebrovascular health offers the opportunity to mitigate the impact of one of the most disabling human afflictions.

/pdf/the-overlap-between-neurodegenerative-and-vascular-factors-53adutgkg6.pdf

The overlap between neurodegenerative and vascular factors in the pathogenesis of dementia

Background and Purpose— The aim of this study was to explore the possible contribution of alterations in cerebral hemodynamics to the evolution of cognitive impairment in patients with Alzheimer disease (AD). Method— Fifty-three patients with AD were investigated. The evolution of cognitive decline over 12 months was evaluated by means of changes in Mini Mental State Examination (MMSE) and AD Assessment Scale for Cognition (ADAS-Cog) scores. Demographic characteristics, vascular risk profile, pharmacological treatment, and presence of white matter lesions were assessed at entry. Further, a basal evaluation of cerebrovascular reactivity to hypercapnia was measured with transcranial Doppler ultrasonography using the breath-holding index (BHI). Results— Of all the variables considered, both MMSE and ADAS-Cog changes had the highest correlation with BHI, followed by age and diabetes. After subdividing both cognitive measures reductions into bigger and smaller-than-average decline (2 points for MMSE; 5 points ...

Cerebrovascular Reactivity and Cognitive Decline in Patients With Alzheimer Disease

The purpose of this study was to evaluate the efficacy of topiramate in the treatment of chronic migraine. This was a double-blind, randomized, placebo controlled, parallel-group study. Patients suffering from chronic migraine with analgesic overuse were randomly assigned in a 1 : 1 ratio to receive topiramate or placebo. Following a baseline phase of eight weeks, the study drug was titrated in 25-mg increments over one week to 50 mg daily. Titration phase was followed by a 8-week maintenance phase. Number of days with headache during a 28-day period was the efficacy variable. At baseline, there was no difference in the number of days with headache between patients treated with topiramate and those treated with placebo (mean +/- SD: 20.9 +/- 3.2 and 20.8 +/- 3.2, respectively). During the last 4 week-maintenance phase, topiramate-treated patients experienced a significantly lower 28-day headache frequency in comparison to those treated with placebo (mean number of days with headache +/- SD: 8.1 +/- 8.1 vs. 20.6 +/- 3.4, P < 0.0007). Topiramate at low doses proved to be an effective therapeutic approach to reduce headache frequency in patients with chronic migraine and analgesic overuse.

Topiramate in the treatment of chronic migraine.

Background and Purpose— Epidemiological studies have suggested a pathophysiological link between sleep apnea syndrome and cerebrovascular diseases. The mechanism by which sleep disturbance can affect the predisposition to developing stroke is not clear. The aim of this study was to investigate whether patients with obstructive sleep apnea syndrome have an increase in atherosclerosis indicators at the carotid artery level. Methods— We included 23 male patients with severe obstructive sleep apnea syndrome (respiratory disturbance index >30). Intima-media thickness and the presence of steno-occlusive lesions in the common carotid arteries were investigated with B-mode high-resolution ultrasonography. Results of the ultrasonographic examination were compared with those of a group of 23 subjects without obstructive sleep apnea syndrome who were matched for age and comorbid factors. Results— The intima-media thickness of the common carotid arteries of patients with obstructive sleep apnea syndrome was significa...

Carotid Artery Wall Thickness in Patients With Obstructive Sleep Apnea Syndrome

Objective: The aim of this study was to investigate whether the presence of severe internal carotid artery stenosis may be associated with different cognitive performance in relation to the side of the stenosis and its hemodynamic consequences. Methods: Eighty-three patients with asymptomatic severe unilateral internal carotid stenosis were included. A neuropsychological investigation including Verbal Fluency using phonemic and category access, Coloured Progressive Matrices, and Complex Figure Test Copy was performed. Each patient underwent an assessment of cerebrovascular reactivity (CVR) to hypercapnia with transcranial Doppler ultrasonography using the breath-holding index (BHI). Thirty healthy subjects comparable for demographic characteristics and vascular risk profile served as controls. Subjects with carotid stenosis were classified into two groups: preserved CVR (BHI ≥0.69), 48 patients (25 with left and 23 with right stenosis); and impaired CVR (BHI Results: Subjects with left stenosis and reduced CVR had significantly lower performances at phonemic verbal fluency with respect to controls and the other groups of stenosis. In subjects with right stenosis and reduced CVR, scores obtained in Coloured Progressive Matrices and in Complex Figure Test Copy were significantly lower with respect to the other groups. Conclusions: These results suggest that an alteration of cerebrovascular reactivity may be responsible for reduction in some cognitive abilities involving the function of the hemisphere ipsilateral to carotid stenosis. Such findings may be of interest for providing a more comprehensive indication to surgical treatment in subgroups of subjects with asymptomatic carotid stenosis.

Cerebral hemodynamics and cognitive performance in patients with asymptomatic carotid stenosis

Background.—Migraine has been reported as a possible risk factor for ischemic stroke. The mechanisms underlying this association are unknown.



Objective.—To evaluate cerebrovascular reactivity to hypercapnia in the anterior and posterior circulation of patients with migraine, as reduced cerebrovascular reactivity is associated with a predisposition to stroke in various clinical conditions.



Methods.—Using transcranial Doppler ultrasonography, changes in flow velocity during apnea were measured in both middle cerebral arteries and in the basilar artery of 15 control subjects and 30 patients with migraine (15 with aura and 15 without aura) during an attack-free period. Cerebrovascular reactivity was evaluated using the breath-holding index, which is calculated by dividing the percent increase in mean flow velocity recorded during a breath-holding episode by its duration (in seconds) after a normal inspiration.



Results.—Vascular reactivity in the middle cerebral arteries was similar in patients and controls and significantly lower in the basilar artery of patients with migraine with aura compared with the other 2 groups (P < .0001).



Conclusions.—These findings show that in patients with migraine with aura, there is an impairment in the adaptive cerebral hemodynamic mechanisms in the posterior circulation. This fact could have pathogenetic implications since the association between migraine and stroke frequently regards patients with migraine with aura, and cerebral infarcts occur more commonly in the vertebrobasilar district.

Roberto Baruffaldi

Papers

Cerebrovascular Reactivity and Cognitive Decline in Patients With Alzheimer Disease

Topiramate in the treatment of chronic migraine.

Carotid Artery Wall Thickness in Patients With Obstructive Sleep Apnea Syndrome

Cerebral hemodynamics and cognitive performance in patients with asymptomatic carotid stenosis

Basilar and middle cerebral artery reactivity in patients with migraine.