scholarly journals Symptomatic Treatment of Vascular Cognitive Impairment (STREAM-VCI): Protocol for a Cross-Over Trial (Preprint)

2017 ◽  
Author(s):  
Jolien Fleur Leijenaar ◽  
Geert Jan Groeneveld ◽  
Wiesje Maria van der Flier ◽  
Philip Scheltens ◽  
Erica Surya Klaassen ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Functional Connectivity ◽  
Positive Response ◽  
Medical Center ◽  
Competent Authority ◽  
Executive Dysfunction ◽  
Symptomatic Treatment ◽  
Vascular Cognitive Impairment ◽  
Vascular Damage ◽  
Double Blind

BACKGROUND People with vascular cognitive impairment (VCI) constitute a clinically heterogeneous group, but previous symptomatic drug trials in VCI did not take this clinical heterogeneity into account. Executive dysfunction and memory impairment are the cognitive domains that are most frequently impaired in VCI, and these impairments are likely to reflect vascular damage to specific neurotransmitter systems, which opens the possibility for targeted symptomatic treatment directed at specific neurotransmitters. OBJECTIVE Here we describe the design of the “Symptomatic Treatment of Vascular Cognitive Impairment” (STREAM-VCI) trial. In this proof-of-concept study, we investigate whether people with VCI with executive dysfunction due to vascular damage to the monoaminergic neurotransmitter system differentially respond to a monoaminergic challenge, whereas people with VCI with memory dysfunction associated with vascular damage to the cholinergic system will in turn respond to a cholinergic challenge. METHODS The STREAM-VCI is a single center, double blind, three-way cross-over trial among 30 people with VCI, in which subjects received a single dose of galantamine, methylphenidate, or placebo on separate occasions. The most important inclusion criteria were a diagnosis of VCI with a Mini-Mental State Examination score of ≥16 and a Clinical Dementia Rating of 0.5-1.0. For each person, the challenges consisted of a single 16 mg dose of galantamine, 10 mg of methylphenidate, and placebo, in random order on three separate visits. Change in performance in executive functioning and memory was assessed directly after the challenge using standardized neuropsychological tests. We will correlate a positive response to the cholinergic and monoaminergic treatment with differences in structural and functional connectivity at baseline using structural magnetic resonance imaging (MRI), diffusion tension MRI, and resting-state functional MRI. RESULTS The protocol of this study is approved by the Medical Ethics Committee of VU University Medical Center and the competent authority. The first participant was enrolled in April 2014. In September 2017, enrolment for the study was completed. We expect to publish the results in 2018. CONCLUSIONS STREAM-VCI is the first study to investigate the association of a response to a cholinergic and monoaminergic treatment with structural and functional connectivity of the monoaminergic and/or cholinergic systems on MRI. We aim to predict on an individual basis which individuals show a positive response to a cholinergic and/or monoaminergic challenge in people with VCI. This may be instrumental in moving in the direction of individually-tailored pharmacological interventions based on MRI measures in people with VCI. CLINICALTRIAL ClinicalTrials.gov NCT02098824; https://clinicaltrials.gov/ct2/show/NCT02098824 (Archived by WebCite at http://www.webcitation.org/6xhO7Ya1q)

scholarly journals AEROBIC TRAINING, THE DEFAULT MODE NETWORK, AND COGNITION IN OLDER ADULTS WITH MILD VASCULAR COGNITIVE IMPAIRMENT

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S55-S55
Author(s):  
Rachel A Crockett ◽  
Chun Liang Hsu ◽  
Cindy Barha ◽  
Ging-Yuek Robin Hsiung ◽  
Teresa Liu-Ambrose
Keyword(s):  
Older Adults ◽  
Cognitive Impairment ◽  
Cognitive Function ◽  
Functional Connectivity ◽  
Default Mode Network ◽  
Resting State ◽  
Aerobic Training ◽  
Vascular Cognitive Impairment ◽  
Default Mode ◽  
Global Cognitive Function

Abstract Aerobic training has been shown to be effective at improving cognitive and brain outcomes in older adults with mild subcortical ischemic vascular cognitive impairment (SIVCI). However, uncertainty remains regarding the underlying neurobiological mechanisms by which exercise elicits these improvements in cognition. Increased aberrant functional connectivity of the default mode network has been highlighted as a factor contributing to cognitive decline in older adults with cognitive impairment. Greater connectivity of the DMN at rest is associated with poorer performance on attention-demanding tasks, indicative of a lack of ability to deactivate the network on task. Our previous work on a randomized controlled trial of participants with mild SIVCI, demonstrated that 6-months of thrice weekly aerobic training led to improved global cognitive function, as measured by Alzheimer’s disease Assessment Scale-Cognitive subscale (ADAS-Cog), compared with a health education program. Thus, we conducted secondary analyses to investigate whether these changes in global cognitive function were associated with changes in resting state DMN connectivity. A subsample of 21 participants underwent a resting state functional magnetic resonance imaging (fMRI) scan before and after trial completion. Change in resting state DMN connectivity was found to significantly predict change in ADAS-Cog score (β = -.442, p=.038) after controlling for age, intervention group, and baseline functional capacity (R2=.467, F(4,16)= 3.507, p=.031). These findings suggest that functional connectivity of the DMN may underlie changes in global cognitive function. Furthermore, aerobic exercise is a promising intervention by which to elicit these changes in older adults with mild SIVCI.

scholarly journals Executive dysfunction and altered cerebrovascular activity in a rodent model of vascular cognitive impairment

2018 ◽  
Vol 45 (S1) ◽  
pp. S4-S5
Author(s):  
K.D. Langdon ◽  
C. Cordova ◽  
S. Granter-Button ◽  
J. Boyd ◽  
J. Peeling ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Small Vessel Disease ◽  
Executive Dysfunction ◽  
Vascular Cognitive Impairment ◽  
Cerebral Hypoperfusion ◽  
Small Vessel ◽  
Sprague Dawley ◽  
Middle Aged ◽  
Metabolic Disturbances ◽  
Vessel Disease

Most basic science research has focused on overt stroke caused by blockage of major blood vessels. Less attention has been paid to small vessel disease giving rise to covert stroke that often leads to vascular cognitive impairment (VCI). One reason for this may be the relative lack of relevant animal models. This talk will describe a model of VCI induced in middle-aged Sprague-Dawley rats exposed to a diet high in saturated fats, salt and refined sugar (HFSS). In Experiment 1, rats fed HFSS and subjected to a small mediodorsal (MD) thalamic stroke with or without concomitant cerebral hypoperfusion experienced significant executive dysfunction. In Experiment 2, dietary influences on functional, physiological and anatomical parameters were assessed. We found significant hypertension, blockage of brain microvessels (2-photon microscopy) and white matter atrophy in HFSS diet animals. As in Experiment 1, profound, specific set-shifting executive dysfunction was noted following both small MD infarcts (0.332 mm3) and the HFSS diet. In summary, these data describe a middle-aged animal model of VCI that includes clinically-relevant metabolic disturbances and small vessel disease and as such may be helpful in developing new cognitive therapies.

scholarly journals Postseptic Cognitive Impairment and Expression of APOE in Peripheral Blood: The Cognition After SepsiS (CASS) Observational Pilot Study

2020 ◽  
pp. 088506661989760
Author(s):  
Samuel M. Brown ◽  
Sarah J. Beesley ◽  
Chris Stubben ◽  
Emily L. Wilson ◽  
Angela P. Presson ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Executive Function ◽  
Peripheral Blood ◽  
Medical Center ◽  
Executive Dysfunction ◽  
Clinical Problem ◽  
Primary Analysis ◽  
Tertiary Referral Center ◽  
Peripheral Leukocytes

Background: Cognitive impairment after sepsis is an important clinical problem. Determinants of postseptic cognitive impairment are not well understood. We thus undertook a systems biology approach to exploring a possible role for apolipoprotein E (APOE) in postseptic cognitive impairment. Design: Prospective, observational cohort. Setting: Intermountain Medical Center, a tertiary referral center in Utah. Patients/Participants: Patients with sepsis admitted to study intensive care units. Interventions: None. Methods: We obtained peripheral blood for deep sequencing of RNA and followed up survivors at 6 months with a battery of cognitive instruments. We defined cognitive impairment based on the 6-month Hayling test of executive function. In our primary analysis, we employed weighted network analysis. Secondarily, we compared variation in gene expression between patients with normal versus impaired cognition. Measurements and Main Results: We enrolled 40 patients, of whom 34 were follow-up eligible and 31 (91%) completed follow-up; 1 patient’s RNA sample was degraded—the final analytic cohort was 30 patients. Mean Hayling test score was 5.8 (standard deviation 1.1), which represented 20% with impaired executive function. The network module containing APOE was dominated by low-expression genes, with no association on primary analysis ( P = .8). Secondary analyses suggested several potential lines of future investigation, including oxidative stress. Conclusions: In this prospective pilot cohort, executive dysfunction affected 1 in 5 survivors of sepsis. The APOE gene was sparsely transcribed in peripheral leukocytes and not associated with cognitive impairment. Future lines of research are suggested.

Donepezil in patients with subcortical vascular cognitive impairment: a randomised double-blind trial in CADASIL

2008 ◽  
Vol 7 (4) ◽  
pp. 310-318 ◽  
Author(s):  
Martin Dichgans ◽  
Hugh S Markus ◽  
Stephen Salloway ◽  
Auli Verkkoniemi ◽  
Margaret Moline ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Vascular Cognitive Impairment ◽  
Double Blind Trial ◽  
Double Blind ◽  
Blind Trial ◽  
Subcortical Vascular Cognitive Impairment

Abstract 2749: Amyloid-beta (1-42) is Reduced in CSF in Vascular Cognitive Impairment

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Gary A Rosenberg ◽  
Jillian Prestopnik ◽  
Jeffrey Thompson ◽  
Charles Gasparovic ◽  
Branko N Huisa-Garate ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
White Matter ◽  
Vascular Disease ◽  
Small Vessel Disease ◽  
Executive Dysfunction ◽  
Vascular Cognitive Impairment ◽  
Small Vessel ◽  
Matrix Metalloproteinase 2 ◽  
Resonance Spectroscopy ◽  
Mri Findings

Introduction: Vascular cognitive impairment (VCI) and Alzheimer’s disease (AD) have a high degree of overlap in a number of large autopsy series. However, few studies have examined the overlap during life. VCI is a heterogeneous disorder due to large and small vessel vascular disease (SVD). Biomarkers of inflammation are present in the SVD, which is a progressive form of VCI that is characterized by MRI findings of lacunar strokes and white matter hyperintensities (WMHs), executive dysfunction, focal neurological findings, apathy, urinary problems and gait imbalance. Recently, we showed an association between a reduced matrix metalloproteinase-2 (MMP-2) CSF index and disruption of the blood-brain barrier (BBB) in SVD. We hypothesized that patients with both VCI and AD would show CSF and MRI biomarkers for both diseases. Patients and Methods: Patients (N=60) with VCI underwent neurological and neuropsychological testing. MRI was done with FLAIR, proton magnetic resonance spectroscopy (1H-MRS) to measure ischemia with N-acetylaspartate (NAA), and dynamic contrast-enhanced MRI (DCEMRI) to measure BBB transfer constants (K i ). CSF (N=37) was obtained by lumbar puncture for measurements of albumin index, MMP-2 and MMP-9 indexes, ABeta 1-42, total-tau (T-Tau) and hyperphosphorylated-tau (P-Tau). Results: BD patients had large WMHs, while large vessel (multi-infarct and single strategic stroke) patients had small WMHs. NAA was used as a biomarker of lesion size due to ischemic damage in the white matter. ROC plots showed that a NAA cut-point of 12 separated patients with large WMHs (low NAA) from small WMHs (p<0.0001). K i transfer constants above 0.0018 (ROC; p<0.0001) and MMP-2 below 0.0099 (ROC; p<0.0001) were considered abnormal. SVD patients had reduced ABeta 1-42 compared to control CSF. P-Tau was unaffected. Abnormal values for K i and MMP-2 index were present in both large and small vessel disease patients. Conclusions: Our results show that SVD patients have significantly reduced levels of ABeta 1-42 in CSF, suggesting impairment in amyloid metabolism associated with vascular disease. These findings conform to the autopsy findings and suggest that multimodal biomarkers may provide information during life about the presence of both AD and VCI.

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