Joint diffusional kurtosis magnetic resonance imaging analysis of white matter and the thalamus to identify subcortical ischemic vascular disease.

Identifying subcortical ischemic vascular disease (SIVD) in older adults is important but challenging. Growing evidence suggests that diffusional kurtosis imaging (DKI) can detect SIVD-relevant microstructural pathology, and a systematic assessment of the discriminant power of DKI metrics in various brain tissue microstructures is urgently needed. Therefore, the current study aimed to explore the value of DKI and diffusion tensor imaging (DTI) metrics in detecting early-stage SIVD by combining multiple diffusion metrics, analysis strategies, and clinical-radiological constraints. This prospective study compared DKI with diffusivity and macroscopic imaging evaluations across the aging spectrum including SIVD, Alzheimer's disease (AD), and cognitively normal (NC) groups. Using a white matter atlas and segregated thalamus analysis with considerations of the pre-identified macroscopic pathology, the most effective diffusion metrics were selected and then examined using multiple clinical-radiological constraints in a two-group or three-group paradigm. A total of 122 participants (mean age, 74.6 ± 7.38 years, 72 women) including 42 with SIVD, 50 with AD, and 30 NC were evaluated. Fractional anisotropy, mean kurtosis, and radial kurtosis were critical metrics in detecting early-stage SIVD. The optimal selection of diffusion metrics showed 84.4-100% correct classification of the results in a three-group paradigm, with an area under the curve of .909-.987 in a two-group paradigm related to SIVD detection (all P < .001). We therefore concluded that greatly resilient to the effect of pre-identified macroscopic pathology, the combination of DKI/DTI metrics showed preferable performance in identifying early-stage SIVD among adults across the aging spectrum.

Neurovascular Correlates of Cobalamin, Folate, and Homocysteine in Dementia.

BACKGROUND: Cobalamin (Cbl) and folate are common supplements clinicians prescribe as an adjuvant therapy for dementia patients, on the presumption of their neurotrophic and/or homocysteine (Hcy) lowering effect. However, the treatment efficacy has been found mixed and the effects of Cbl/folate/Hcy on the human brain remain to be elucidated. OBJECTIVE: To explore the neurovascular correlates of Cbl/folate/Hcy in Alzheimer's disease (AD) and subcortical ischemic vascular dementia (SIVD). METHODS: Sixty-seven AD patients and 57 SIVD patients were prospectively and consecutively recruited from an outpatient clinic. Multimodal 3-Tesla magnetic resonance imaging was performed to quantitatively evaluate cerebral blood flow (CBF) and white matter integrity. The relationship between neuroimaging metrics and the serum levels of Cbl/folate/Hcy was examined by using the Kruskal-Wallis test, partial correlation analysis, and moderation analysis, at a significance level of 0.05. RESULTS: As a whole, CBF mainly associated with Cbl/folate while white matter hyperintensities exclusively associated with Hcy. As compared with AD, SIVD exhibited more noticeable CBF correlates (spatially widespread with Cbl and focal with folate). In SIVD, a bilateral Cbl-moderated CBF coupling was found between medial prefrontal cortex and ipsilateral basal ganglia, while in the fronto-subcortical white matter tracts, elevated Hcy was associated with imaging metrics indicative of increased injury in both axon and myelin sheath. CONCLUSIONS: We identified the neurovascular correlates of previously reported neurotrophic effect of Cbl/folate and neurotoxic effect of Hcy in dementia. The correlates exhibited distinct patterns in AD and SIVD. The findings may help improving the formulation of supplemental Cbl/folate treatment for dementia.

Prospective Memory and Default Mode Network Functional Connectivity in Normal and Pathological Aging.

BACKGROUND: Prospective memory (PM), the ability to execute a previously formed intention given the proper circumstance, has been proven to be vulnerable to Alzheimer's disease. Previous studies have indicated the involvement of the frontoparietal networks; however, it is proposed that PM may also be associated with other neural substrates that support stimulus-dependent spontaneous cognition. OBJECTIVE: The present study aimed to examine the hypothesis that PM deficit in Alzheimer's disease is related to altered functional connectivity (FC) within the default mode network (DMN). METHODS: Thirty-four patients with very mild or mild dementia (17 with Alzheimer's disease and 17 with subcortical ischemic vascular disease) and 22 cognitively-normal participants aged above 60 received a computerized PM task and resting-state functional magnetic resonance imaging study. Seed-based functional connectivity analysis was performed at group level within the DMN. RESULTS: We found that the dementia groups showed worse PM performance and altered FC within the DMN as compared to the normal aging individuals. The FC between the medial prefrontal cortices and precuneus/posterior cingulate cortex was significantly correlated with PM in normal aging, while the FC between the right precuneus and bilateral inferior parietal lobules was correlated with PM in patients with Alzheimer's disease. CONCLUSION: These findings support a potential role for the DMN in PM, and corroborate that PM deficit in Alzheimer's disease was associated with altered FC within the posterior hubs of the DMN, with spatial patterning different from normal aging.

Stage-Dependent Cerebral Blood Flow and Leukoaraiosis Couplings in Subcortical Ischemic Vascular Disease and Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) and subcortical ischemic vascular disease (SIVD) have both been associated with white matter hyperintensities (WMHs) and altered cerebral blood flow (CBF) although the etiology of AD is still unclear. OBJECTIVE: To test the hypothesis that CBF and WMHs have differential effects on cognition and that the relationship between CBF and WMHs changes with the subtypes and stages of dementia. METHODS: Forty-two patients with SIVD, 50 patients with clinically-diagnosed AD, and 30 cognitively-normal subjects were included. Based on the Clinical Dementia Rating (CDR), the patients were dichotomized into early-stage (CDR = 0.5) and late-stage (CDR = 1 or 2) groups. CBF and WMH metrics were derived from magnetic resonance imaging and correlated with cognition. RESULTS: Hierarchical linear regression revealed that CBF metrics had distinct contribution to global cognition, memory, and attention, whereas WMH metrics had distinct contribution to executive function (all p < 0.05). In SIVD, the WMHs in frontotemporal areas correlated with the CBF in bilateral thalami at the early stage; the correlation then became between the WMHs in basal ganglia and the CBF in frontotemporal areas at the late stage. A similar corticosubcortical coupling was observed in AD but involved fewer areas. CONCLUSION: A stage-dependent coupling between CBF and WMHs was identified in AD and SIVD, where the extent of cortical WMHs correlated with subcortical CBF for CDR = 0.5, whereas the extent of subcortical WMHs correlated with cortical CBF for CDR = 1-2.

Prospective Memory and Regional Functional Connectivity in Subcortical Ischemic Vascular Disease.

Objectives: Patients with subcortical ischemic vascular disease (SIVD) often have prominent frontal dysfunction. However, it remains unclear how SIVD affects prospective memory (PM), which strongly relies on the frontoparietal network. The present study aimed to investigate PM performance in patients with early stage SIVD as compared to those with Alzheimer's disease (AD) and to older adults with normal cognition, and to explore the neural correlates of PM deficits. Method: Patients with very-mild to mild dementia due to SIVD or AD and normal controls (NC) aged above 60 years were recruited. Seventy-three participants (20 SIVD, 22 AD, and 31 NC) underwent structural magnetic resonance imaging (MRI), cognitive screening tests, and a computerized PM test. Sixty-five of these participants (19 SIVD, 20 AD, and 26 NC) also received resting-state functional MRI. Results: The group with SIVD had significantly fewer PM hits than the control group on both time-based and non-focal event-based PM tasks. Among patients in the very early stage, only those with SIVD but not AD performed significantly worse than the controls. Correlational analyses showed that non-focal event-based PM in SIVD was positively correlated with regional homogeneity in bilateral superior and middle frontal gyri, while time-based PM was not significantly associated with regional homogeneity in any of the regions of interest within the dorsal frontoparietal regions. Conclusions: The findings of this study highlight the vulnerability of non-focal event-based PM to the disruption of regional functional connectivity in bilateral superior and middle frontal gyri in patients with SIVD.

Discriminating subcortical ischemic vascular disease and Alzheimer's disease by diffusion kurtosis imaging in segregated thalamic regions.

Differentiating between subcortical ischemic vascular disease (SIVD), Alzheimer's disease (AD), and normal cognition (NC) remains a challenge, and reliable neuroimaging biomarkers are needed. The current study, therefore, investigated the discriminative ability of diffusion kurtosis imaging (DKI) metrics in segregated thalamic regions and compare with diffusion tensor imaging (DTI) metrics. Twenty-three SIVD patients, 30 AD patients, and 24 NC participants underwent brain magnetic resonance imaging. The DKI metrics including mean kurtosis (MK), axial kurtosis (Kaxial ) and radial kurtosis (Kradial ) and the DTI metrics including diffusivity and fractional anisotropy (FA) were measured within the whole thalamus and segregated thalamic subregions. Strategic correlations by group, thalamo-frontal connectivity, and canonical discriminant analysis (CDA) were used to demonstrate the discriminative ability of DKI for SIVD, AD, and NC. Whole and segregated thalamus analysis suggested that DKI metrics are less affected by white matter hyperintensities compared to DTI metrics. Segregated thalamic analysis showed that MK and Kradial were notably different between SIVD and AD/NC. The correlation analysis between Kaxial and MK showed a nonsignificant relationship in SIVD group, a trend of negative relationship in AD group, and a significant positive relationship in NC group. A wider spatial distribution of thalamo-frontal connectivity differences across groups was shown by MK compared to FA. CDA showed a discriminant power of 97.4% correct classification using all DKI metrics. Our findings support that DKI metrics could be more sensitive than DTI metrics to reflect microstructural changes within the gray matter, hence providing complementary information for currently outlined pathogenesis of SIVD and AD.

Dissociable Functional Brain Networks Associated With Apathy in Subcortical Ischemic Vascular Disease and Alzheimer's Disease.

Few studies have investigated differences in functional connectivity (FC) between patients with subcortical ischemic vascular disease (SIVD) and Alzheimer's disease (AD), especially in relation to apathy. Therefore, the aim of this study was to compare apathy-related FC changes among patients with SIVD, AD, and cognitively normal subjects. The SIVD group had the highest level of apathy as measured using the Apathy Evaluation Scale-clinician version (AES). Dementia staging, volume of white matter hyperintensities (WMH), and the Beck Depression Inventory were the most significant clinical predictors for apathy. Group-wise comparisons revealed that the SIVD patients had the worst level of "Initiation" by factor analysis of the AES. FCs from four resting state networks (RSNs) were compared, and the connectograms at the level of intra- and inter-RSNs revealed dissociable FC changes, shared FC in the dorsal attention network, and distinct FC in the salient network across SIVD and AD. Neuronal correlates for "Initiation" deficits that underlie apathy were explored through a regional-specific approach, which showed that the right inferior frontal gyrus, left middle frontal gyrus, and left anterior insula were the critical hubs. These findings broaden the disconnection theory by considering the effect of FC interactions across multiple RSNs on apathy formation.

Attention and Functional Connectivity Among Patients With Early-Stage Subcortical Ischemic Vascular Disease and Alzheimer's Disease.

The current study compared attention profiles and functional connectivity of frontal regions in patients with early-stage subcortical ischemic vascular disease (SIVD) and Alzheimer's disease (AD). Twenty patients with SIVD, 32 patients with AD, and 23 subjects with normal cognition (NC) received cognition and resting-state functional MRI (rs-fMRI) evaluations. The Cognitive Abilities Screening Instrument (CASI) was used to assess global cognition, and simple attention, processing speed, divided attention, and vigilance/sustained attention were evaluated using the Digit Span Forward, Trail Making Test, Symbol Digit Modality Test, and Conners Continuous Performance Test, respectively. Voxel-based regional homogeneity (ReHo) derived from rs-fMRI data was analyzed to identify significant clusters, which were further correlated with attention profiles. Although the patients with SIVD and AD had comparable global cognitive ability, those with SIVD exhibited worse divided attention and vigilance/sustained attention than those with AD. Compared with the NC group, the patients with SIVD exhibited decreased ReHo within the right middle frontal gyrus (MFG) and left anterior cingulate gyrus (ACG), whereas the patients with AD exhibited increased ReHo within the right orbital part of frontal regions. Correlations between these three clusters with attention exhibited distinct patterns according to the dementia subtype, as did attention indices with significance in predicting global cognition. In summary, our study suggested that worse attention performance was associated with functional disconnection within the frontal regions among patients with SIVD than in those with AD. Frontal functional disconnection may underlie the pathogenesis responsible for defective divided attention, vigilance/sustained attention, and notable within-group variations identified in SIVD.

Nitric oxide donors attenuate clongenic potential in rat C6 glioma cells treated with alkylating chemotherapeutic agents.

1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) kills tumor cells via multiple actions including alkylation and carbamoylation. Previously, we have reported that formation of S-nitrosoglutathione (GSNO) in glioma cells overexpressing inducible nitric oxide synthase (iNOS) contributed to nitric oxide (NO)-dependent carbamoylating chemoresistance against BCNU. To further characterize the effects of NO on alkylating cytotoxicity, colony formation assay was applied to evaluate the effects of various NO donors on rat C6 glioma cells challenged with alkylating agents. We demonstrate that NO donors including GSNO, diethylamine NONOate (DEA/NO), and sodium nitroprusside (SNP) substantially reduced the extent of colony formation in glioma cells treated with alkylating agents, namely methyl methanesulfonate (MMS), N-methyl-N-nitrosourea (MNU), and N-ethyl-N-nitrosourea (ENU). Without alkylating agents these NO-releasing agents alone had no effects on clongenic potential of rat C6 glioma cells. Among these three NO donors used, the effectiveness in potentiating alkylating cytotoxicity is in the order of "GSNO>DEA/NO>SNP" when applied at the same dosages. GSNO also exerted similar synergistic actions reducing the extents of colony formation when co-administrated with 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-hydrazine (compound #1), another alkylating agent that mimics the chloroethylating action of BCNU. Together with our previous findings, we propose that NO donors may be used as adjunct chemotherapy with alkylating agents for such malignant brain tumors as glioblastoma multiforme (GBM). In contrast, production of NO as a result of iNOS induction, such as that occurring after surgical resection of brain tumors, may compromise the efficacy of carbamoylating chemotherapy.