Ischemic Small Vessel Disease Research Articles

The MRI central vein marker; differentiating PPMS from RRMS and ischemic SVD.

ObjectiveTo determine whether the assessment of brain white matter lesion (WML) central veins differentiate patients with primary progressive MS (PPMS) from relapsing-remitting MS (RRMS) and ischemic small vessel disease (SVD) using 3T MRI.MethodsIn this cross-sectional study, 71 patients with PPMS, RRMS, and SVD were imaged using a T2*-weighted sequence. Two blinded raters identified the total number of WMLs, proportion of WMLs in periventricular, deep white matter (DWM) and juxtacortical regions, and proportion of WMLs with central veins in all patient groups. The proportions were compared between disease groups, including effect sizes. MS or SVD was categorized using a threshold of ≥40% WMLs with central veins as indicative of MS. Interrater and intrarater reproducibility was calculated.ResultsThe mean proportion of WMLs with central veins was 68.4% in PPMS, 74.3% in RRMS, and 4.7% in SVD. The difference in proportions between PPMS and SVD groups was significant (p < 0.0005; effect size: 3.8) but not significant between MS subtypes (p = 0.3; effect size: 0.29). Distribution of WMLs was similar across both MS groups, but despite SVD patients having more DWM lesions than PPMS patients, proportions of WMLs with central veins remained low (2.75% in SVD; 62.5% in PPMS). Interrater and intrarater reproducibility comparing proportions of WMLs with central veins across all patients was 0.86 and 0.90, respectively. Level of agreement between the proportion of WML central veins and established diagnosis was 0.84 and 0.82 for each rater.ConclusionsWML central veins could be used to differentiate PPMS from SVD but not between MS subtypes.

Using high-dimensional machine learning methods to estimate an anatomical risk factor for Alzheimer's disease across imaging databases

IntroductionThe main goal of this work is to investigate the feasibility of estimating an anatomical index that can be used as an Alzheimer's disease (AD) risk factor in the Women's Health Initiative Magnetic Resonance Imaging Study (WHIMS-MRI) using MRI data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), a well-characterized imaging database of AD patients and cognitively normal subjects. We called this index AD Pattern Similarity (AD-PS) scores. To demonstrate the construct validity of the scores, we investigated their associations with several AD risk factors. The ADNI and WHIMS imaging databases were collected with different goals, populations and data acquisition protocols: it is important to demonstrate that the approach to estimating AD-PS scores can bridge these differences. MethodsMRI data from both studies were processed using high-dimensional warping methods. High-dimensional classifiers were then estimated using the ADNI MRI data. Next, the classifiers were applied to baseline and follow-up WHIMS-MRI GM data to generate the GM AD-PS scores. To study the validity of the scores we investigated associations between GM AD-PS scores at baseline (Scan 1) and their longitudinal changes (Scan 2 –Scan 1) with: 1) age, cognitive scores, white matter small vessel ischemic disease (WM SVID) volume at baseline and 2) age, cognitive scores, WM SVID volume longitudinal changes respectively. In addition, we investigated their associations with time until classification of independently adjudicated status in WHIMS-MRI. ResultsHigher GM AD-PS scores from WHIMS-MRI baseline data were associated with older age, lower cognitive scores, and higher WM SVID volume. Longitudinal changes in GM AD-PS scores (Scan 2 – Scan 1) were also associated with age and changes in WM SVID volumes and cognitive test scores. Increases in the GM AD-PS scores predicted decreases in cognitive scores and increases in WM SVID volume. GM AD-PS scores and their longitudinal changes also were associated with time until classification of cognitive impairment. Finally, receiver operating characteristic curves showed that baseline GM AD-PS scores of cognitively normal participants carried information about future cognitive status determined during follow-up. DiscussionWe applied a high-dimensional machine learning approach to estimate a novel AD risk factor for WHIMS-MRI study participants using ADNI data. The GM AD-PS scores showed strong associations with incident cognitive impairment and cross-sectional and longitudinal associations with age, cognitive function, cognitive status and WM SVID volume lending support to the ongoing validation of the GM AD-PS score.

Remote ischaemic conditioning for preventing and treating ischaemic stroke.

Remote ischaemic conditioning (RIC) has been developed as a neuroprotective strategy to prevent and treat ischaemic stroke. It usually involves restricting blood flow to limbs and then releasing the ischaemic blood to promote a neuroprotective effect. Preclinical studies have suggested that RIC may have beneficial effects in ischaemic stroke patients and those at risk of ischaemic stroke. However, existing evidence is insufficient to demonstrate the efficacy and safety of RIC in preventing and treating ischaemic stroke. To assess the benefits and harms of RIC for preventing ischaemic stroke and for treating people with ischaemic stroke and those at risk for ischaemic stroke. We searched the Cochrane Stroke Group Trials Register (16 January 2018), the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 12) in the Cochrane Library (January 2018), MEDLINE Ovid (1946 to January 2018), Embase Ovid (1974 to January 2018), Web of Science Core Collection (1950 to January 2018) and three Chinese databases (January 2018). We also searched four ongoing trials registers, reference lists, and conference proceedings. We included randomised controlled trials (RCTs) comparing RIC with sham RIC or medical management in people with ischaemic stroke or at risk of ischaemic stroke. Two review authors independently selected studies, assessed trial quality and risk of bias, and extracted data. We used the GRADE approach to assess the quality of the evidence. We included seven trials, involving 735 participants, in this review. We analysed the effects of RIC on preventing and treating ischaemic stroke respectively.We evaluated risk of bias and judged it to be low for generation of allocation sequence in six studies and unclear in one study; unclear for allocation concealment in four studies and low in three studies; high for incomplete outcome data (attrition bias) in five studies and low in two studies; high for blinding in three studies and low in four studies; low for selective reporting; and high for other sources of bias in six studies and low in one study.We included three trials (involving 371 participants) in the analysis of the effects of RIC on ischaemic stroke prevention. In people with symptomatic intracerebral artery stenosis, recurrent stroke was significantly reduced by RIC (risk ratio (RR) 0.32, 95% confidence interval (CI) 0.12 to 0.83; 2 trials, 182 participants, low-quality evidence). In people with carotid stenosis undergoing carotid stenting, there was no significant difference in the incidence of ischaemic stroke between participants treated with RIC and non-RIC (RR 0.22, 95% CI 0.01 to 4.03; 1 trial, 189 participants, low-quality evidence); however the stroke severity (assessed by infarct volume) was significantly lower in participants treated with RIC (mean difference (MD) -0.17 mL, 95% CI -0.23 to -0.11; 1 trial, 189 participants, low-quality evidence). Adverse events associated with RIC were significantly higher in participants treated with RIC (RR 10.91; 95% CI 2.01 to 59.28; 3 trials, 371 participants, low-quality evidence), but no severe adverse event was attributable to RIC treatment. No participants experienced death or cardiovascular events during the period of the studies; and no trial reported haemorrhagic stroke or improvement in neurological, phycological or cognitive impairment.We included four trials (involving 364 participants) in the analysis of the effects of RIC on ischaemic stroke treatment. In acute ischaemic stroke, for people receiving intravenous thrombolysis, the rate of death or dependency was significantly increased by RIC treatment compared with non-RIC treatment (RR 2.34; 95% 1.19 to 4.61; 1 trial, 285 participants, low-quality evidence). In people with acute ischaemic stroke, there was no significant difference between RIC and non-RIC for reducing stroke severity as assessed by the National Institutes of Health Stroke Scale score and the final infarct volume (standardised mean difference (SMD) -0.24 mL, 95% CI -1.02 to 0.54; 2 trials, 175 participants, very low quality evidence). There was no significant difference between RIC and non-RIC for improving the psychological impairment (SMD -0.37 points, 95% CI -1.15 to 0.41; 1 trial, 26 participants, very low quality evidence) and the cognitive impairment (SMD -0.26 points; 95% CI -0.72 to 0.21; 3 trials, 79 participants, low-quality evidence) in people with acute ischaemic stroke and cerebral small vessel disease. No trial reported ischaemic stroke, recurrent ischaemic stroke, improvement in neurological impairment, hemorrhagic stroke, cardiovascular events, and RIC associated adverse events. We found low-quality evidence that RIC may reduce the risk of recurrent stroke in participants with intracerebral artery stenosis and reduce stroke severity in participants undergoing carotid stenting, but it may increase death or dependence in participants with acute ischaemic stroke who are undergoing intravenous thrombolysis. However, there is considerable uncertainty about these conclusions because of the small number of studies and low quality of the evidence.

Paroxysmal Nocturnal Hemoglobinuria (Pnh): Brain Mri Ischemic Lesions In Neurologically Asymtomatic Patients

This study investigated for the first time brain ischemic involvement in 19 consecutive neurologically asymptomatic PNH patients by non-enhanced cerebral MRI, and by intracranial arterial and venous angio-MRI. Eleven cases (58%, 7 aged <65) showed pathological findings: 9 white matter (WM) abnormalities related to chronic ischemic small vessel disease, 2 a focal abnormality >5 mm, and 5 cases a score >4 by the age-related white matter changes (ARWMC) scale. Compared with age and sex-matched controls (1:2 ratio), patients showed an increased frequency of periventricular WM vascular degeneration (32% versus 5.2%, p = 0.04) and of severe lesions (ARWMC scale score >4) (26% versus 2.6%, p = 0.05), and a higher overall ARWMC scale score (3.5 ± 1.07 versus 2.0 ± 0.8, mean ± SD, p < 0.0001). Notably, vascular abnormalities suspected for prior partial venous thrombosis, were observed in PNH cases only. MRI lesions were not related to blood counts, hemolytic markers, clone size, disease duration, and therapy with eculizumab. Neurological examination was unremarkable in all patients but one (Parkinson disease). Psychiatric assessment revealed a case of generalized anxiety disorder, 1 bipolar disorder type 2, and 1 adjustment disorder. In conclusion, brain MRI may be useful at diagnosis and during the course of the disease to explore subclinical neurological involvement.

Peripheral lipid oxidative stress markers are related to vascular risk factors and subcortical small vessel disease

Subcortical white matter hyperintensities (WMH), presumed to indicate small vessel ischemic vascular disease, are found commonly in elderly individuals with and without Alzheimer's disease (AD). Oxidative stress may instigate or accelerate the development of vascular disease, and oxidative stress markers are elevated in AD. Here, we assess independent relationships between three serum lipid peroxidation markers (lipid hydroperoxides [LPH], 8-isoprostane, and 4-hydroxynonenal) and the presence of extensive subcortical WMH and/or AD. Patients were recruited from memory and stroke prevention clinics into four groups: minimal WMH, extensive WMH, AD with minimal WMH, and AD with extensive WMH. Extensive WMH, but not AD, was associated with higher serum concentrations of 8-isoprostane and LPH. Peripheral LPH concentrations mediated the effect of hypertension on deep, but not periventricular, WMH volumes. 4-hydroxynonenal was associated with hyperlipidemia and cerebral microbleeds, but not with extensive WMH or AD. We conclude that lipid peroxidation mediates hypertensive injury to the deep subcortical white matter and that peripheral blood lipid peroxidation markers indicate subcortical small vessel disease regardless of an AD diagnosis.

Brain MRI Findings and Neuro-Psychiatric Involvement in Paroxysmal Nocturnal Hemoglobinuria (PNH)

▪PNH is a rare disorder characterized by hemolytic anemia, marrow failure and thrombosis, due to a deficiency in GPI-anchored proteins. Thrombotic events in PNH are commonly described in hepatic, portal, mesenteric, splenic, and renal veins, along with anecdotic case reports of cerebral venous sinus thrombosis and arterial ischemic strokes.This study was aimed at investigate brain involvement in 19 asymptomatic PNH patients by non-enhanced cerebral magnetic resonance imaging (MRI), and by intracranial arterial and venous angio-MRI. Neuroradiological findings were completed with a neuro-psychiatric evaluation, and correlated with clinical/hematologic features and therapy.Seventeen out of 19 patients were classical hemolytic (63% transfusion dependent before treatment with eculizumab and 1 patient also after), and 2 PNH in the context of aplastic anemia (all transfusion-dependent until treatment with ATG-CyA). Median age at diagnosis was 44 years (range 17-80); asthenia and dyspnea on exertion were present in all patients, abdominal pain in 8, and a thrombotic event in 4. Median Hb was 9.6 g/dL (range 6.7-12.9), LDH 3.7-fold (range 1.2-16.3) over upper limit of normal (ULN), and 73% of patients displayed a clone size greater than 50% GPI negative cells; 10/19 of patients were on eculizumab at the moment of the study.On MRI, 11 subjects showed pathological findings: 9 cases displayed white matter (WM) abnormalities related to chronic ischemic small vessel disease, of whom 6 periventricular WM vascular degeneration, and 8 deep WM focal chronic ischemic lesions (5 cases have both sites involved). Moreover, 1 subject showed a focal abnormality >5 mm and 5 subjects a score > 4 as evaluated in WM and basal ganglia by the age related white matter changes (ARWMC) scale. No subject displayed active or previous bleeding, nor were focal alterations of the basal nuclei by the ARWMC scale found. Two patients (80 and 81 yrs) showed atrophy of the cerebral hemispheres. Regarding vascular abnormalities, one subject had hypoplastic left transverse sinus with irregularities in the sinus wall, suspected for prior partial venous thrombosis. Three further cases displayed hypoplastic transverse sinus associated with collateral draining cortical veins, indistinguishable from anatomical variants. Intracranial artery stenosis or aneurysm, and Moya-Moya like alterations were not observed. Finally, cerebral MRI was unremarkable in 8/19 subjects.By comparing patients with or without any MRI abnormality (WM and vascular alterations), mean age was significantly higher in the former (60+17 vs 43+8 yrs, mean+SD, p<0.05), whereas blood counts, hemolytic markers and clone size showed no remarkable differences. Hemoglobin at diagnosis was slightly lower (9.5+1.5 vs 9.9+1.6 g/dL, mean+SD), and LDH greater (5.8+4.4 vs 4.1+2.9 over ULN, mean+SD) in subjects who displayed MRI abnormalities. Moreover, individual hemoglobin levels negatively correlated with the ARWMC score (r=-0.45, p<0.05). No relationship was found between history of abdominal pain/thrombosis and MRI pathological findings. Likewise, MRI abnormalities were not correlated with disease duration. As regards therapy with eculizumab, a pathological MRI was found in 6/10 subjects under treatment and in 5/9 without; the sole significant vascular alteration was detected in a patient under treatment.Neurological examination was unremarkable in all patients but one, who complained of progressive rest tremor in his left arm and leg (twelve years after PNH diagnosis), and was diagnosed with possible Parkinson disease. Previous history of neurological disorders was observed in 3 patients: one typical transient global amnesia (at the age of 60), one seizures (at 5 years), and one headache before the diagnosis of PNH. Regarding psychiatric evaluation, 3/18 patients had a psychiatric disorder according to structured clinical interview for axis I DSM-IV-TR disorders (1 generalized anxiety disorder, 1 bipolar disorder type 2, and 1 adjustment disorder as a consequence of PNH diagnosis). No relationship was observed between MRI findings and neuro-psychiatric assessment.In conclusion, brain MRI revealed chronic ischemic and vascular lesions in 58% of asymptomatic PNH patients. Brain MRI is advisable at diagnosis and during the course of the disease, and WM lesion burden may be useful in the decision to start therapy. DisclosuresBarcellini:Agios: Consultancy.

Building on a Legacy of Hypertension Research: Charting Our Future Together.

In partnership with other public and private funders of biomedical research, the NHLBI has pursued its mission to provide global leadership in research that advances the prevention, treatment, and control of hypertension over the last half-century. Since its founding in 1948, NHLBI has fostered investigator- and institute-initiated research in hypertension that encompassed studies in basic, translational, clinical, and population science research. In fact, 60% of the overall National Institutes of Health (NIH) investment in hypertension research, by dollar amount of funding or by number of grants, comes through the NHLBI, followed by the National Institute of Digestive Disorders and Kidney (15%).1 These many research advances have ushered in a wide spectrum of safe and effective interventions for the prevention, detection, evaluation, treatment, and control of hypertension. In spite of these remarkable achievements, hypertension remains the leading cause of global death and disability from heart disease and stroke and a major contributor to all-cause mortality worldwide.2 In 2013 alone, high systolic blood pressure accounted for more than 10 million deaths and 208 million disability adjusted life years (DALYs) lost globally.2 In the United States, hypertension continues to play a major role in mortality disparities because of its high prevalence and earlier age of onset in non-Hispanic blacks compared to other race/ethnic groups.3,4 Hypertension explains approximately 50% of the excess cardiovascular risk among non-Hispanic blacks compared to non-Hispanic whites.5 These persisting challenges compel a continued commitment to identify effective strategies for the prevention of hypertension-related morbidity, mortality, and disparities. In this endeavor, the NHLBI remains committed to the full spectrum of hypertension research from molecular, genomic, cellular, and pathophysiological origins to the role of important social and environmental determinants and conditions under which people live and work. We support continued exploration of these social determinants and conditions, especially obesity, sedentary lifestyle, sleep disordered breathing, and dietary factors such as higher sodium intake6 and lower potassium intake. Key mechanistic insights and connections remain incompletely understood and constitute ripe opportunities for future hypertension research. For instance, future improvements will critically depend on answering fundamental enduring questions about the relations of hypertension and associated target organ damage, chronic kidney disease, cognitive impairment, and small-vessel cerebral ischemic disease. In order to translate the latest fundamental discoveries to real-world health impact, the NHLBI seeks to identify and enable the most meritorious research with the firm understanding that all the various types of research are needed to inform each other, and is thus committed to a balanced overall research portfolio.7 In this article, we highlight a few NHLBI-supported advances from basic and early translational research, clinical trials, and population science encompassing hypertension research over the prior fifty years and the foundational insights they provide for future research. We also address the NHLBI enduring principles and propose how collectively, we can seize unprecedented opportunities to address the challenges we face today by setting the agenda for hypertension research over the coming decade.8,9

The Central Vein Sign in Multiple Sclerosis Lesions Is Present Irrespective of the T2* Sequence at 3 T.

Previous T2*-weighted magnetic resonance imaging (MRI) studies have used white matter lesion (WML) central veins to distinguish multiple sclerosis (MS) from its mimics. To be clinically applicable, the "central vein sign" needs to be detectable across different T2* sequences. Our objective was to determine if the central vein sign is reliably present in MS and absent in patients with ischemic small vessel disease (SVD) across different T2* sequences at 3T MRI. Ten patients with MS and 10 with SVD were each scanned on a 3 T Philips and GE scanner. The MRI protocol included 3-dimensional (3D) T2* GRE, T2* with high echo planar imaging (EPI) factor and susceptibility-weighted angiography (SWAN). Total WML numbers, central vein numbers, and proportion of WMLs with central veins were calculated using each sequence. Three blinded raters identified a subset of six WMLs with central veins to diagnose MS or SVD. Irrespective of the sequence, MS patients were identified based on a higher proportion of WMLs with central veins. This proportion was dependent on the T2* sequence used. T2* with high EPI allowed the highest median proportion (69.6%) in MS patients; 6.1% in SVD patients (P < .0004). Rater reproducibility varied depending on the T2* sequence used. T2* with high EPI produced good agreement with the clinical diagnosis (Cohen's kappa range; .78-.89), as did SWAN imaging with some raters; ĸ = .69. The central vein sign can diagnose MS in the clinical setting of modern 3T scanners. However, variations in the T2* sequences need to be considered when defining a threshold for diagnosis.

No evidence for increased brain iron deposition in patients with ischemic white matter disease

Besides specific iron accumulation in some neurodegenerative disorders, increased iron deposition in cerebral deep gray matter (DGM) is found in multiple sclerosis. As this is considered largely a white matter (WM) disease, we speculated that patients with more severe ischemic WM hyperintensities (WMH) might also have an increased iron concentration in DGM structures and tested this assumption by using magnetic resonance imaging–based quantitative R2* relaxometry. WMH severity was measured in 61 patients with acute transient neurological symptoms (mean age: 71.5 ± 8.3 years) undergoing 3-Tesla magnetic resonance imaging. Despite a 6-year higher age of patients with more severe (i.e., early confluent or confluent) WMH, their DGM R2* rates did not differ from patients with punctate or no WMH. In the globus pallidum, R2* rates were even lower in patients with severe WMH. WMH volume was not correlated with R2* levels in any of the analyzed DGM structures. These findings argue against WM damage per se causing increased DGM iron deposition in multiple sclerosis and suggest no role of iron accumulation in ischemic small vessel disease.

Abstract 49: Cerebral Microbleeds are Associated With Incident Dementia: The Framingham Heart Study

Background: CMB represent hemorrhage-prone small vessel disease (SVD), attributed to hypertensive vasculopathy or cerebral amyloid angiopathy (CAA). CMB are associated with adverse outcomes including prevalent stroke and dementia, but the relation with incident dementia in the community has not been studied. Objective: To study the association of cerebral microbleeds (CMB) on MRI and incidence of dementia in a community based cohort. Methods: We evaluated 1296 dementia-free Framingham Original and Offspring Cohort participants (mean age 72years; 54% women) with available brain MRI and incident dementia data (mean follow-up 6.7 years). Using Cox-proportional hazards models we related all CMB and CMB stratified by brain location to incident dementia. Multivariable models were adjusted for age, sex, APOE status, and education, with additional models adjusting for vascular risk factors and MRI markers of ischemic SVD. Results: CMB were observed in 10.8% of subjects (64% lobar, 36% deep and mixed). Incident dementia was observed in 85 participants (6.6% over study period). We observed a 1.74 times higher risk of dementia in participants with any CMB (HR 1.74, 95% CI 1.00-3.01), and three fold higher risk in those with deep and/or mixed CMB (HR 2.99, 95% CI 1.52-5.90). The associations remained significant after adjusting for vascular risk factors. Although they were attenuated after adjustment for MRI markers of ischemic SVD, they remained significant for participants with deep and/or mixed CMB (HR 2.44, 95% CI 1.22-4.88). Purely lobar CMB were not associated with incident dementia. Conclusions: CMB were associated with increased risk of incident dementia, and for non-lobar CMB, the associations were independent of vascular risk factors and ischemic markers of small vessel disease. Our findings support a role for hypertensive vasculopathy and the interplay of hypertensive and cerebral amyloid angiopathy in risk of dementia, and highlight the role of CMB as markers of adverse neurological outcomes.

Carotid artery wall stiffness is increased in patients with small vessel disease: A case-control study

Cerebral ischemic small-vessel disease (SVD), causing lacunar infarcts and white matter hyperintensities on brain magnetic resonance imaging (MRI), is a progressive disease associated with an increased risk of stroke, dementia and death. Increased arterial stiffness has been associated with ischemic stroke and cerebral SVD independently of common vascular risk factors. The aim of the study was to analyze arterial stiffness in our patients with symptomatic SVD. In a cross-sectional study design we included 30 patients with clinical and MRI evidence of cerebral SVD and 30 age-, gender- and risk factor-matched control subjects with no neurological diseases. Patients were evaluated at the Ultrasound Laboratory at the Neurology Clinic, Clinical Center of Serbia in Belgrade, during a three-month period (from September 1st to December 1st 2012). Baseline demographic and vascular risk factors were recorded. All patients underwent standard carotid ultrasound scans with measuring of intima-media thickness (IMT) and analysis of atheromatous plaques. Internal carotid artery stiffness was evaluated with the use of e-tracking option as beta stiffness index (BSI) value. There were no differences between study groups in regard to degree of carotid stenosis and type of carotid plaques (p > 0.05). Patients in SVD group had significantly higher mean IMT (p = 0.0093) and mean BSI (p < 0.0001) than subjects in the control group. No significant correlation was detected between IMT and BSI in SVD group (r = 0.168; p = 0.376). Brain lesions severity correlated with BSI (r = 0.733; p < 0.0001). Arterial stiffness is increased in symptomatic patients with SVD, independently of vascular risk factors and IMT.

MULTIMODAL NEUROREHABILITATION AND CLINICAL NUTRITION PROGRAM IMPROVE PURSUITS AND DRIVING ABILITY IN 69 YEAR OLD FEMALE

Event Abstract Back to Event MULTIMODAL NEUROREHABILITATION AND CLINICAL NUTRITION PROGRAM IMPROVE PURSUITS AND DRIVING ABILITY IN 69 YEAR OLD FEMALE David J. Clark1* 1 Carrick Institute of Clinical Neuroscience and Rehabilitation, United States Background: A 69 year old woman presented with chief complaints of difficulty moving the left leg during walking, subjective problems with maintaining balance, back and hip pain, and difficulty driving. Symptoms began twelve years prior subsequent to a fall and head injury. MRI one year prior to presentation discovered extensive and non-specific white matter changes likely secondary to small vessel ischemic disease. Methods: Neurological examination revealed freezing during dual tasking of gait, Grade 2 on the Unified Parkinson’s Disease Rating Scale (UPDRS) on the left side during finger tapping and fist making tests, small amplitude titubation, normal strength and sensation in all 4 limbs. VNG testing revealed large amplitude square wave jerks with a right bias, saccadic horizontal pursuits with gains as follows: 0.1 Hz 0.66, at 0.2 Hz 0.77, and at 0.4 Hz 0.58. VNG showed saccadic vertical pursuits with gains as follows: at 0.1 Hz 0.63, at 0.2 Hz 0.40 and 0.4 Hz 0.22. Patient was treated with a three day multimodal rehabilitation program utilizing a gap stimulus and small amplitude saccades. Then, for two weeks the patient was placed on an anti-inflammatory diet, and supplement protocol featuring turmeric, resveratrol and omega fatty acids. Results: After the initial three days of treatment the horizontal pursuit gains had changed to the following: at 0.1 Hz 62, at 0.2 Hz 75 and at 0.4 Hz 0.73. The amplitude of the square wave jerks had decreased. After two weeks of the anti-inflammatory diet and supplementation the horizontal pursuit gains had improved as follows: at 0.1 Hz 0.82, at 0.2 Hz 0.74, at 0.4 Hz 0.72. The frequency of the square wave jerks was unchanged but the amplitude was smaller than before treatment. The patient reported that driving was no longer difficult. Patient did not exhibit freezing during dual tasking of gait. Fist making and finger tapping tests were Grade 1 UPDRS. Conclusion: The author suggests further investigation into the combination of multimodal forms of neurorehabilitation with anti-inflammatory diet and supplementation in the treatment of patients with saccadic pursuits and square wave jerks subsequent to head injury. Keywords: smooth pursuit eye movements, Head injury, Gait Disorders, Neurologic, Square wave jerks, driving Conference: International Symposium on Clinical Neuroscience: Clinical Neuroscience for Optimization of Human Function, Orlando, United States, 7 Oct - 9 Oct, 2016. Presentation Type: Poster Presentation Topic: Abstracts ISCN 2016 Citation: Clark DJ (2016). MULTIMODAL NEUROREHABILITATION AND CLINICAL NUTRITION PROGRAM IMPROVE PURSUITS AND DRIVING ABILITY IN 69 YEAR OLD FEMALE . Front. Neurol. Conference Abstract: International Symposium on Clinical Neuroscience: Clinical Neuroscience for Optimization of Human Function. doi: 10.3389/conf.fneur.2016.59.00062 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 01 Sep 2016; Published Online: 07 Sep 2016. * Correspondence: Dr. David J Clark, Carrick Institute of Clinical Neuroscience and Rehabilitation, Cape Canaveral, FL, United States, mail@doctordavidclark.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers David J Clark Google David J Clark Google Scholar David J Clark PubMed David J Clark Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Pathobiology of tobacco smoking and neurovascular disorders: untied strings and alternative products.

Tobacco smoke (TS) is the leading cause of preventable deaths worldwide. In addition to a host of well characterized diseases including chronic obstructive pulmonary disease, oral and peripheral cancers and cardiovascular complications, epidemiological evidence suggests that chronic smokers are at equal risk to develop neurological and neurovascular complications such as multiple sclerosis, Alzheimer’s disease, stroke, vascular dementia and small vessel ischemic disease (SVID). Unfortunately, few direct neurotoxicology studies of tobacco smoking and its pathogenic pathways have been produced so far. A major link between TS and CNS disorders is the blood–brain barrier (BBB). In this review article, we summarize the current understanding of the toxicological impact of TS on BBB physiology and function and major compensatory mechanisms such as nrf2- ARE signaling and anti-inflammatory pathways activated by TS. In the same context, we discuss the controversial role of antioxidant supplementation as a prophylactic and/or therapeutic approach in delaying or decreasing the disease complications in smokers. Further, we cover a number of toxicological studies associated with “reduced exposure” cigarette products including electronic cigarettes. Finally, we provide insights on possible avenues for future research including mechanistic studies using direct inhalation rodent models.

The effects of DL-3-n-butylphthalide in patients with vascular cognitive impairment without dementia caused by subcortical ischemic small vessel disease: A multicentre, randomized, double-blind, placebo-controlled trial

IntroductionVascular cognitive impairment without dementia is very common among the aged and tends to progress to dementia, but there have been no proper large-scale intervention trials dedicated to it. Vascular cognitive impairment without dementia caused by subcortical ischemic small vessel disease (hereinafter, subcortical Vascular cognitive impairment without dementia) represents a relatively homogeneous disease process and is a suitable target for therapeutic trials investigating Vascular cognitive impairment without dementia. Preclinical trials showed that dl-3-n-butylphthalide (NBP) is effective for cognitive impairment of vascular origin. MethodsIn this randomized, double-blind, placebo-controlled trial, we enrolled patients aged 50–70 years who had a diagnosis of subcortical Vascular cognitive impairment without dementia at 15 academic medical centers in China. Inclusion criteria included a clinical dementia rating ≥0.5 on at least one domain and global score ≤0.5; a mini-mental state examination score ≥20 (primary school) or ≥24 (junior school or above); and brain magnetic resonance imaging consistent with subcortical ischemic small vessel disease. Patients were randomly assigned to NBP 200 mg three times daily or matched placebo (1:1) for 24 weeks according to a computer-generated randomization protocol. All patients and study personnel were masked to treatment assignment. Primary outcome measures were the changes in Alzheimer's disease assessment scale-cognitive subscale (ADAS-cog) and clinician's interview-based impression of change plus caregiver input (CIBIC-plus) after 24 weeks. All patients were monitored for adverse events (AEs). Outcome measures were analyzed for both the intention-to-treat (ITT) population and the per protocol population. ResultsThis study enrolled 281 patients. NBP showed greater effects than placebo on ADAS-cog (NBP change −2.46 vs. placebo −1.39; P = .03; ITT) and CIBIC-plus (80 [57.1%] vs. 59 [42.1%] patients improved; P = .01; ITT). NBP-related AE were uncommon and primarily consisted of mild gastrointestinal symptoms. DiscussionOver the 6-month treatment period, NBP was effective for improving cognitive and global functioning in patients with subcortical vascular cognitive impairment without dementia and exhibited good safety.

Risk Factors Associated With Incident Cerebral Microbleeds According to Location in Older People: The Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study.

The spatial distribution of cerebral microbleeds (CMBs), which are asymptomatic precursors of intracerebral hemorrhage, reflects specific underlying microvascular abnormalities of cerebral amyloid angiopathy (lobar structures) and hypertensive vasculopathy (deep brain structures). Relatively little is known about the occurrence of and modifiable risk factors for developing CMBs, especially in a lobar location, in the general population of older people. To investigate whether lifestyle and lipid factors predict new CMBs in relation to their anatomic location. We enrolled 2635 individuals aged 66 to 93 years from the population-based Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study in a brain imaging study. Participants underwent a baseline magnetic resonance imaging (MRI) examination of the brain from September 1, 2002, through February 28, 2006, and returned for a second MRI examination from April 1, 2007, through September 30, 2011. Lifestyle and lipid factors assessed at baseline included smoking, alcohol consumption, body mass index, and serum levels of total cholesterol, high- and low-density lipoprotein cholesterol, and triglycerides. Incident CMBs detected on MRIs, which were further categorized as exclusively lobar or as deep. During a mean follow-up of 5.2 years, 486 people (18.4%) developed new CMBs, of whom 308 had lobar CMBs only and 178 had deep CMBs. In the multivariate logarithm-binomial regression model adjusted for baseline cardiovascular risk factors, including blood pressure, antihypertensive use, prevalent CMBs, and markers of cerebral ischemic small-vessel disease, heavy alcohol consumption (vs light to moderate consumption; relative risk [RR], 2.94 [95% CI, 1.23-7.01]) was associated with incident CMBs in a deep location. Baseline underweight (vs normal weight; RR, 2.41 [95% CI, 1.21-4.80]), current smoking (RR, 1.47 [95% CI, 1.11-1.94]), an elevated serum level of high-density lipoprotein cholesterol (RR per 1-SD increase, 1.13 [95% CI, 1.02-1.25]), and a decreased triglyceride level (RR per 1-SD decrease in natural logarithm-transformed triglyceride level, 1.17 [95% CI, 1.03-1.33]) were significantly associated with an increased risk for lobar CMBs exclusively but not for deep CMBs. Lifestyle and lipid risk profiles for CMBs were similar to those for symptomatic intracerebral hemorrhage and differed for lobar and deep CMBs. Modification of these risk factors could have the potential to prevent new-onset CMBs, particularly those occurring in a lobar location.

Abstract T P412: Cerebral Microbleeds and Cognition: The Framingham Heart Study

Objective: To study the association of cerebral microbleeds (CMB) on MRI and performance on a comprehensive neuropsychological test battery in a community based cohort free of stroke and dementia. Background: CMB represent hemorrhage-prone cerebral small vessel disease (SVD) and have been related to increased risk of dementia. In non-demented individuals, CMB may negatively affect cognition and the pattern of impaired cognitive performance may differ according to lesion topography. Methods: We evaluated 1744 Framingham Offspring Study participants (mean age 64.6 years, 54% women) attending a baseline examination (1998-2008), who had brain MRI allowing for CMB detection and underwent concurrent NP testing. Using multivariable linear regression we related CMB presence overall and stratified by brain location (lobar, deep or mixed) to performance on NP tests representing cognitive domains including memory, executive function, abstraction, language and visuospatial function. Results: CMB were observed in 7.7% of subjects (66% lobar, 20% deep, 14% mixed). After adjustment for sex, age, level of education and MRI markers of ischemic small vessel disease, presence of any CMB was associated with impaired performance on tests of abstraction (β -0.71, p=0.02) and language (β -0.13, p=0.04). The associations were attenuated after adjustment for vascular risk factors (hypertension, diabetes, smoking, prevalent cardiovascular disease). Lobar CMB showed similar marginal associations (p=0.05), also attenuated after adjustment for vascular risk factors. Mixed location CMB were associated with tests of executive function, an association that remained significant after adjustment for MRI markers of ischemic SVD and vascular risk factors (β-0.12, p= 0.02). CMB in only deep location did not show any significant association with NP test performance. Conclusions: CMB were associated with lower cognitive performance in a community-based sample of middle-aged adults. Our findings are limited given the cross sectional study design and small sample in subgroups of deep and mixed CMB, but concur with studies suggesting a negative impact of CMB on cognition, and expand prior studies by showing that the relations are independent of ischemic cerebral SVD.

Abstract T MP111: Cerebral Amyloid Angiopathy Is Associated With Arteriolar Sclerosis And Microinfarcts, But Not Overt Ischemic Stroke Or Hemorrhage In A Large Autopsy Series

Introduction: Cerebral amyloid angiopathy (CAA) has been associated with various types of cerebrovascular pathology independent of Alzheimer’s disease (AD), including atherosclerosis, arteriosclerosis, ischemic and hemorrhagic infarction. Available studies have frequently produced conflicting results in regards to specific cerebrovascular associations, likely due to confounds of subject selection biases, small sample sizes, and incomplete pathologic analyses. The present study represents one of the largest and most comprehensive clinical-pathologic series to date focused on examining clinical, genetic, and pathologic associations in CAA. Hypothesis: As CAA represents a vasculopathy of the small arterioles and capillaries, we hypothesized that cerebrovascular associations with CAA would include small vessel pathologies and microinfarcts rather than large or medium vessel pathologies. Methods: Cases were derived from the University of Kentucky brain bank (n=741). Vascular pathology was graded on semiquantitative scale or as present/absent. Cases were grouped by presence (n=414) or absence of CAA (n=327). Standard descriptive and comparative statistics were used for the analysis. Results: ApoE status (p&lt;0.001), but not age, was associated with CAA. Cases with and without CAA did not differ in regards to large vessel or lacunar ischemic stroke, hemorrhagic stroke, hippocampal sclerosis, or circle of Willis atherosclerosis. A significant increase in arteriolar sclerosis (p&lt;0.001) and microinfarct burden (p&lt;0.01) was seen in the CAA-positive group. Conclusions: CAA across the cognitive continuum, appears independent of age, and is a significant contributor to small vessel ischemic changes that may have a profound effect on brain health, including risk for stroke and cognitive impairment. Comprehensive treatment strategies for small vessel ischemic disease need to acknowledge and potentially address the role of CAA as therapeutic treatments for this unique vasculopathy become available in the future.

Abstract W P164: Cerebral Microbleeds and Physical performance: The Framingham Heart Study

Objective: To study the association of cerebral microbleeds (CMB) on MRI and physical performance in a community based cohort free of stroke and dementia. Background: Impaired mobility and physical function are associated with increased morbidity and mortality. CMB are believed to be subclinical markers of hemorrhage-prone small vessel disease, but CMB-induced neuronal injury may promote physical impairment in individuals free of stroke and dementia by disrupting the complex cerebral pathways involved in gait control and balance. Methods: We evaluated 1710 Framingham Offspring Study participants (mean age 64.6 years, 54% women) attending a baseline examination (1998-2008), who had brain MRI allowing for CMB detection and available measurements of physical performance. Walking speed was available in all, while a subset (N≈500) had available standing balance, chair standing and short physical battery scores. Using multivariable logistic regression we related CMB presence overall and stratified by brain location (lobar or deep) to the physical performance measures. Results: CMB were observed in 7.7% of subjects. We observed an association of presence of any CMB with lower walking speed score (4 vs. &lt;4) after adjustment for age, sex, time between MRI and study exam, and MRI markers of ischemic small vessel disease (OR 0.53, 95% CI 0.30-0.93, p=0.03). The association was no longer significant after adjusting for vascular risk factors (hypertension, diabetes, smoking, prevalent cardiovascular disease) instead of MRI markers (OR 0.63, 95% CI 0.36-1.11, p=0.11). There were no significant associations by CMB location and CMB were not associated with the remaining physical performance measures in the smaller samples. Conclusions: CMB were associated with lower gait speed, a relation that was partly dependent on presence of vascular risk factors. Our findings are limited by the small sample in subgroups of CMB across physical performance measures other than gait speed, but if replicated in other studies, would suggest a negative impact of CMB on physical function in community dwelling persons without stroke or dementia. These findings are significant given longer life expectancy and increasing prevalence of CMB with age.

LOW GLUCOSE UTILIZATION AND HIGH LACTATE PRODUCTION IN THE ALZHEIMER'S DISEASE BRAIN

Background: Age-related changes in the cerebral white matter (WM) have been demonstrated in cognitively intact elderly, and are associated with cognition. The etiology of microstructuralWMdegeneration and its relation to cerebral blood flow (CBF) and white matter hyperintensities (WMH) are uncertain.Methods: 61 cognitively intact elderly volunteers (mean age 85, CDR 0) underwent 3T MRI Q2TIPS pulsed arterial spin labeling (PASL), diffusion tensor imaging (DTI), and cognitive assessment. Voxelwise Tract-Based Spatial Statistics (TBSS) was performed. A general linear model using permutation-based nonparametric testing (FSLRANDOMIZE) examined regional associations betweenWMCBF,WMHs, and microstructural measures. WMHs and WM CBF were examined in relation to fractional anisotropy using both voxel-based and mean WMH volume and WM CBF values. Region of interest (ROI) analyses included atlas-based segmentation of the corpus callosum (CC), limited to the TBSS-derived WM skeleton, and examined CC integrity in relation to cognitive function. Analyses were corrected for partial volume effects and adjusted for age and gender. Matched pairs t-test examined differences in anterior and poster WM integrity.Results: In TBSS voxel-based analysis, associations between WM integrity and WMHs were observed in regions commonly associated with small vessel ischemic disease, along the periventricular WM tracts. WM integrity was significantly decreased in relation to lowerWMperfusion in similar regions. Findings were largely replicated when WMH and WM CBF were entered into the model as mean values, rather than voxel-wise analysis. In addition, clusters of decreased WM integrity were seen in areas of normal appearing white matter in the anterior and posterior cc and WM tracts in the frontal and parietal lobes. ROI analyses showed greater WM integrity disruption in the anterior compared with posterior CC. Anterior CC integrity was associated with performance on executive and memory function tests. Conclusions: Greater WMH and lower WM perfusion are independently associated with decreased WM integrity both within and outside of commonly observedWMlesions.Anterior> poster cc involvement may represent greater susceptibility of this region to hypoperfusion.WMCBF may serve as a potentiallymodifiable target in trials aimed at preserving cognitive function in elderly individuals, prior to cognitive impairment.

White Matter Tracts of Speech and Language

Diffusion tensor imaging (DTI) has been used to investigate the white matter (WM) tracts underlying the perisylvian cortical regions known to be associated with language function. The arcuate fasciculus is composed of 3 segments (1 long and 2 short) whose separate functions correlate with traditional models of conductive and transcortical motor or sensory aphasia, respectively. DTI mapping of language fibers is useful in presurgical planning for patients with dominant hemisphere tumors, particularly when combined with functional magnetic resonance imaging. DTI has found damage to language networks in stroke patients and has the potential to influence poststroke rehabilitation and treatment. Assessment of the WM tracts involved in the default mode network has been found to correlate with mild cognitive impairment, potentially explaining language deficits in patients with apparently mild small vessel ischemic disease. Different patterns of involvement of language-related WM structures appear to correlate with different clinical subtypes of primary progressive aphasias.