Investigation of reactive astrogliosis effect on post-stroke cognitive impairment.

BACKGROUND: The aim of this study is to investigate the associations between post-stroke cognitive impairment (PSCI) severity and reactive astrogliosis (RA) extent on normalized 18F-THK-5351 positron-emission tomography (PET) imaging in amyloid-negative patients with first-ever stroke. METHODS: We prospectively enrolled 63 amyloid-negative patients with first-ever stroke. Neurocognitive evaluation, MRI, 18F-THK-5351, and 18F-florbetapir PET were performed around 3 months after stroke. The 18F-THK-5351 uptake intensity was normalized using a signal distribution template to obtain the Z-SUM scores as the RA extent in the whole brain and cerebral hemisphere ipsilateral to stroke lesion. We evaluated stroke volume, leukoaraiosis, and brain atrophy on MRI. We used a comprehensive neurocognitive battery to obtain composite cognitive scores, and defined PSCI as a general cognitive function score < - 1. We analyzed the influence of Z-SUM scores on PSCI severity after adjusting for demographic, vascular, and neurodegenerative variables. RESULTS: Twenty-five of 63 stroke patients had PSCI. Patients with PSCI had older age, lower education, and more severe cortical atrophy and total Z-SUM scores. Total Z-SUM scores were significantly associated with general cognitive and executive functions at multiple regression models. Path analyses showed that stroke can exert cognitive influence directly by stroke itself as well as indirectly through RA, including total and ipsilateral Z-SUM scores, in patients with either right or left hemisphere stroke. CONCLUSION: The patterns and intensity of 18F-THK-5351 uptake in amyloid-negative patients with first-ever stroke were associated with PSCI manifestations, which suggests that RA presents a modulating effect in PSCI development.

Mediating roles of leukoaraiosis and infarcts in the effects of unilateral carotid artery stenosis on cognition.

Background and objectives: Leukoaraiosis and infarcts are common in patients with carotid artery stenosis (CAS), and CAS severity, leukoaraiosis and infarcts all have been implicated in cognitive impairments. CAS severity was not only hypothesized to directly impede specific cognitive domains, but also transmit its effects indirectly to cognitive function through ipsilateral infarcts as well as periventricular leukoaraiosis (PVL) and deep white matter leukoaraiosis (DWML). We aimed to delineate the contributions of leukoaraiosis, infarcts and CAS to different specific cognitive domains. Materials and methods: One hundred and sixty one participants with unilateral CAS (>50%) on the left (n = 85) or right (n = 76) side and 65 volunteers without significant CAS (<50%) were recruited. The PVL, DWML, and infarct severity were visually rated on MRI. A comprehensive cognitive battery was administered and standardized based on age norms. Correlation and mediation analyses were adopted to examine the direct and indirect influence of CAS, leukoaraiosis, and infarct on specific cognitive domains with adjustment for education, hypertension, diabetes mellitus, and hyperlipidemia. Results: Carotid artery stenosis severity was associated with ipsilateral leukoaraiosis and infarct. Left CAS had direct effects on most cognitive domains, except for visual memory and constructional ability, and transmitted its indirect effects on all cognitive domains through ipsilateral PVL, and on constructional ability and psychomotor through infarcts. Right CAS only had negative direct effects on visual memory, psychomotor, design fluency and color processing speed, and transmitted its indirect effects on visual memory, word and color processing speed through ipsilateral infarcts. The trends of direct and indirect cognitive effects remained similar after covariate adjustment. Conclusion: Left and right CAS would predominantly lead to verbal and non-verbal cognitive impairment respectively, and such effects could be mediated through CAS-related leukoaraiosis and infarct. Given that cognition is subject to heterogeneous pathologies, the exact relationships between markers of large and small vessel diseases and their composite prognostic effects on cognition requires further investigation.

Impact of silent ischemic lesions on cognition following carotid artery stenting.

OBJECTIVE: The occurrence of silent ischemic lesions (SILs) is a common finding after carotid artery stenting (CAS). This study aimed to evaluate the impact of SILs on cognitive functioning following CAS. METHODS: The retrospective study separated 131 patients with unilateral carotid stenosis into three groups: medication only, MRI-evaluated CAS and CT-evaluated CAS, and compared the sociodemographic factors, post-CAS images and Mini-Mental State Examination scores performed before and 6-12 months after enrollment. RESULTS: Seven minor strokes occurred in the 99 patients receiving CAS. SILs were detected in 12 of 55 patients with diffusion-weighted MR imaging (DWI) and in 3 of 37 patients with CT 1 week after CAS. In patients with DWI follow-up, the frequency of SILs was 8, 24, 43 and 60% in patients with 0-, 1-, 2- and 3-vessel coronary artery disease (p = 0.006). The frequency of SILs on DWI was 0, 32 and 33% in patients with improved, unchanged, or deteriorated cognitive functioning (p = 0.02). Such an association was not observed if based on SILs on CT or manifesting stroke. CONCLUSION: The presence of coronary artery disease increases the risk for having post-CAS SILs, and the occurrence of SILs may be associated with cognitive changes after CAS.

Neurodegeneration and Vascular Burden on Cognition After Midlife: A Plasma and Neuroimaging Biomarker Study.

Background and Objectives: Neurodegeneration and vascular burden are the two most common causes of post-stroke cognitive impairment. However, the interrelationship between the plasma beta-amyloid (Aß) and tau protein, cortical atrophy and brain amyloid accumulation on PET imaging in stroke patients is undetermined. We aimed to explore: (1) the relationships of cortical thickness and amyloid burden on PET with plasma Aß40, Aß42, tau protein and their composite scores in stroke patients; and (2) the associations of post-stroke cognitive presentations with these plasma and neuroimaging biomarkers. Methods: The prospective project recruited first-ever ischemic stroke patients around 3 months after stroke onset. The plasma Aß40, Aß42, and total tau protein were measured with the immunomagnetic reduction method. Cortical thickness was evaluated on MRI, and cortical amyloid plaque deposition was evaluated by 18F-florbetapir PET. Cognition was evaluated with Mini-Mental State Examination (MMSE), Geriatric Depression Scale (GDS), Dementia Rating Scale-2 (DRS-2). Results: The study recruited 24 stroke patients and 13 normal controls. The plasma tau and tau*Aß42 levels were correlated with mean cortical thickness after age adjustment. The Aß42/Aß40 ratio was correlated with global cortical 18F-florbetapir uptake value. The DRS-2 and GDS scores were associated with mean cortical thickness and plasma biomarkers, including Aß42/Aß40, tau, tau*Aß42, tau/Aß42, and tau/Aß40 levels, in stroke patients. Conclusion: Plasma Aß, tau, and their composite scores were associated with cognitive performance 3 months after stroke, and these plasma biomarkers were correlated with corresponding imaging biomarkers of neurodegeneration. Further longitudinal studies with a larger sample size are warranted to replicate the study results.

Cognitive Sequelae of Silent Ischemic Lesions Following Carotid Artery Stenting: Possible Role of Age-Related Moderation.

Background: The occurrence of ischemic lesions is common in patients receiving carotid artery stenting (CAS), and most of them are clinically silent. However, few studies have directly addressed the cognitive sequelae of these procedure-related silent ischemic lesions (SILs). Objective: In this study, we attempted to investigate the effects of SILs on cognition using a comprehensive battery of neuropsychological tests. Method: Eighty-five patients with unilateral carotid stenosis and 25 age-matched healthy volunteers participated in this study. Brain MRI was performed within 1 week before and 1 week after CAS to monitor the occurrence of post-CAS SILs. A comprehensive battery tapping reading ability, verbal and non-verbal memory, visuospatial function, manual dexterity, executive function, and processing speed was administered 1 week before and 6 months after CAS. To control for practice effects on repeated cognitive testing, the reliable change index (RCI) derived from the healthy volunteers was used to determine the cognitive changes in patients with carotid stenosis. Results: Among the 85 patients with carotid stenosis, 21 patients received medical treatment (MED group), and procedure-related SILs were noted in 17 patients (SIL+ group) but not observed in 47 patients (SIL- group) after undergoing CAS. Two-way (group × phase) ANOVA revealed that the volunteer group showed improved scores in most cognitive tests while only limited improvement was noted in the SIL- group. The MED and control groups tended to show improvement in the follow-up cognitive testing than the SIL+ group. However, most of the cognitive changes for each patient group did not exceed the upper or lower limits (z = ±1.0) of the RCI. Conclusions: Although the occurrence of procedure-related SILs is common in patients undergoing CAS, their impacts on cognitive changes after CAS may be limited. The practice effect should be taken into consideration when interpreting cognitive changes following CAS.

Estimation of premorbid general fluid intelligence using traditional Chinese reading performance in Taiwanese samples.

AIMS: The aims of the present study were to (i) investigate if traditional Chinese word reading ability can be used for estimating premorbid general intelligence; and (ii) to provide multiple regression equations for estimating premorbid performance on Raven's Standard Progressive Matrices (RSPM), using age, years of education and Chinese Graded Word Reading Test (CGWRT) scores as predictor variables. METHODS: Four hundred and twenty-six healthy volunteers (201 male, 225 female), aged 16-93 years (mean +/- SD, 41.92 +/- 18.19 years) undertook the tests individually under supervised conditions. Seventy percent of subjects were randomly allocated to the derivation group (n = 296), and the rest to the validation group (n = 130). RESULTS: RSPM score was positively correlated with CGWRT score and years of education. RSPM and CGWRT scores and years of education were also inversely correlated with age, but the declining trend for RSPM performance against age was steeper than that for CGWRT performance. Separate multiple regression equations were derived for estimating RSPM scores using different combinations of age, years of education, and CGWRT score for both groups. The multiple regression coefficient of each equation ranged from 0.71 to 0.80 with the standard error of estimate between 7 and 8 RSPM points. When fitting the data of one group to the equations derived from its counterpart group, the cross-validation multiple regression coefficients ranged from 0.71 to 0.79. There were no significant differences in the 'predicted-obtained' RSPM discrepancies between any equations. CONCLUSION: The regression equations derived in the present study may provide a basis for estimating premorbid RSPM performance.

The correlation of asymmetrical functional connectivity with cognition and reperfusion in carotid stenosis patients.

Objective: Neural disruption and cognitive impairment have been reported in patients with carotid stenosis (CS), but carotid artery stenting (CAS) may not contribute to the cognitive recovery. Although functional hyper-connectivity is one of the physiological over-compensation phenomena in neurological diseases, the literature on the cognitive influence of functional hyper-connectivity in CS patients is limited. We aimed to investigate the longitudinal changes of hyper-connectivity after CAS and its association with cognition in CS patients. Methods: Thirteen patients with unilateral CS and 17 controls without CS were included. Cognitive function was evaluated at baseline, and resting-state functional MRI was performed 1 week before and 1 month and 1 year after CAS. Comparisons of functional connectivity (FC) between CS patients and controls in multiple brain networks were performed. Results: In patients before CAS, FC in the cerebral hemispheres ipsilateral and contralateral to CS was mainly decreased and increased, respectively, compared with normal controls. Part of the FC alterations gradually recovered to the normal condition after CAS. The stronger FC abnormality (both hypo- and hyper-connectivity compared with normal controls) was associated with poorer cognitive performances, especially in memory and executive functions. Conclusion: The study demonstrated the lateralization of hyper-connectivity and hypo-connectivity in patients with unilateral CS in contrast to the FC in normal controls. These FC alterations were associated with poor cognitive performances and tended to recover after CAS, implying that hyper-connectivity is served as a compensation for neural challenge.

Visualization of ischemic stroke-related changes on 18F-THK-5351 positron emission tomography.

BACKGROUND: The 18F-THK-5351 radiotracer has been used to detect the in vivo tau protein distribution in patients with tauopathy, such as Alzheimer's disease and corticobasal syndrome. In addition, 18F-THK-5351 can also monitor neuroinflammatory process due to high affinity to astrogliosis. We aimed to explore 18F-THK-5351 distribution patterns and characteristics in patients with recent ischemic stroke. RESULTS: Fifteen patients received 18F-THK-5351 positron emission tomography (PET) and diffusion tensor imaging (DTI) approximately 3 months after ischemic stroke. A region of interest (ROI) was placed in the peri-ischemic area and was mirrored on the contralateral side as the control, and a proportional value was derived from the ratio of the peri-ischemic ROI value over the mirrored ROI value. Increased 18F-THK-5351 retention was observed in the areas around and remote from the stroke location. The proportional 18F-THK-5351 values were negatively correlated with the proportional fractional anisotropy values (r = - 0.39, P = 0.04). CONCLUSION: 18F-THK-5351 PET imaging provides a potential tool for in vivo visualization of the widespread ischemia-related changes associated with a microstructural disruption in recent ischemic stroke patients.

Early-phase 18F-AV-45 PET Imaging can Detect Crossed Cerebellar Diaschisis Following Carotid Artery Stenosis and Cerebral Hypoperfusion.

BACKGROUND: Carotid artery stenosis (CAS) may induce cerebral hypoperfusion. Early-phase 18F-Florbetapir (AV-45/Amyvid, 18F-AV-45) positron emission tomography (PET) imaging can provide perfusion-like property (pAV-45) for the estimation of cerebral blood flow (CBF). Supra-tentorial lesions may cause decreased blood flow and metabolism in the contralateral cerebellum known as crossed cerebellar diaschisis (CCD). OBJECTIVE: The aim was to study the occurrence of CCD after CAS using pAV-45 PET. METHODS: Eleven healthy controls and 21 patients with unilateral CAS were studied. All subjects underwent 18F-AV-45 PET imaging and arterial spin labeling (ASL) CBF magnetic resonance perfusion imaging. The pAV-45 and ASL CBF values were first correlated. Then, cerebral and cerebellar hypoperfusion volume was analyzed. The cerebral and cerebellar perfusion asymmetry indices (AIs) were calculated from the pAV-45 standard uptake value ratios (SUVRs) of bilateral cerebral and cerebellar cortices, respectively. RESULTS: We found that pAV-45 SUVR was significantly correlated to ASL CBF (p<0.0001, r=0.5731). The AI of cerebellar perfusion was negatively correlated to that of cerebral perfusion (p<0.0001, r=-0.8751). Multiple linear regression showed the cerebral AI (p<0.0001) and hypoperfusion volume (p=0.02) but not the infarction severity and CAS degree significantly correlated to cerebellar AI. If the lower limit of 95% confidence interval of cerebellar AI in healthy controls was set as cut-off for positive CCD, the occurrence of CCD correlated to infarction severity in CAS patients (p=0.03). CONCLUSION: Our results suggest pAV-45 is reliable to study CBF change. Under unilateral CAS, cerebral AI and hypoperfusion severity may determine the occurrence of CCD.

Asymmetric Cerebrovascular Collateral Supply Affects Cognition in Patients with Unilateral Carotid Artery Stenosis.

BACKGROUND: The time to maximum of the residue function (TMax) has been employed to identify the penumbra in acute ischemic stroke. Cognitive impairment in patients with Carotid Artery Stenosis (CAS) has been attributed to chronic cerebral hypoperfusion. The study aimed to examine whether cognitive impairment can be detected based on a preliminary TMax cutoff in patients with unilateral CAS. METHODS: Fifty unilateral CAS patients underwent dynamic susceptibility contrast MR perfusion. The preliminary TMax cutoff (3 seconds) was derived on the basis of the upper limit of 95% confidence interval of TMax in the Middle Cerebral Artery (MCA) contralateral to the CAS side. All patients were allocated to the Right-delayed group (n=18), Left-delayed group (n=12), and Nondelayed group (n=20) by the cutoff. Cognitive assessment was also administered on all patients and 22 healthy volunteers. RESULTS: No significant interhemispheric mean TMax differences of the Non-delayed group were noted (p=0.75), but the mean TMax of ipsilateral MCA was significantly longer than that of the contralateral MCA of the Left- and Right-delayed groups (ps<0.001), respectively. Compared to healthy volunteers, the Right-delayed group performed significantly worse on most of the visuospatial tests (ps<0.04), while the Left-delayed group performed significantly worse on most of the verbal tests (ps<0.05). The performance of the Non-delayed group on all cognitive domains was similar to that of healthy volunteers (ps>0.07). CONCLUSION: TMax can be used to differentiate the chronic hypoperfusion state in unilateral CAS patients. Prolonged TMax in the MCA of either hemisphere may lead to lateralized impairment in cognition functions in patients with unilateral CAS.

Graph theoretical analysis of functional networks and its relationship to cognitive decline in patients with carotid stenosis.

Significant carotid stenosis compromises hemodynamics and impairs cognitive functions. The interplay between these changes and brain connectivity has rarely been investigated. We aimed to discover the changes of functional connectivity and its relation to cognitive decline in carotid stenosis patients. Twenty-seven patients with unilateral carotid stenosis (≥60%) and 20 age- and sex-matched controls underwent neuropsychological tests and resting-state functional magnetic resonance imaging. The patients also received perfusion magnetic resonance imaging. The relationships between cognitive function and functional networks among the patients and controls were evaluated. Graph theory was applied on resting-state functional magnetic resonance imaging network analysis, which revealed that the hemispheres ipsilateral to the stenosis were significantly impaired in "degree" and "global efficiency." The neuropsychological performances were positively correlated with degree, clustering coefficient, local efficiency, and global efficiency, and negatively correlated with characteristic path length, modularity, and small-worldness in the patients, whereas these relationships were not observed in the controls. In this study, we identified the networks that were impaired in the affected hemispheres in patients with carotid stenosis. Specific indices (global efficiency, characteristic path length, and modularity) were highly correlated with neuropsychological performance in our patients. Analysis of brain connectivity may help to elucidate the relationship between hemodynamic impairment and cognitive decline.

Relationships between ophthalmic artery flow direction and cognitive performance in patients with unilateral carotid artery stenosis.

BACKGROUND: Cerebral hypoperfusion is responsible for cognitive impairment in patients with severe carotid artery stenosis (CAS). The manifestation of reversed ophthalmic artery flow (ROAF) is not uncommon in patients with CAS, suggesting a state of intensified cerebral hypoperfusion. This study aimed to examine whether the presence of ROAF can exacerbate cognitive impairment in patients with severe unilateral CAS. METHODS: One-hundred-and-two patients with CAS and 37 age-matched volunteers participated in this case-control study. Depending on the side of CAS and occurrences of ROAF, the patients were allocated to four groups: left CAS groups with ROAF (n=28) or without ROAF (n=22), and right CAS groups with ROAF (n=26) or without ROAF (n=26). All subjects underwent a battery of neuropsychological tests. RESULTS: All patients performed worse than the control group on most tests. No significant differences were observed between patient groups (ps>0.05), except for inferior performance on psychomotor speed and visuospatial tests in the right ROAF group (ps<0.03). Hierarchical regression analyses indicated strong contributions of estimated premorbid intelligence to performance on most tests (ps<0.05). The severity of left and right CAS was distinctively associated with different functions. To a lesser extent, the severity of infarcts was also associated with impairment of psychomotor speed and some executive functions (ps<0.05). The contributions of ROAF to performance on most tests were negligible. CONCLUSION: Patients with unilateral CAS may present with specific cognitive impairment relevant to the ipsilateral hemispheric functions. However, the manifestation of ROAF does not necessarily imply more extensive or severe cognitive impairment.

Amyloid deposition after cerebral hypoperfusion: evidenced on [(18)F]AV-45 positron emission tomography.

Animal studies have shown that cerebral hypoperfusion may be associated with amyloid plaque accumulation. Amyloid plaque is known to be associated with dementia and [(18)F]AV-45 is a positron emission tomography (PET) ligand that binds to extracelluar plaques. We hypothesized that demented patients with cerebral hypoperfusion may have increased [(18)F]AV-45 uptake. Five demented patients with cerebral hypoperfusion due to unilateral carotid artery stenosis (CAS) were examined with [(18)F]AV-45 PET, and the results were compared with six elderly controls. The standard uptake value ratio (SUVR) of each region of interest (ROI) was created using whole cerebellum as the reference region. All subjects underwent magnetic resonance imaging (MRI) for obtaining structural information. Patients with dementia and unilateral CAS had a higher global [(18)F]AV-45 SUVR (1.34 ± 0.06) as compared with controls (1.10 ± 0.04, p=0.0043), especially over the frontal, temporal, precuneus, anterior cingulate and occipital regions. The statistical distribution maps revealed a significantly increased [(18)F]AV-45 SUVR in the medial frontal, caudate, thalamus, posterior cingulate, occipital and middle and superior temporal regions ipsilateral to the side of CAS (p<0.01). The present study found that cerebral [(18)F]AV-45 binding is increased in demented patients with CAS, and its distribution is lateralized to the CAS side, suggesting that amyloid-related dementia may occur under cerebral hypoperfusion.