Kerstin Bettermann

Statins, Risk of Dementia, and Cognitive Function: Secondary Analysis of the Ginkgo Evaluation of Memory Study

BACKGROUND Lipid-lowering medications (LLMs) and especially statin drugs can delay cognitive decline and dementia onset in individuals with and without mild cognitive impairment (MCI) at baseline. METHODS A longitudinal, observational study was conducted of 3069 cognitively healthy elderly patients (≥75 years of age) who were enrolled in the Ginkgo Evaluation of Memory Study. The primary outcome measure was the time to adjudicated all-cause dementia and Alzheimer dementia (AD). The secondary outcome measure was the change in global cognitive function over time measured by scores from the Modified Mini-Mental State Exam (3MSE) and the cognitive subscale of the AD Assessment Scale (ADAS-Cog). RESULTS Among participants without MCI at baseline, the current use of statins was consistently associated with a reduced risk of all-cause dementia (hazard ratio [HR], 0.79; 95% confidence interval [95% CI], 0.65-0.96; P = .021) and AD (HR, 0.57; 95% CI, 0.39-0.85; P = .005). In participants who initiated statin therapy, lipophilic statins tended to reduce dementia risk more than nonlipophilic agents. In contrast, there was no significant association between LLM use (including statins), dementia onset, or cognitive decline in individuals with baseline MCI. However, in individuals without MCI at baseline, there was a trend for a neuroprotective effect of statins on cognitive decline. CONCLUSIONS Statins may slow the rate of cognitive decline and delay the onset of AD and all-cause dementia in cognitively healthy elderly individuals, whereas individuals with MCI may not have comparable cognitive protection from these agents. However, the results from this observational study need to be interpreted with caution and will require confirmation by randomized clinical trials stratifying treatment groups based on MCI status at baseline.

Postmenopausal hormone therapy and subclinical cerebrovascular disease: The WHIMS-MRI Study

Objective: The Womens Health Initiative Memory Study (WHIMS) hormone therapy (HT) trials reported that conjugated equine estrogen (CEE) with or without medroxyprogesterone acetate (MPA) increases risk for all-cause dementia and global cognitive decline. WHIMS MRI measured subclinical cerebrovascular disease as a possible mechanism to explain cognitive decline reported in WHIMS. Methods: We contacted 2,345 women at 14 WHIMS sites; scans were completed on 1,424 (61%) and 1,403 were accepted for analysis. The primary outcome measure was total ischemic lesion volume on brain MRI. Mean duration of on-trial HT or placebo was 4 (CEE+MPA) or 5.6 years (CEE-Alone) and scans were conducted an average of 3 (CEE+MPA) or 1.4 years (CEE-Alone) post-trial termination. Cross-sectional analysis of MRI lesions was conducted; general linear models were fitted to assess treatment group differences using analysis of covariance. A (two-tailed) critical value of α = 0.05 was used. Results: In women evenly matched within trials at baseline, increased lesion volumes were significantly related to age, smoking, history of cardiovascular disease, hypertension, lower post-trial global cognition scores, and increased incident cases of on- or post-trial mild cognitive impairment or probable dementia. Mean ischemic lesion volumes were slightly larger for the CEE+MPA group vs placebo, except for the basal ganglia, but the differences were not significant. Women assigned to CEE-Alone had similar mean ischemic lesion volumes compared to placebo. Conclusions: Conjugated equine estrogen–based hormone therapy was not associated with a significant increase in ischemic brain lesion volume relative to placebo. This finding was consistent within each trial and in pooled analyses across trials.

Comparison of retinal vasodilator and constrictor responses in type 2 diabetes

Purpose:  The retinal blood vessels provide a unique way to directly examine the human microvasculature, which is frequently damaged in individuals with diabetes. Previous studies have demonstrated that retinal flickering light‐induced vasodilation and hyperoxia‐induced vasoconstriction may operate by enhancing or reducing similar vasoregulatory factor(s), but a comparison between these two provocative stimuli in individuals with diabetes has not been studied. The purpose of the study was to examine the association between retinal flickering light‐induced vasodilation and retinal hyperoxia‐induced vasoconstriction in type 2 diabetic subjects and in healthy controls.

Impaired retinal vasodilator responses in prediabetes and type 2 diabetes

Purpose:  In diabetes, endothelial dysfunction and subsequent structural damage to blood vessels can lead to heart attacks, retinopathy and strokes. However, it is unclear whether prediabetic subjects exhibit microvascular dysfunction indicating early stages of arteriosclerosis and vascular risk. The purpose of this study was to examine whether retinal reactivity may be impaired early in the hyperglycaemic continuum and may be associated with markers of inflammation.

Diagnostic potential of the NMDA receptor peptide assay for acute ischemic stroke.

Background The acute assessment of patients with suspected ischemic stroke remains challenging. The use of brain biomarker assays may improve the early diagnosis of ischemic stroke. The main goal of the study was to evaluate whether the NR2 peptide, a product of the proteolytic degradation of N-methyl-D-aspartate (NMDA) receptors, can differentiate acute ischemic stroke (IS) from stroke mimics and persons with vascular risk factors/healthy controls. A possible correlation between biomarker values and lesion sizes was investigated as the secondary objective. Methods and Findings A total of 192 patients with suspected stroke who presented within 72 h of symptom onset were prospectively enrolled. The final diagnosis was determined based on clinical observations and radiological findings. Additionally gender- and age-matched healthy controls (n = 52) and persons with controlled vascular risk factors (n = 48) were recruited to compare NR2 peptide levels. Blinded plasma was assayed by rapid magnetic particles (MP) ELISA for NR2 peptide within 30 min and results for different groups compared using univariate and multivariate statistical analyses. There was a clinical diagnosis of IS in 101 of 192 (53%) and non-stroke in 91 (47%) subjects. The non-stroke group included presented with acute stroke symptoms who had no stroke (n = 71) and stroke mimics (n = 20). The highest NR2 peptide elevations where found in patients with IS that peaked at 12 h following symptom onset. When the biomarker cut off was set at 1.0 ug/L, this resulted in a sensitivity of 92% and a specificity of 96% to detect IS. A moderate correlation (rs = 0.73) between NR2 peptide values and acute ischemic cortical lesions (<200 mL) was found. Conclusions This study suggests that the NR2 peptide may be a brain specific biomarker to diagnose acute IS and may allow the differentiation of IS from stroke mimics and controls. Additional larger scale clinical validation studies are required.

Biomarkers for Stroke: In Search of Fingerprints

We have become accustomed to relying on cardiac enzymes for diagnosis of acute myocardial infarction since the mid-1970s, but comparable sensitive and specific biomarkers for acute brain injury, including stroke, are not yet within the realm of clinical practice. Although the concept is intuitively simple, markers of brain injury are difficult to detect due to the complexity of the ischemic cascade, which involves multiple molecular pathways of neurodegeneration and neuroregeneration, metabolic compromise, oxidative stress, inflammation, vascular dysfunction, and secondary tissue injury, making it difficult to isolate brain specific biomarkers. 1 Furthermore, the detection of markers of brain tissue injury is complicated by the blood-brain barrier. Any potentially useful biomarker must penetrate this barrier to be released into the bloodstream in sufficient quantities to allow detection by a blood test. An ideal stroke biomarker is brain-specific, sufficiently sensitive and specific, detectable in blood within minutes of symptom onset, and inexpensive and easily measured. Moreover, the concentration of the biomarker should correspond to lesion size, location and functional outcome. Its predictive value needs to be compared with the sensitivity and specificity of brain magnetic resonance imaging (MRI), the gold standard for stroke diagnosis. Currently, no specific and sensitive single biomarker or panel of biomarkers has been validated by large clinical trials. Thus, many questions regarding the clinical utility of biomarkers remain. Stroke biomarkers may prove reliable and cost-effective for the diagnosis and management of patients with stroke if they can truly help diagnose and classify stroke, anticipate outcome, and assess the risk of complications, such as edema and hemorrhagic transformation after thrombolysis. In the acute setting, they should help diagnose acute stroke in patients who have limited access to advanced neuroimaging and allow

Impaired coronary and retinal vasomotor function to hyperoxia in Individuals with Type 2 diabetes.

PURPOSE Adults with diabetes are at a high risk of developing coronary heart disease. The purpose of this study was to assess coronary artery vascular function non-invasively in individuals with and without Type 2 diabetes and to compare these coronary responses to another microvascular bed (i.e. retina). We hypothesized that individuals with diabetes would have impaired coronary reactivity and that these impairments would be associated with impairments in retinal reactivity. METHODS Coronary blood velocity (Transthoracic Doppler Echocardiography) and retinal diameters (Dynamic Vessel Analyzer) were measured continuously during five minutes of breathing 100% oxygen (i.e. hyperoxia) in 15 persons with Type 2 diabetes and 15 age-matched control subjects. Using fundus photographs, retinal vascular calibers were also measured (central retinal arteriole and venule equivalents). RESULTS Individuals with diabetes compared to controls had impaired coronary (-2.34±16.64% vs. -14.27±10.58%, P=0.03) and retinal (arteriole: -0.04±3.34% vs. -3.65±5.07%, P=0.03; venule: -1.65±3.68% vs. -5.23±5.47%, P=0.05) vasoconstrictor responses to hyperoxia, and smaller central arteriole-venule equivalent ratios (0.83±0.07 vs. 0.90±0.07, P=0.014). Coronary reactivity was associated with central retinal arteriole equivalents (r=-0.516, P=0.005) and retinal venular reactivity (r=0.387, P=0.034). CONCLUSION Diabetes impairs coronary and retinal microvascular function to hyperoxia. Impaired vasoconstrictor responses may be part of a systemic diabetic vasculopathy, which may contribute to adverse cardiovascular events in individuals with diabetes.

Retinal vasoreactivity as a marker for chronic ischemic white matter disease

UNLABELLED The cerebral microvasculature cannot be easily studied non-invasively. Because the retina and brain share embryological, anatomical and physiological similarities, studies of retinal blood vessels may prove to be useful as a surrogate marker for cerebrovascular disease. In epidemiological studies abnormal retinal arteriovenous ratios (AVRs) predict the risk of stroke and vascular dementia. However, the association between retinal vasoreactivity, cerebral small vessel ischemic disease, and cerebral blood vessel function remains unknown. STUDY GOALS To examine (1) the association between cerebral ischemic white matter disease (WMD) and retinal microvessel behavior and (2) the relationship between retinal blood vessel reactivity and measures of cerebrovascular function. METHODS Cohort study of 12 patients with ischemic WMD and 14 healthy controls. Retinal vasoreactivity was measured following high frequency flicker light stimulation. Middle cerebral artery (MCA) vasoreactivity was measured using transcranial Doppler ultrasound (TCD). Magnetic resonance imaging scans (MRIs) were reviewed for evidence of ischemic WMD. RESULTS Patients with ischemic WMD had attenuated retinal venous (2.2% ± 0.27 SD, vs. controls 6% ± 0.7 SD, p=0.002, CI 95%) and arterial (1.9% ± 0.8 SD, vs. controls 4.9% ± 0.8 SD, p=0.004, CI 95%) vasoreactivity compared to controls. An attenuated retinal venous light flicker response was associated with a significant decrease of MCA vasoreactivity (r=0.45, p=0.05, CI 95%). Decreased AVRs, an indicator for altered retinal vessel architecture in patients with cerebral chronic ischemic WMD, were also significantly correlated with dysfunction of cerebral vasoreactivity (r=0.69, p=0.001, CI 95%). CONCLUSION In this study functional and structural impairment of the retinal microvasculature were associated with ischemic WMD and measures of cerebral vascular function. Microvascular dysfunction in the eye may predict cerebral small vessel disease, but validation by larger studies is needed.

Toole's Cerebrovascular Disorders

Toole’s Cerebrovascular Disorders was the first modern book devoted to the care of stroke, originally published more than 40 years ago. Drs. E. Steve Roach, Kerstin Bettermann, and Jose Biller have completely revised and updated this sixth edition of the highly respected standard for stroke diagnosis and treatment, adding chapters on genetics, pregnancy-related stroke, and acute treatment. The practical focus of the book has not changed, retaining its emphasis on bedside diagnosis and treatment. Easily accessible for both stroke specialists and residents, this sixth edition has been modernized to keep pace with the rapid expansion of knowledge in stroke care and includes evidence-based recommendations, the latest technology and imaging, and risk factors. The text is supplemented with more than 200 images, many in color. E. Steve Roach, MD, FAAN, FAHA, is Professor of Pediatrics and Neurology and Director of the Division of Child Neurology at The Ohio State University College of Medicine, Columbus, Ohio.

Impaired Retinal Vasoreactivity: An Early Marker of Stroke Risk in Diabetes

Diabetes is a common cause of small vessel disease leading to stroke and vascular dementia. While the function and structure of large cerebral vessels can be easily studied, the brains microvasculature remains difficult to assess. Previous studies have demonstrated that structural changes in the retinal vessel architecture predict stroke risk, but these changes occur at late disease stages. Our goal was to examine whether retinal vascular status can predict cerebral small vessel dysfunction during early stages of diabetes. Retinal vasoreactivity and cerebral vascular function were measured in 78 subjects (19 healthy controls, 22 subjects with prediabetes, and 37 with type‐2 diabetes) using a new noninvasive retinal imaging device (Dynamic Vessel Analyzer) and transcranial Doppler studies, respectively. Cerebral blood vessel responsiveness worsened with disease progression of diabetes. Similarly, retinal vascular reactivity was significantly attenuated in subjects with prediabetes and diabetes compared to healthy controls. Subjects with prediabetes and diabetes with impaired cerebral vasoreactivity showed mainly attenuation of the retinal venous flicker response. This is the first study to explore the relationship between retinal and cerebral vascular function in diabetes. Impairment of venous retinal responsiveness may be one of the earliest markers of vascular dysfunction in diabetes possibly indicating subsequent risk of stroke and vascular dementia.