Person: Novak, Vera
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Novak, Vera
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Publication Hypertension and Cerebral Vasoreactivity(Ovid Technologies (Wolters Kluwer Health), 2010-11) Hajjar, Ihab; Zhao, Peng; Alsop, David; Novak, VeraHypertension is associated with microvascular and macrovascular brain injury but its direct influence on the cerebral circulation is not fully clear. Our objective was to investigate the association of hypertension with global and regional cerebral vasoreactvity to CO2 using continuous arterial spin labeling magnetic resonance imaging, independent of stroke and white matter hyperintensities. Participants (n=62; mean age 66.7±1.0 years, 55% women, 84% white, 65% hypertension, 47% stroke) underwent arterial spin labeling perfusion MRI during normal breathing, 5% CO2 rebreathing, and hyperventilation as well as 24-hour ambulatory blood pressure monitoring. Vasoreactivity was the slope of the regression between cerebral perfusion and end-tidal CO2. White matter hyperintensity volumes were quantified. Nighttime dipping was calculated as the percent decline in nighttime/daytime blood pressure. After accounting for stroke and white matter hyperintensity volume, hypertensive participants had lower global vasoreactivity (1.11±0.13 vs. 0.43±0.1 ml/100gm/min/mmHg, p= 0.0012). Regionally, this was significant in the frontal, temporal and parietal lobes. Higher mean systolic blood pressure was associated with lower vasoreactivity (decreased by 0.11 units/10 mm Hg increase in systolic blood pressure, p=0.04), but nighttime dipping was not (p=0.2). The magnitude of decrease in vasoreactivity in hypertension without stroke was comparable to the magnitude of decrease in vasoreactivity in stroke without hypertension. Hypertension has a direct negative effect on the cerebrovascular circulation independent of white matter hyperintensities and stroke that is comparable to that seen with stroke. Since lower vasoreactivity is associated with poor outcomes, studies of the impact of antihypertensive on vasoreactivity are important.Publication Global and Regional Effects of Type 2 Diabetes on Brain Tissue Volumes and Cerebral Vasoreactivity(American Diabetes Association, 2007-02-08) Last, David; Alsop, David; Abduljalil, Amir; Marquis, Robert P.; de Bazelaire, Cedric; Hu, Kun; Cavallerano, Jerry; Novak, VeraOBJECTIVE—The aim of this study was to evaluate the regional effects of type 2 diabetes and associated conditions on cerebral tissue volumes and cerebral blood flow (CBF) regulation. RESEARCH DESIGN AND METHODS—CBF was examined in 26 diabetic (aged 61.6 ± 6.6 years) and 25 control (aged 60.4 ± 8.6 years) subjects using continuous arterial spin labeling (CASL) imaging during baseline, hyperventilation, and CO2 rebreathing. Regional gray and white matter, cerebrospinal fluid (CSF), and white matter hyperintensity (WMH) volumes were measured on a T1-weighted inversion recovery fast-gradient echo and a fluid attenuation inversion recovery magnetic resonance imaging at 3 Tesla. RESULTS—The diabetic group had smaller global white (P = 0.006) and gray (P = 0.001) matter and larger CSF (36.3%, P < 0.0001) volumes than the control group. Regional differences were observed for white matter (−13.1%, P = 0.0008) and CSF (36.3%, P < 0.0001) in the frontal region, for CSF (20.9%, P = 0.0002) in the temporal region, and for gray matter (−3.0%, P = 0.04) and CSF (17.6%, P = 0.01) in the parieto-occipital region. Baseline regional CBF (P = 0.006) and CO2 reactivity (P = 0.005) were reduced in the diabetic group. Hypoperfusion in the frontal region was associated with gray matter atrophy (P < 0.0001). Higher A1C was associated with lower CBF (P < 0.0001) and greater CSF (P = 0.002) within the temporal region. CONCLUSIONS—Type 2 diabetes is associated with cortical and subcortical atrophy involving several brain regions and with diminished regional cerebral perfusion and vasoreactivity. Uncontrolled diabetes may further contribute to hypoperfusion and atrophy. Diabetic metabolic disturbance and blood flow dysregulation that affects preferentially frontal and temporal regions may have implications for cognition and balance in elderly subjects with diabetes.Publication Multi-Scale Glycemic Variability: A Link to Gray Matter Atrophy and Cognitive Decline in Type 2 Diabetes(Public Library of Science, 2014) Cui, Xingran; Abduljalil, Amir; Manor, Brad D.; Peng, Chung-Kang; Novak, VeraObjective: Type 2 diabetes mellitus (DM) accelerates brain aging and cognitive decline. Complex interactions between hyperglycemia, glycemic variability and brain aging remain unresolved. This study investigated the relationship between glycemic variability at multiple time scales, brain volumes and cognition in type 2 DM. Research Design and Methods Forty-three older adults with and 26 without type 2 DM completed 72-hour continuous glucose monitoring, cognitive tests and anatomical MRI. We described a new analysis of continuous glucose monitoring, termed Multi-Scale glycemic variability (Multi-Scale GV), to examine glycemic variability at multiple time scales. Specifically, Ensemble Empirical Mode Decomposition was used to identify five unique ultradian glycemic variability cycles (GVC1–5) that modulate serum glucose with periods ranging from 0.5–12 hrs. Results: Type 2 DM subjects demonstrated greater variability in GVC3–5 (period 2.0–12 hrs) than controls (P<0.0001), during the day as well as during the night. Multi-Scale GV was related to conventional markers of glycemic variability (e.g. standard deviation and mean glycemic excursions), but demonstrated greater sensitivity and specificity to conventional markers, and was associated with worse long-term glycemic control (e.g. fasting glucose and HbA1c). Across all subjects, those with greater glycemic variability within higher frequency cycles (GVC1–3; 0.5–2.0 hrs) had less gray matter within the limbic system and temporo-parietal lobes (e.g. cingulum, insular, hippocampus), and exhibited worse cognitive performance. Specifically within those with type 2 DM, greater glycemic variability in GVC2–3 was associated with worse learning and memory scores. Greater variability in GVC5 was associated with longer DM duration and more depression. These relationships were independent of HbA1c and hypoglycemic episodes. Conclusions: Type 2 DM is associated with dysregulation of glycemic variability over multiple scales of time. These time-scale-dependent glycemic fluctuations might contribute to brain atrophy and cognitive outcomes within this vulnerable population.Publication Slow gait speed – an indicator of lower cerebral vasoreactivity in type 2 diabetes mellitus(Frontiers Media S.A., 2014) Jor’dan, Azizah J.; Manor, Brad; Novak, VeraObjective: Gait speed is an important predictor of health that is negatively affected by aging and type 2 diabetes. Diabetes has been linked to reduced vasoreactivity, i.e., the capacity to regulate cerebral blood flow in response to CO2 challenges. This study aimed to determine the relationship between cerebral vasoreactivity and gait speed in older adults with and without diabetes. Research design and methods: We studied 61 adults with diabetes (65 ± 8 years) and 67 without diabetes (67 ± 9 years) but with similar distribution of cardiovascular risk factors. Preferred gait speed was calculated from a 75 m walk. Global and regional perfusion, vasoreactivity and vasodilation reserve were measured using 3-D continuous arterial spin labeling MRI at 3 Tesla during normo-, hyper- and hypocapnia and normalized for end-tidal CO2. Results: Diabetic participants had slower gait speed as compared to non-diabetic participants (1.05 ± 0.15 m/s vs. 1.14 ± 0.14 m/s, p < 0.001). Lower global vasoreactivity (r2adj = 0.13, p = 0.007), or lower global vasodilation reserve (r2adj = 0.33, p < 0.001), was associated with slower walking in the diabetic group independently of age, BMI and hematocrit concentration. For every 1 mL/100 g/min/mmHg less vasodilation reserve, for example, gait speed was 0.05 m/s slower. Similar relationships between vasodilation reserve and gait speed were also observed regionally within the cerebellum, frontal, temporal, parietal, and occipital lobes (r2adj = 0.27–0.33, p < 0.0001). In contrast, vasoreactivity outcomes were not associated with walking speed in non-diabetic participants, despite similar vasoreactivity ranges across groups. Conclusion: In the diabetic group only, lower global vasoreactivity was associated with slower walking speed. Slower walking in older diabetic adults may thus hallmark reduced vasomotor reserve and thus the inability to increase perfusion in response to greater metabolic demands during walking.Publication Advanced BrainAGE in older adults with type 2 diabetes mellitus(Frontiers Media S.A., 2013) Franke, Katja; Gaser, Christian; Manor, Brad; Novak, VeraAging alters brain structure and function and diabetes mellitus (DM) may accelerate this process. This study investigated the effects of type 2 DM on individual brain aging as well as the relationships between individual brain aging, risk factors, and functional measures. To differentiate a pattern of brain atrophy that deviates from normal brain aging, we used the novel BrainAGE approach, which determines the complex multidimensional aging pattern within the whole brain by applying established kernel regression methods to anatomical brain magnetic resonance images (MRI). The “Brain Age Gap Estimation” (BrainAGE) score was then calculated as the difference between chronological age and estimated brain age. 185 subjects (98 with type 2 DM) completed an MRI at 3Tesla, laboratory and clinical assessments. Twenty-five subjects (12 with type 2 DM) also completed a follow-up visit after 3.8 ± 1.5 years. The estimated brain age of DM subjects was 4.6 ± 7.2 years greater than their chronological age (p = 0.0001), whereas within the control group, estimated brain age was similar to chronological age. As compared to baseline, the average BrainAGE scores of DM subjects increased by 0.2 years per follow-up year (p = 0.034), whereas the BrainAGE scores of controls did not change between baseline and follow-up. At baseline, across all subjects, higher BrainAGE scores were associated with greater smoking and alcohol consumption, higher tumor necrosis factor alpha (TNFα) levels, lower verbal fluency scores and more severe deprepession. Within the DM group, higher BrainAGE scores were associated with longer diabetes duration (r = 0.31, p = 0.019) and increased fasting blood glucose levels (r = 0.34, p = 0.025). In conclusion, type 2 DM is independently associated with structural changes in the brain that reflect advanced aging. The BrainAGE approach may thus serve as a clinically relevant biomarker for the detection of abnormal patterns of brain aging associated with type 2 DM.Publication Complexity-Based Measures Inform Effects of Tai Chi Training on Standing Postural Control: Cross-Sectional and Randomized Trial Studies(Public Library of Science, 2014) Wayne, Peter; Gow, Brian J.; Costa, Madalena; Peng, C.-K.; Lipsitz, Lewis; Hausdorff, Jeffrey M.; Davis, Roger; Walsh, Jacquelyn N.; Lough, Matthew; Novak, Vera; Yeh, Gloria; Ahn, Andrew; Macklin, Eric; Manor, BradBackground: Diminished control of standing balance, traditionally indicated by greater postural sway magnitude and speed, is associated with falls in older adults. Tai Chi (TC) is a multisystem intervention that reduces fall risk, yet its impact on sway measures vary considerably. We hypothesized that TC improves the integrated function of multiple control systems influencing balance, quantifiable by the multi-scale “complexity” of postural sway fluctuations. Objectives: To evaluate both traditional and complexity-based measures of sway to characterize the short- and potential long-term effects of TC training on postural control and the relationships between sway measures and physical function in healthy older adults. Methods: A cross-sectional comparison of standing postural sway in healthy TC-naïve and TC-expert (24.5±12 yrs experience) adults. TC-naïve participants then completed a 6-month, two-arm, wait-list randomized clinical trial of TC training. Postural sway was assessed before and after the training during standing on a force-plate with eyes-open (EO) and eyes-closed (EC). Anterior-posterior (AP) and medio-lateral (ML) sway speed, magnitude, and complexity (quantified by multiscale entropy) were calculated. Single-legged standing time and Timed-Up–and-Go tests characterized physical function. Results: At baseline, compared to TC-naïve adults (n = 60, age 64.5±7.5 yrs), TC-experts (n = 27, age 62.8±7.5 yrs) exhibited greater complexity of sway in the AP EC (P = 0.023), ML EO (P<0.001), and ML EC (P<0.001) conditions. Traditional measures of sway speed and magnitude were not significantly lower among TC-experts. Intention-to-treat analyses indicated no significant effects of short-term TC training; however, increases in AP EC and ML EC complexity amongst those randomized to TC were positively correlated with practice hours (P = 0.044, P = 0.018). Long- and short-term TC training were positively associated with physical function. Conclusion: Multiscale entropy offers a complementary approach to traditional COP measures for characterizing sway during quiet standing, and may be more sensitive to the effects of TC in healthy adults. Trial Registration ClinicalTrials.gov NCT01340365Publication Tai Chi Training may Reduce Dual Task Gait Variability, a Potential Mediator of Fall Risk, in Healthy Older Adults: Cross-Sectional and Randomized Trial Studies(Frontiers Media S.A., 2015) Wayne, Peter; Hausdorff, Jeffrey M.; Lough, Matthew; Gow, Brian J.; Lipsitz, Lewis; Novak, Vera; Macklin, Eric; Peng, Chung-Kang; Manor, BradBackground: Tai Chi (TC) exercise improves balance and reduces falls in older, health-impaired adults. TC’s impact on dual task (DT) gait parameters predictive of falls, especially in healthy active older adults, however, is unknown. Purpose To compare differences in usual and DT gait between long-term TC-expert practitioners and age-/gender-matched TC-naïve adults, and to determine the effects of short-term TC training on gait in healthy, non-sedentary older adults. Methods: A cross-sectional study compared gait in healthy TC-naïve and TC-expert (24.5 ± 12 years experience) older adults. TC-naïve adults then completed a 6-month, two-arm, wait-list randomized clinical trial of TC training. Gait speed and stride time variability (Coefficient of Variation %) were assessed during 90 s trials of undisturbed and cognitive DT (serial subtractions) conditions. Results: During DT, gait speed decreased (p < 0.003) and stride time variability increased (p < 0.004) in all groups. Cross-sectional comparisons indicated that stride time variability was lower in the TC-expert vs. TC-naïve group, significantly so during DT (2.11 vs. 2.55%; p = 0.027); by contrast, gait speed during both undisturbed and DT conditions did not differ between groups. Longitudinal analyses of TC-naïve adults randomized to 6 months of TC training or usual care identified improvement in DT gait speed in both groups. A small improvement in DT stride time variability (effect size = 0.2) was estimated with TC training, but no significant differences between groups were observed. Potentially important improvements after TC training could not be excluded in this small study. Conclusion: In healthy active older adults, positive effects of short- and long-term TC were observed only under cognitively challenging DT conditions and only for stride time variability. DT stride time variability offers a potentially sensitive metric for monitoring TC’s impact on fall risk with healthy older adults.Publication Association of Statins with Sensory and Autonomic Ganglionopathy(Frontiers Media S.A., 2015) Novak, Peter; Pimentel, Daniela A.; Sundar, Banu; Moonis, Majaz; Qin, Lan; Novak, VeraObjective: To examine if statins have an effect on small nerve fibers. Methods: This retrospective study evaluated the effect of statins in pure small-fiber neuropathy (SFN). Outcome measures were symptom scales (numbness, tingling, and autonomic symptoms), skin biopsies assessing epidermal nerve fiber density (ENFD), sweat gland nerve fiber density (SGNFD), and quantitative autonomic testing. Results: One hundred and sixty participants with pure SFN were identified. Eighty participants (women/men, age ± SD 33/47, 68.1 ± 11.6 years old) were on statins for 53.5 ± 28.7 months to treat dyslipidemia and they were age and gender matched with 80 participants (33/47, 68.1 ± 9.5) that were off statins. ANOVA showed reduced ENFD/SGNFD at the proximal leg in the statin group [(count/mm) 8.3 ± 3.6/51.3 ± 14.2] compared to the off statin group (10.4 ± 3.8, p = 0.0008/56.4 ± 12.7, p = 0.018). There was no difference in ENFD/SGNFD at the distal leg in the statin group (4.9 ± 3.2/39.8 ± 15.7) compared to the off statin group (5.9 ± 3.4, p = 0.067/41.8 ± 15.9, p = 0.426). Statins did not affect symptom scales and the outcome of autonomic testing. Conclusion: Statin use is associated with degeneration of sensory and autonomic fibers. The pattern of abnormalities, e.g., degeneration of proximal while sparing of distal fibers, is consistent with a non-length-dependent process with lesions in the dorsal root and the autonomic ganglia. The statin-associated sensory and autonomic ganglionopathy is mild.Publication Enhancement of Vasoreactivity and Cognition by Intranasal Insulin in Type 2 Diabetes(American Diabetes Association, 2014) Novak, Vera; Milberg, William; Hao, Ying; Munshi, Medha; Novak, Peter; Galica, Andrew; Manor, Bradley; Roberson, Paula; Craft, Suzanne; Abduljalil, AmirOBJECTIVE To determine acute effects of intranasal insulin on regional cerebral perfusion and cognition in older adults with type 2 diabetes mellitus (DM). RESEARCH DESIGN AND METHODS This was a proof-of-concept, randomized, double-blind, placebo-controlled intervention evaluating the effects of a single 40-IU dose of insulin or saline on vasoreactivity and cognition in 15 DM and 14 control subjects. Measurements included regional perfusion, vasodilatation to hypercapnia with 3-Tesla MRI, and neuropsychological evaluation. RESULTS Intranasal insulin administration was well tolerated and did not affect systemic glucose levels. No serious adverse events were reported. Across all subjects, intranasal insulin improved visuospatial memory (P ≤ 0.05). In the DM group, an increase of perfusion after insulin administration was greater in the insular cortex compared with the control group (P = 0.0003). Cognitive performance after insulin administration was related to regional vasoreactivity. Improvements of visuospatial memory after insulin administration in the DM group (R2adjusted = 0.44, P = 0.0098) and in the verbal fluency test in the control group (R2adjusted = 0.64, P = 0.0087) were correlated with vasodilatation in the middle cerebral artery territory. CONCLUSIONS Intranasal insulin administration appears safe, does not affect systemic glucose control, and may provide acute improvements of cognitive function in patients with type 2 DM, potentially through vasoreactivity mechanisms. Intranasal insulin-induced changes in cognitive function may be related to vasodilatation in the anterior brain regions, such as insular cortex that regulates attention-related task performance. Larger studies are warranted to identify long-term effects and predictors of positive cognitive response to intranasal insulin therapy.Publication A Nonlinear Dynamic Approach Reveals a Long-Term Stroke Effect on Cerebral Blood Flow Regulation at Multiple Time Scales(Public Library of Science, 2012) Hu, Kun; Lo, Men-Tzung; Peng, Chung-Kang; Liu, Yanhui; Novak, VeraCerebral autoregulation (CA) is an important vascular control mechanism responsible for relatively stable cerebral blood flow despite changes of systemic blood pressure (BP). Impaired CA may leave brain tissue unprotected against potentially harmful effects of BP fluctuations. It is generally accepted that CA is less effective or even inactive at frequencies >∼0.1 Hz. Without any physiological foundation, this concept is based on studies that quantified the coupling between BP and cerebral blood flow velocity (BFV) using transfer function analysis. This traditional analysis assumes stationary oscillations with constant amplitude and period, and may be unreliable or even invalid for analysis of nonstationary BP and BFV signals. In this study we propose a novel computational tool for CA assessment that is based on nonlinear dynamic theory without the assumption of stationary signals. Using this method, we studied BP and BFV recordings collected from 39 patients with chronic ischemic infarctions and 40 age-matched non-stroke subjects during baseline resting conditions. The active CA function in non-stroke subjects was associated with an advanced phase in BFV oscillations compared to BP oscillations at frequencies from ∼0.02 to 0.38 Hz. The phase shift was reduced in stroke patients even at > = 6 months after stroke, and the reduction was consistent at all tested frequencies and in both stroke and non-stroke hemispheres. These results provide strong evidence that CA may be active in a much wider frequency region than previously believed and that the altered multiscale CA in different vascular territories following stroke may have important clinical implications for post-stroke recovery. Moreover, the stroke effects on multiscale cerebral blood flow regulation could not be detected by transfer function analysis, suggesting that nonlinear approaches without the assumption of stationarity are more sensitive for the assessment of the coupling of nonstationary physiological signals.