Longitudinal tracing of neurochemical metabolic disorders in working memory neural circuit and optogenetics modulation in rats with vascular cognitive impairment

Abstract Objective: Chronic cerebral ischemia leads to vascular cognitive impairment (VCI) that exacerbates along with ischemia time and eventually develops into dementia. Recent advances in molecular neuroimaging contribute to understand its pathological characteristics. We previously traced the anisotropic diffusion of water molecules suggests that chronic cerebral ischemia leads to irreversible progressive damage to white matter integrity. However, the abnormalities of gray matter activity following chronic cerebral ischemia remains not entirely understood.Methods: In this study, in vivo hydrogen proton magnetic resonance spectroscopy (1H-MRS) was applied to longitudinally track the neurochemical metabolic disorder of gray matter associated with working memory, and optogenetics modulation of neurochemical metabolism was performed for targeted treatment of VCI. Results: The results showed that the concentration of N-acetylaspartate (NAA) in the right hippocampus, left hippocampus, right medial prefrontal cortex (mPFC) and mediodorsal thalamus was decreased as early as 7 days after chronic cerebral ischemia, subsequently gamma-aminobutyric acid (GABA) declined whereas myo-inositol (mI) and glutamate (Glu) increased at 14 days, as well as choline (Cho) lost at 28 days, concurrently the change of Glu and GABA in the mPFC and hippocampus was ischemia time-dependent manner within 1 month. Behaviorally, working memory and object recognition memory were impaired at 14 days, 28 days that significantly correlated with neurochemical metabolic disorders. Interestingly, using optogenetics modulation of PV neurons in the mPFC, the metabolic abnormalities of NAA and GABA in working memory neural circuit could be repaired after chronic cerebral ischemia, together with behavior improvements. Conclusions: These findings suggested that as early as 1~4 weeks after chronic cerebral ischemia, the metabolism of NAA, Glu, mI and Cho was synchronously impaired in neural circuit of hippocampus-mediodorsal thalamus-mPFC, and the loss of GABA delayed in the hippocampus, and optogenetics modulation of parvalbumin (PV) neurons in the mPFC can improve the neurochemical metabolism of working memory neural circuit and enhance working memory.

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Goal Setting Improves Cognitive Performance in a Randomized Trial of Chronic Stroke Survivors

Stroke ◽

10.1161/strokeaha.120.032131 ◽

2021 ◽

Vol 52 (2) ◽

pp. 458-470

Author(s):

Keera N. Fishman ◽

Andrea R. Ashbaugh ◽

Richard H. Swartz

Keyword(s):

Working Memory ◽

Cognitive Impairment ◽

Executive Function ◽

Cognitive Performance ◽

Goal Setting ◽

Verbal Learning ◽

Chronic Phase ◽

Vascular Cognitive Impairment ◽

Stroke Survivors ◽

Verbal Recall

Background and Purpose: Cognitive impairment after stroke, especially executive and attention dysfunction, is common, negatively affects daily functioning, and has limited treatment options. A single-blind, parallel-design, randomized controlled trial was used to examine the impact of goal setting on poststroke cognitive performance. Methods: Stroke survivors (n=72; mean age, 68.38 [SD=11.84] years; 69.4% men) in the chronic phase (≥3 months) after stroke from an academic stroke prevention clinic were randomly assigned to receive goal-setting instructions (n=36) or standard instructions (n=36) after completing baseline cognitive measures of executive function (primary outcome), attention/working memory, verbal learning, and verbal recall. Results: A one-way mixed multivariate analysis of covariance (MANCOVA) found a group by instructional manipulation interaction effect for executive function (Wilks λ=0.66; F [3,66]=11.30; P ≤0.001; η 2 p =0.34), after adjusting for age and years of education. After similar adjustment, attention/working memory (Wilks λ=0.86; F [5,63]=2.10; P =0.043; η 2 p =0.16) and verbal learning ( F [1,60]=5.81; P =0.019; η 2 p =0.09) also showed improvement after instruction but not verbal recall (Wilks λ=0.95; F [1,56]=2.82; P =0.099; η 2 p =0.05). There were no adverse events. Conclusions: Goal setting improved executive function, attention/working memory, and learning in a heterogeneous sample in the chronic phase after stroke. This suggests that >3 months after stroke, vascular cognitive impairment is not a fixed deficit; there is a motivational contributor. Brief treatments targeting goal-oriented behavior and motivation may serve as a novel approach or adjunct treatment to improve cognitive outcomes after stroke. Future research should investigate the use of goal setting on functional outcomes (eg, instrumental activities of daily living and vocational function) in this population, highlighting new potential avenues for treatment for vascular cognitive impairment. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03511300.

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The Contribution of White Matter Diffusion and Cortical Perfusion Pathology to Vascular Cognitive Impairment: A Multimode Imaging-Based Machine Learning Study

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.687001 ◽

2021 ◽

Vol 13 ◽

Author(s):

Yao Wang ◽

Peiwen Lu ◽

Yafeng Zhan ◽

Xiaowei Wu ◽

Yage Qiu ◽

...

Keyword(s):

Machine Learning ◽

Cognitive Impairment ◽

White Matter ◽

Neural Circuit ◽

Diffusion Tensor ◽

Small Vessel Disease ◽

Critical Role ◽

Vascular Cognitive Impairment ◽

Imaging Features ◽

Leave One Out

Widespread impairments in white matter and cerebrovascular integrity have been consistently implicated in the pathophysiology of patients with small vessel disease (SVD). However, the neural circuit mechanisms that underlie the developing progress of clinical cognitive symptoms remain largely elusive. Here, we conducted cross-modal MRI scanning including diffusion tensor imaging and arterial spin labeling in a cohort of 113 patients with SVD, which included 74 patients with vascular mild cognitive impairment (vMCI) and 39 patients without vMCI symptoms, and hence developed multimode imaging-based machine learning models to identify markers that discriminated SVD subtypes. Diffusion and perfusion features, respectively, extracted from individual white matter and gray matter regions were used to train three sets of classifiers in a nested 10-fold fashion: diffusion-based, perfusion-based, and combined diffusion-perfusion-based classifiers. We found that the diffusion-perfusion combined classifier achieved the highest accuracy of 72.57% with leave-one-out cross-validation, with the diffusion features largely spanning the capsular lateral pathway of the cholinergic tracts, and the perfusion features mainly distributed in the frontal-subcortical-limbic areas. Furthermore, diffusion-based features within vMCI group were associated with performance on executive function tests. We demonstrated the superior accuracy of using diffusion-perfusion combined multimode imaging features for classifying vMCI subtype out of a cohort of patients with SVD. Disruption of white matter integrity might play a critical role in the progression of cognitive impairment in patients with SVD, while malregulation of coritcal perfusion needs further study.

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Working Memory Impairment in Transient Ischaemic Attack: N-back as a Sensitive Measure for Detection

Brain Impairment ◽

10.1017/brimp.2021.25 ◽

2021 ◽

pp. 1-8

Author(s):

Laura J. Smith ◽

Polly Gregory ◽

Philip Clatworthy ◽

Lucy Gallop ◽

George Stothart

Keyword(s):

Working Memory ◽

Cognitive Impairment ◽

Transient Ischaemic Attack ◽

Vascular Cognitive Impairment ◽

Screening Tools ◽

Cognitive Screening ◽

Cross Sectional ◽

Sensitive Measure ◽

Brain Structure And Function ◽

Ischaemic Attack

Abstract Background: Transient ischaemic attack (TIA) can lead to lasting changes in brain structure and function resulting in cognitive impairment. Cognitive screening tools may lack sensitivity for detecting cognitive impairments, particularly executive function, which tends to be the earliest affected domain in vascular cognitive impairment. Aim: In this preliminary study, we examine a working memory (WMem) task as a sensitive measure of cognitive impairment in TIA. Method: Patients referred to a TIA clinic for transient neurological symptoms completed a general cognitive screening tool (Montreal Cognitive Assessment; MoCA), and a WMem task (2-N-back) in a cross-sectional design. Results: TIA patients (n = 12) showed significantly reduced WMem performance on the N-back compared to patients diagnosed with mimic clinical conditions with overlapping symptoms (n = 16). No group differences were observed on the MoCA. Conclusions: Assessing WMem may provide a sensitive measure of cognitive impairment after TIA, with implications for cognitive screening in TIA services to triage patients for further neuropsychological support, or for interventions to prevent vascular dementia.

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Exploring the Potential of Mesenchymal Stem Cell-Based Therapy in Mouse Models of Vascular Cognitive Impairment

International Journal of Molecular Sciences ◽

10.3390/ijms21155524 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5524

Author(s):

Na Kyung Lee ◽

Hyeongseop Kim ◽

Jong Wook Chang ◽

Hyemin Jang ◽

Hunnyun Kim ◽

...

Keyword(s):

Working Memory ◽

Cognitive Impairment ◽

Carotid Artery ◽

Treatment Option ◽

Carotid Artery Stenosis ◽

Spatial Working Memory ◽

Vascular Cognitive Impairment ◽

Artery Stenosis ◽

Therapeutic Benefits ◽

Time Point

Closely linked to Alzheimer’s disease (AD), the pathological spectrum of vascular cognitive impairment (VCI) is known to be wide and complex. Considering that multiple instead of a single targeting approach is considered a treatment option for such complicated diseases, the multifaceted aspects of mesenchymal stem cells (MSCs) make them a suitable candidate to tackle the heterogeneity of VCI. MSCs were delivered via the intracerebroventricular (ICV) route in mice that were subjected to VCI by carotid artery stenosis. VCI was induced in C57BL6/J mice wild type (C57VCI) mice by applying a combination of ameroid constrictors and microcoils, while ameroid constrictors alone were bilaterally applied to 5xFAD (transgenic AD mouse model) mice (5xVCI). Compared to the controls (minimal essential medium (MEM)-injected C57VCI mice), changes in spatial working memory were not noted in the MSC-injected C57VCI mice, and unexpectedly, the mortality rate was higher. In contrast, compared to the MEM-injected 5xVCI mice, mortality was not observed, and the spatial working memory was also improved in MSC-injected 5xVCI mice. Disease progression of the VCI-induced mice seems to be affected by the method of carotid artery stenosis and due to this heterogeneity, various factors must be considered to maximize the therapeutic benefits exerted by MSCs. Factors, such as the optimal MSC injection time point, cell concentration, sacrifice time point, and immunogenicity of the transplanted cells, must all be adequately addressed so that MSCs can be appropriately and effectively used as a treatment option for VCI.

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