Subcortical Dementia Research Articles

Alzheimer’s and vascular disease classification using regional texture biomarkers in FLAIR MRI

Interactions between subcortical vascular disease and dementia due to Alzheimer’s disease (AD) are unclear, and clinical overlap between the diseases makes diagnosis challenging. Existing studies have shown regional microstructural changes specific to each disease, and that textures in fluid-attenuated inversion recovery (FLAIR) MRI images may characterize abnormalities in tissue microstructure. This work aims to investigate regional FLAIR biomarkers that can differentiate dementia cohorts with and without subcortical vascular disease. FLAIR and diffusion MRI (dMRI) volumes were obtained in 65 mild cognitive impairment (MCI), 21 AD, 44 subcortical vascular MCI (scVMCI), 22 Mixed etiology, and 48 healthy elderly patients. FLAIR texture and intensity biomarkers were extracted from the normal appearing brain matter (NABM), WML penumbra, blood supply territory (BST), and white matter tract regions of each patient. All FLAIR biomarkers were correlated to dMRI metrics in each region and global WML load, and biomarker means between groups were compared using ANOVA. Binary classifications were performed using Random Forest classifiers to investigate the predictive nature of the regional biomarkers, and SHAP feature analysis was performed to further investigate optimal regions of interest for differentiating disease groups. The regional FLAIR biomarkers were strongly correlated to MD, while all biomarker regions but white matter tracts were strongly correlated to WML burden. Classification between Mixed disease and healthy, AD, and scVMCI patients yielded accuracies of 97%, 81%, and 72% respectively using WM tract biomarkers. Classification between scVMCI and healthy, MCI, and AD patients yielded accuracies of 89%, 84%, and 79% respectively using penumbra biomarkers. Only the classification between AD and healthy patients had optimal results using NABM biomarkers. This work presents novel regional FLAIR biomarkers that may quantify white matter degeneration related to subcortical vascular disease, and which indicate that investigating degeneration in specific regions may be more important than assessing global WML burden in vascular disease groups.

Transcranial Doppler assessment of patients with cerebral small vessel disease

BackgroundCerebral small vessel disease (SVD) is associated with acute events such as lacunar and hemorrhagic strokes, or chronic events such as cognitive deficit in the form of subcortical dementia, mood deficit in the form of late onset depression, sphincteric affection, and gait apraxia. Under conditions of moderate blood flow deficit, the inability of sclerotic vessels to dilate due to impairment of the cerebral autoregulation, renders the periventricular white matter seriously ischemic. Therefore, it is important to detect the implications of cerebral large artery disease on the severity of SVD, and the ability of transcranial duplex (TCD) to evaluate it in people at risk.MethodsFifty lacunar stroke patients were recruited, and evaluated using MRI brain to assess SVD score, carotid duplex and TCD to assess extracranial and intracranial stenoses, respectively.ResultsBoth intracranial and extracranial stenoses showed significant relation to the severity of cerebral SVD. Moreover, there were significant relation between intracranial stenosis and presence of lacuna and EPVS.ConclusionCerebral large artery disease contributes to the pathogenesis and severity of cerebral SVD. Therefore, TCD may be a useful tool for the prediction of occurrence of cerebral SVD in high-risk individuals, especially hypertensives.

TSPO gene polymorphism in Korean population

AbstractBackground18‐kDA translocator protein (TSPO protein) expression increases in neuroinflammation. Specific ligands that binds to TSPO protein can be used to visualize neuroinflammation. Due to the reported dependency of binding properties of the second‐generation TSPO ligands on a genetic polymorphism of the TSPO gene, all individuals were genotyped and classified as low‐, medium‐, or high‐affinity binder (LAB, MAB, and HAB). The objective of this study is to investigate the rs6971 gene polymorphism in Korean population.MethodWe performed genetic testing in 109 subjects including Alzheimer’s disease, mild cognitive decline, Lewy body disease, subcortical vascular dementia, and cognitively unimpaired participants. All of them performed MRI and detailed neuropsychological test. 29 participants also took 18F‐DPA714 PET. Exon 4 of the TSPO gene containing the polymorphism rs6971 (Ala or Thr at position 147) as well as exon/intron junctions were PCR amplified and sequenced using Sanger method. The identified rs6971 genotypes (C/C, C/T, or T/T) code for the amino acids Ala/ Ala, Ala/Thr, or Thr/Thr at position 147 of the TSPO protein and were considered to generate a high‐, medium‐, or low‐affinity binding phenotype, respectively.ResultWe found 96.3% of the study subjects were HAB (105 out of 109 subjects), and 3.7% of the subjects were MAB (4 out of 109 subjects). There was no participant who was LAB. From HapMap data allele frequency, American group had 69.2%of HABs, 28% of MABs, and 2.8% of LABs. In African group, 67.4% was HABs, 29.4% was MABs, and 3.2% was LABs. In Asian group, 96.9% was HABs, 6.1% was MABs, and 0.1% was LABs. In Europe group, 45.7% was HABs, 43.8% was MABs, and 10.5% was LABs.ConclusionKorean population had lesser frequency of MABs and LABs like other Asian population. Therefore, availability of second‐generation TSPO PET related to rs6971 gene polymorphism would be lesser affected.

The Ties That Bind: Glial Transplantation in White Matter Ischemia and Vascular Dementia.

White matter injury is a progressive vascular disease that leads to neurological deficits and vascular dementia. It comprises up to 30% of all diagnosed strokes, though up to ten times as many events go undiagnosed in early stages. There are several pathologies that can lead to white matter injury. While some studies suggest that white matter injury starts as small infarcts in deep penetrating blood vessels in the brain, others point tothe breakdown of endothelial function or the blood-brain barrieras the primary cause of the disease. Whether due to local endothelial or BBB dysfunction, or to local small infarcts (or a combination), white matter injury progresses, accumulates, and expands from preexisting lesions into adjacent white matter to produce motor and cognitive deficits that present as vascular dementia in the elderly. Vascular dementia is the second leading cause of dementia, and white matter injury-attributed vascular dementia represents 40% of all diagnosed dementias and aggravates Alzheimer's pathology. Despite the advances in the last 15years, there are few animal models of progressive subcortical white matter injury or vascular dementia. This review will discuss recent progress in animal modeling of white matter injury and the emerging principles to enhance glial function as a means of promoting repair and recovery.

Cognitive Impairment Among HIV-positive Individuals in a Tertiary Infectious Disease Hospital in the Philippines

Background: Disruption of neurocognitive functioning is one of the most frequent complications in patients infected with Human immunodeficiency virus. It manifests as a form of subcortical dementia characterized by psychomotor slowing, changes in mood and anxiety levels and deficits in memory, abstraction, information processing, verbal fluency, decision-making, and attention. The primary objective of this study is to determine the prevalence of neurocognitive impairment among HIV-positive individuals in the Philippines. Methods: This is a cross-sectional study done at the outpatient department of a tertiary infectious disease hospital located in Manila, Philippines conducted from May to July 2015. The Montreal Cognitive Assessment – Filipino (MoCA-P) was used to differentiate non-cognitively impaired and cognitively impaired participants. Demographic data was obtained using structured interviews including the CD4 count. Results: One hundred and twelve HIV positive patients were examined and 56.7% of them were noted to have cognitive impairment while none of them met the criteria for dementia. After logistics regression analysis, only the CD4 count (x=224) was shown to have significant association with cognitive impairment (p=0.0001, OR 0.96). Conclusion: Cognitive impairment was significantly associated with low CD4 count, with a sensitivity of 100% for a count of <224. More than half or 58.7% of subjects with cognitive impairment did not show any neuropsychiatric symptoms. Neurocognitive impairment is still an important component of HIV infection and this study highlights the need to further increase awareness regarding this HIV complication.

Diagnostic performance of deep learning-based automatic white matter hyperintensity segmentation for classification of the Fazekas scale and differentiation of subcortical vascular dementia

PurposeTo validate the diagnostic performance of commercially available, deep learning-based automatic white matter hyperintensity (WMH) segmentation algorithm for classifying the grades of the Fazekas scale and differentiating subcortical vascular dementia.MethodsThis retrospective, observational, single-institution study investigated the diagnostic performance of a deep learning-based automatic WMH volume segmentation to classify the grades of the Fazekas scale and differentiate subcortical vascular dementia. The VUNO Med-DeepBrain was used for the WMH segmentation system. The system for segmentation of WMH was designed with convolutional neural networks, in which the input image was comprised of a pre-processed axial FLAIR image, and the output was a segmented WMH mask and its volume. Patients presented with memory complaint between March 2017 and June 2018 were included and were split into training (March 2017–March 2018, n = 596) and internal validation test set (April 2018–June 2018, n = 204).ResultsOptimal cut-off values to categorize WMH volume as normal vs. mild/moderate/severe, normal/mild vs. moderate/severe, and normal/mild/moderate vs. severe were 3.4 mL, 9.6 mL, and 17.1 mL, respectively, and the AUC were 0.921, 0.956 and 0.960, respectively. When differentiating normal/mild vs. moderate/severe using WMH volume in the test set, sensitivity, specificity, and accuracy were 96.4%, 89.9%, and 91.7%, respectively. For distinguishing subcortical vascular dementia from others using WMH volume, sensitivity, specificity, and accuracy were 83.3%, 84.3%, and 84.3%, respectively.ConclusionDeep learning-based automatic WMH segmentation may be an accurate and promising method for classifying the grades of the Fazekas scale and differentiating subcortical vascular dementia.

Effect of White Matter Hyperintensities on Daily Function via Depressive Symptoms: A Longitudinal Study in Patients With Dementia Including Alzheimer's Disease and Subcortical Ischemic Vascular Dementia.

Objective This study aimed to investigate the mediation effect of depressive symptoms on the relationship between white matter hyperintensities and the basic activities of daily living (BADL) using an integrated approach to overcome the limitations of previous studies and examine the relationship among the three variables simultaneously. Methods We performed structural equation modeling using cross-sectional data from 497 Alzheimer’s disease (AD), AD with small vessel disease, and subcortical ischemic vascular dementia patients enrolled in the Clinical Research for Dementia of South Korea registry who were diagnosed with mild-to-moderate dementia. Periventricular white matter hyperintensities (PWMHs) and deep white matter hyperintensities (DWMHs) were visualized separately at baseline using magnetic resonance imaging. Depressive symptoms were assessed using the Korean Form of the Geriatric Depression Scale at the follow-up assessment conducted after 1 year. BADL were assessed using the Barthel Index at the follow-up assessment conducted after 2 years. Results The direct and indirect effects of DWMHs on the BADL as mediated via depression were significant. However, neither the direct effect of PWMHs on the BADL nor the indirect effect of PWMHs on the BADL via depression were significant. Conclusion This study presented a mediation model that included a longitudinal developmental pathway from DWMHs to deterioration in the BADL mediated via depressive symptoms. Moreover, the mediation model of depressive symptoms could not be applied to the longitudinal developmental pathway from DWMHs to the deterioration in BADL.

A-297 Analysis of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Cortical-Subcortical Deviation Index and Subtest Scores in Differentiating Between Cortical and Subcortical Dementia Profiles

Abstract Objective: This study examines the utility, both broadly and at the subtest level, of the cortical-subcortical index (CSI) of the RBANS in classifying cortical and subcortical cognitive profiles. Methods: Outpatients in a southeast hospital were grouped by diagnosis: Alzheimer’s Disease (AD, n=33; age=77.03[6.04], ed=13.55[2.58], 88% female, 91% Caucasian), Subcortical (n=36, age=72.17[11.51], ed=12.63[3.70], 50% female, 75% Caucasian) and No Diagnosis (n=30, age=71.97[5.59], ed=13.24[3.04], 80% female, 70% Caucasian). The CSI formula ([visuospatial construction + attention]/2]–[delayed memory + language]/2)) was calculated for patients. Groups were compared on CSI score using one-way analysis of variance (ANOVA) and Tukey’s HSD. ROC analysis was used to identify CSI cutoff that optimizes classification. Independent t-tests for subtests comprising the CSI were run comparing Cortical/Subcortical groups, with stepwise regression to evaluate significant subtests. Results: CSI differed significantly between groups (F[2, 96]=30.58, p<.001]). Tukey’s HSD found CSI was significantly different between Cortical/Subcortical (p<.001, 95% CI=16.38, 31.27) and Cortical/No Diagnosis (p<.001, 95% CI=9.62, 25.20), but not Subcortical/No Diagnosis (p=.118, 95% CI=-14.04, 1.22). ROC yielded a CSI cutoff of <-1 for optimal classification (AUC=.888, SE .039, p<.001, 95%CI .813-.964, Sensitivity=.750, Specificity=.909). Independent t-tests resulted in significance in 6 subtests. Stepwise regression using significant subtests revealed the best CSI-prediction model explained 28% of the variance (F[1,111]=44.06, p<.001) and included only List Recall (B=-2.96, p<.001). Conclusions: CSI’s accuracy in classifying Cortical from Subcortical profiles was 81.6% using a cut score of -1. List Recall accounted for most of the variance in the CSI. Limitations included small sample size and using RBANS scores to determine original diagnostic category.

Contribution of blood-brain barrier-related blood-borne factors for Alzheimer’s disease vs. vascular dementia diagnosis: A pilot study

BackgroundAlzheimer’s disease (AD) and vascular dementia (VaD) are the two most common types of neurodegenerative dementia among the elderly with similar symptoms of cognitive decline and overlapping neuropsychological profiles. Biological markers to distinguish patients with VaD from AD would be very useful. We aimed to investigate the expression of blood-brain barrier (BBB)-related blood-borne factors of soluble low-density lipoprotein receptor-related protein 1 (sLRP1), cyclophilin A (CyPA), and matrix metalloproteinase 9 (MMP9) and its correlation with cognitive function between patients with AD and VaD.Materials and methodsPlasma levels of sLRP1, CyPA, and MMP9 were analyzed in 26 patients with AD, 27 patients with VaD, and 27 normal controls (NCs). Spearman’s rank correlation analysis was used to explore the relationships among biomarker levels, cognitive function, and imaging references. Receiver operating characteristic (ROC) curve analysis was used to discriminate the diagnosis of AD and VaD.ResultsAmong these BBB-related factors, plasma CyPA levels in the VaD group were significantly higher than that in the AD group (p < 0.05). Plasma sLRP1 levels presented an increasing trend in VaD while maintaining slightly low levels in patients with AD (p > 0.05). Plasma MMP9 in different diagnostic groups displayed the following trend: VaD group > AD group > NC group, but the difference was not statistically significant (p > 0.05). Furthermore, plasma sLRP1 levels were positively related to MoCA scores, and plasma CyPA levels were significantly correlated with MTA scores (p < 0.05) in the AD group. Plasma MMP9 levels were negatively correlated with MoCA scores (p < 0.05) in the VaD groups. No significant correlation was detected between the other factors and different cognitive scores (p > 0.05). ROC analysis showed a good preference of plasma CyPA [AUC = 0.725, 95% CI (0.586–0.865); p = 0.0064] in diagnosis.ConclusionThe plasma CyPA level is a reference index when distinguishing between an AD and subcortical ischemic vascular dementia (SIVD) diagnosis. Blood-derived factors associated with the BBB may provide new insights into the differential diagnosis of neurodegenerative dementia and warrant further investigation.

Relationships between educational attainment, hypertension, and amyloid negative subcortical vascular dementia: The brain-battering hypothesis.

PurposeMany epidemiological studies suggest that lower education levels and vascular risk factors increase the likelihood of developing Alzheimer's disease dementia (ADD) and subcortical vascular dementia (SVaD). However, whether the brain-battering hypothesis can explain the relationship between education levels and the clinical diagnosis of dementia remains controversial. The objective of this study was to investigate whether vascular risk factors mediate the association between education level and the diagnosis of amyloid-beta positive (Aβ+) ADD and amyloid-beta negative (Aβ-) SVaD.MethodsWe analyzed 376 participants with Aβ normal cognition (Aβ- NC), 481 with Aβ+ ADD, and 102 with Aβ- SVaD. To investigate the association of education level and vascular risk factors with these diagnoses, multivariable logistic regression analysis was used, with age, sex, and APOE ε4 carrier status used as covariates. Path analysis was performed to investigate the mediation effects of hypertension on the diagnosis of Aβ- SVaD.ResultsThe Aβ- SVaD group (7.9 ± 5.1 years) had lower education levels than did the Aβ- NC (11.8 ± 4.8 years) and Aβ+ ADD (11.2 ± 4.9 years) groups. The frequencies of hypertension and diabetes mellitus were higher in the Aβ- SVaD group (78.4 and 32.4%, respectively) than in the Aβ- NC (44.4 and 20.8%) and Aβ+ ADD (41.8 and 15.8%, respectively) groups. Increased education level was associated with a lower risk of Aβ- SVaD [odds ratio (OR) 0.866, 95% confidence interval (CI), 0.824–0.911], but not Aβ+ ADD (OR 0.971, 95% CI 0.940–1.003). The frequency of hypertension was associated with a higher risk of developing Aβ- SVaD (OR 3.373, 95% CI, 1.908–5.961), but not Aβ+ ADD (OR 0.884, 95% CI, 0.653–1.196). In the path analysis, the presence of hypertension partially mediated the association between education level and the diagnosis of Aβ- SVaD.ConclusionOur findings revealed that education level might influence the development of Aβ- SVaD through the brain-battering hypothesis. Furthermore, our findings suggest that suitable strategies, such as educational attainment and prevention of hypertension, are needed for the prevention of Aβ- SVaD.

Nonalcoholic Fatty Liver Disease and Altered Neuropsychological Functions in Patients with Subcortical Vascular Dementia.

NAFLD is the most common cause of abnormality in liver function tests. NAFLD is considered a potential cardiovascular risk factor and is linked to cardiovascular risk factors such as obesity, hypertension, type 2 diabetes, and dyslipidemia. Few previous studies have investigated whether NAFLD could be independently associated with cognitive impairment. The current study aims to find a possible role of NAFLD in the development of subcortical vascular dementia (sVaD). We considered NAFLD as a possible independent vascular risk factor or, considering its metabolic role, associated with other commonly accepted sVaD risk factors, i.e., lack of folate, vitamin B12, and vitamin D-OH25, and increased levels of homocysteine. We studied 319 patients diagnosed with sVaD. All patients underwent an abdominal ultrasound examination to classify steatosis into four levels (1—none up to 4—severe). sVaD patients were divided into two groups according to the presence or absence of NAFLD. Our results demonstrated a strong correlation between NAFLD and sVaD. Patients with the two comorbidities had worse neuropsychological outcomes and a worse metabolic profile. We also found a robust relationship between NAFLD and severe vitamin B12, folate, vitamin D hypovitaminosis, and higher hyperhomocysteinemia levels. This way, it is evident that NAFLD contributes to a more severe metabolic pathway. However, the strong relationship with the three parameters (B12, folate and vitamin D, and homocysteinemia) suggests that NAFLD can contribute to a proinflammatory condition.

Written Spelling in Patients with Subcortical Vascular Dementia and Subcortical Vascular Mild Cognitive Impairment

Objectives: The purpose of this study is to examine the spelling processing patterns in patients with subcortical vascular dementia (SVaD) and subcortical vascular mild cognitive impairment (svMCI).Methods: The subjects consisted of 10 patients with SVaD, 15with svMCI, and 30 normal controls (NC) subjects. Prior to this study, Korean- Mini Mental Status Examination (K-MMSE), Montreal Cognitive Assessment (MoCA-K), and health screening questionnaires were conducted as pre-tests. After that, subjects were presented with 20 words grouped according to word type (regular word, irregular word, non-word), and then they were asked to dictate the words they heard. After the tests were completed, the number of correct responses and the number of error patterns were compared between groups.Results: First, by word type between groups, the svMCI and SVaD groups showed a significantly lower number of correct responses for regular and irregular words compared to the NC group. In addition, the SVaD group showed a significantly lower number of forward responses than the svMCI group in irregular words. Non-words showed significantly lower number of forward responses in the SVaD group compared to the NC and svMCI groups. Second, the comparison of the number of error types between groups showed a significant difference between the three groups in terms of grapheme substitution; and the SVaD group showed significantly more errors compared with the NC and svMCI groups in addition and omission of graphemes. Third, the SVaD group showed significantly more errors in comparison to the NC and svMCI groups for phonological implausible errors, and the svMCI and SVaD groups showed significantly more errors than the NC group for phonological plausible errors. Fourth, lexicalization errors within non-words were observed only in the SVaD group.Conclusion: For early detection of svMCI, it is necessary to pay attention to irregular word performance.

The Diagnostic Value of the Combined 3D Pseudo-Continuous Arterial Spin Labeling and Diffusion Kurtosis Imaging in Patients With Binswanger's Disease.

Background and PurposeThe clinical diagnosis of Binswanger’s disease (BD), a chronic progressive form of subcortical vascular dementia, remains challenging. 3D pseudo-continuous arterial-spin-labeling (pcASL) and diffusion kurtosis imaging (DKI) can quantitatively reveal the microcirculation changes and heterogeneity of white matter (WM), respectively. We thus aimed to determine the diagnostic value of the combined 3D-pcASL and DKI in BD.Materials and MethodsA total of 35 patients with BD and 33 healthy controls underwent 3D-ASL and DKI experiments. The perfusion parameter of cerebral blood flow (CBF), diffusion parameters of fractional anisotropy (FA), mean/axial/radial diffusivity (MD/Da/Dr), and kurtosis parameters of anisotropy fraction of kurtosis (FAk) and mean/axial/radial kurtosis MK/Ka/Kr were obtained to quantitatively measure the parametric distributions of functional brain subregions. One-way analysis of variance and post hoc t-test were applied to explore the different distributions of DKI/ASL-derived parameters among brain subregions of BD. In addition, all region-specific DKI/ASL parameters were separately analyzed in Pearson correlation analysis to investigate the relationship with Mini-Mental State Examination (MMSE), a typical clinical scale for cognitive function assessment in patients with BD.ResultsFA/FAk/MK/Ka/Kr was significantly declined in all WM hyperintensities (WMHs) of BD compared with healthy controls, while the corresponding MD/Da/Dr was significantly increased (all p < 0.005). In addition, significant changes, similar to the WMHs of patients with BD, were also observed in almost all DKI parameters in WM normal areas and genu/splenium of the corpus callosum (GCC/SCC) in BD (p < 0.005). Finally, CBF was significantly reduced in all of the above regions we measured in patients with BD (p < 0.005). For patients with BD, MMSE showed a negative correlation with MD/Da in thalamus (r = −0.42/−0.58; p < 0.05), and a positive correlation with CBF in PWM/TWM (r = 0.49/0.39; p < 0.05). Using receiver operating characteristic (ROC) analysis, FA/FAk/Kr in GCC, CBF/FA/Dr/FAk in SCC, MD/Da/Ka in thalamus, and the combined FA/MD/Dr/CBF in TWM showed high accuracy [area under the curves (AUCs) 0.957/0.946/0.942/0.986] in distinguishing patients with BD from healthy controls.ConclusionWe found that combined DKI and 3D-ASL are helpful in diagnosing patients with BD, especially with FA, MD, Dr, and CBF in the temporal WM region. Additionally, the kurtosis parameters of DKI can sensitively monitor the potentially damaged WM areas in patients with BD patients, adding complementary clinical value.

Vascular Cognitive Impairment and Dementia.

This article gives a broad overview of vascular cognitive impairment and dementia, including epidemiology, pathophysiology, clinical approach, and management. Emphasis is placed on understanding the common underlying types of cerebrovascular disease (including atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy) and awareness of rare inherited cerebrovascular disorders. The pathophysiology of vascular cognitive impairment and dementia is heterogeneous, and the most recent diagnostic criteria for vascular cognitive impairment and dementia break down the diagnosis of major vascular dementia into four phenotypic categories, including subcortical ischemic vascular dementia, poststroke dementia, multi-infarct dementia, and mixed dementia. Control of cardiovascular risk factors, including management of midlife blood pressure, cholesterol, and blood sugars, remains the mainstay of prevention for vascular cognitive impairment and dementia. Cerebral amyloid angiopathy requires special consideration when it comes to risk factor management given the increased risk of spontaneous intracerebral hemorrhage. Recent trials suggest some improvement in global cognitive function in patients with vascular cognitive impairment and dementia with targeted cognitive rehabilitation. Thorough clinical evaluation and neuroimaging form the basis for diagnosis. As vascular cognitive impairment and dementia is the leading nondegenerative cause of dementia, identifying risk factors and optimizing their management is paramount. Once vascular brain injury has occurred, symptomatic management should be offered and secondary prevention pursued.

Brain Imaging Abnormalities in Mixed Alzheimer's and Subcortical Vascular Dementia.

A large proportion of Alzheimer's disease (AD) patients have coexisting subcortical vascular dementia (SVaD), a condition referred to as mixed dementia (MixD). Brain imaging features of MixD presumably include those of cerebrovascular disease and AD pathology, but are difficult to characterize due to their heterogeneity. To perform an exploratory analysis of conventional and non-conventional structural magnetic resonance imaging (MRI) abnormalities in MixD and to compare them to those observed in AD and SVaD. We conducted a cross-sectional, region-of-interest-based analysis of 1) hyperintense white-matter signal abnormalities (WMSA) on T2-FLAIR and hypointense WMSA on T1-weighted MRI; 2) diffusion tensor imaging; 3) quantitative susceptibility mapping; and 4) effective transverse relaxation rate (R2*) in N = 17 participants (AD:5, SVaD:5, MixD:7). General linear model was used to explore group differences in these brain imaging measures. Model findings suggested imaging characteristics specific to our MixD group, including 1) higher burden of WMSAs on T1-weighted MRI (versus both AD and SVaD); 2) frontal lobar preponderance of WMSAs on both T2-FLAIR and T1-weighted MRI; 3) higher fractional anisotropy values within normal-appear white-matter tissues (versus SVaD, but not AD); and 4) lower R2* values within the T2-FLAIR WMSA areas (versus both AD and SVaD). These findings suggest a preliminary picture of the location and type of brain imaging characteristics associated with MixD. Future imaging studies may employ region-specific hypotheses to distinguish MixD more rigorously from AD or SVaD.

Human Immunodeficiency Virus-Associated Dementia

Human immunodeficiency virus (HIV) continues to be a serious public health problem in our country in the world and has serious effects on the central and peripheral nervous system. HIV-associated dementia (HAD), which may develop due to HIV infection, causes subcortical dementia that can progress with marked slowdown in reaction time and psychomotor speed, impaired cognitive flexibility, emotional lability, and apathy. Neurocognitive tests are the most appropriate tools for the neurocognitive assessment and staging of the disease. In this context, the Addenbrooke's Cognitive Examinations Revised (ACE-R) test may be preferred in the neurocognitive evaluation of patients considered to have HAD, in terms of its repeatability and easy applicability, as it allows us to evaluate many neurocognitive functions in detail.

A3 adenosine receptor agonist IB-MECA reverses chronic cerebral ischemia-induced inhibitory avoidance memory deficit

BackgroundChronic cerebral ischemia (CCI) is a major cause of subcortical ischemic vascular dementia. Here, we examined the neuroprotective action of the A3 adenosine receptor agonist N6-(3-iodobenzyl)-adenosine-5′-N-methylcarboxamide (IB-MECA) on white matter lesions following CCI. MethodsA CCI mouse model was established using unilateral common carotid artery occlusion. IB-MECA and 3-propyl-6-ethyl-5-[(ethylthio)carbonyl]-2 phenyl-4-propyl-3-pyridine carboxylate (MRS1523), an antagonist of the A3 adenosine receptor, were administered by intraperitoneal injection. The inhibitory avoidance test was used to examine changes in memory performance. Microtubule-associated protein 2 (MAP-2) and neurofilament were assessed by immunohistochemistry, while expressions of phosphorylated extracellular signal-regulated kinase (ERK), ERK, interferon-beta (IFN-β), and glial fibrillary acidic protein (GFAP) were assessed by western blot assay. ResultsThe memory retention score was reduced in vehicle-treated mice compared with IB-MECA-treated (p < 0.05) mice. Compared to sham-operated mice, p-ERK, GFAP and IFN-β were increased, while MAP-2 and neurofilament were reduced in vehicle-treated mice (p < 0.01 for each). IB-MECA reduced ERK phosphorylation (p < 0.01) and GFAP expression (p < 0.05), but upregulated MAP-2 and IFN-β (p < 0.01 for both), compared with vehicle. MRS1523 suppressed the effects of IB-MECA on the memory deficit, ERK phosphorylation, and on MAP-2, neurofilament, GFAP and IFN-β levels. ConclusionOur results suggest that A3 adenosine receptor stimulation ameliorates CCI-induced memory deficits, modulates the ERK signaling pathway, preserves MAP-2 and neurofilament expression, regulates GFAP expression, and upregulates the anti-inflammatory cytokine IFN-β. Thus, the A3 adenosine receptor may be a therapeutic target for treatment of cognitive disorders and cerebral inflammatory diseases.

Increased capillary stalling is associated with endothelial glycocalyx loss in subcortical vascular dementia

Proper regulation and patency of cerebral microcirculation are crucial for maintaining a healthy brain. Capillary stalling, i.e., the brief interruption of microcirculation has been observed in the normal brain and several diseases related to microcirculation. We hypothesized that endothelial glycocalyx, which is located on the luminal side of the vascular endothelium and involved in cell-to-cell interaction regulation in peripheral organs, is also related to cerebral capillary stalling. We measured capillary stalling and the cerebral endothelial glycocalyx (cEG) in male mice using in vivo optical coherence tomography angiography (OCT-A) and two-photon microscopy. Our findings revealed that some capillary segments were prone to capillary stalling and had less cEG. In addition, we demonstrated that the enzymatic degradation of the cEG increased the capillary stalling, mainly by leukocyte plugging. Further, we noted decreased cEG along with increased capillary stalling in a mouse model of subcortical vascular dementia (SVaD) with impaired cortical microcirculation. Moreover, gene expression related to cEG production or degradation changed in the SVaD model. These results indicate that cEG mediates capillary stalling and impacts cerebral blood flow and is involved in the pathogenesis of SVaD.

Treadmill Exercise During Cerebral Hypoperfusion Has Only Limited Effects on Cognitive Function in Middle-Aged Subcortical Ischemic Vascular Dementia Mice.

Clinical and basic research suggests that exercise is a safe behavioral intervention and is effective for improving cognitive function in cerebrovascular diseases, including subcortical ischemic vascular dementia (SIVD). However, most of the basic research uses young animals to assess the effects of exercise, although SIVD is an age-related disease. In this study, therefore, we used middle-aged mice to examine how treadmill exercise changes the cognitive function of SIVD mice. As a mouse model of SIVD, prolonged cerebral hypoperfusion was induced in 8-month-old male C57BL/6J mice by bilateral common carotid artery stenosis. A week later, the mice were randomly divided into two groups: a group that received 6-week treadmill exercise and a sedentary group for observation. After subjecting the mice to multiple behavioral tests (Y-maze, novel object recognition, and Morris water maze tests), the treadmill exercise training was shown to only be effective in ameliorating cognitive decline in the Y-maze test. We previously demonstrated that the same regimen of treadmill exercise was effective in young hypoperfused-SIVD mice for all three cognitive tests. Therefore, our study may indicate that treadmill exercise during cerebral hypoperfusion has only limited effects on cognitive function in aging populations.

Characterization of vascular dementia with TMS: A systematic review and meta‐analysis

AbstractBackgroundVascular dementia (VaD) is the second most common cause of dementia. However, the variety of lesions in different vessels make VaD heterogeneous. VaD has been studied using transcranial magnetic stimulation (TMS) in patients with multi‐infarct dementia, subcortical ischemic vascular dementia (SIVD), and with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). There is, however, some controversy about the reported impairment in cortical excitability and cortical circuits in VaD(1–5). Therefore, we reviewed systematically TMS characterization in patients with VaD.MethodWe conducted a systematic review following PRISMA guidelines. Our search strategy included terms related to VaD and TMS and was conducted in 4 databases (MEDLINE, EMBASE, Ovid and Scopus) from origin to April 2021. Two authors screened the studies in a 2‐stepwise approach. Original studies, comparing any type of VaD to healthy controls (HC) using TMS. Case reports and series were excluded. Risk of bias was assessed using QUADAS. Meta‐analyses comparing various TMS parameters between VaD and HC were conducted. Demographic data (age, sex, comorbidities, years of education, onset age, diagnosis information), subtype of vascular dementia, reference standard, and TMS parameters were extracted.ResultAfter duplicates were removed our search yielded 216 results. After applying the eligibility criteria, 26 articles were fully screened and finally 8 articles were reviewed and included in the meta‐analysis(4–11). A total of 145 patients with VaD were analyzed, and most of them had SIVD (69.65%) and CADASIL (11.72%); 140 HC were also analyzed. When compared VaD patients to HC, the mean differences of resting motor threshold (RMT) and short‐latency afferent inhibition (SAI) values were statistically significant (Fig 1‐2).ConclusionThis is the first systematic review to describe the differences of TMS parameters between patients with VaD and HC. RMT and SAI values were significantly altered in patients with VaD suggesting that both cortical excitability and cholinergic transmission are affected. These parameters could be further used to understand the impact of vascular events in neurotransmission. Furthermore, because of the difficulty of detecting vascular lesions in structural imaging studies, TMS characterization may allow a clearer diagnosis of VaD.