Subcortical Vascular Dementia Research Articles

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.

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.

Cerebral Hemodynamics and Carotid Atherosclerosis in Patients With Subcortical Ischemic Vascular Dementia.

A growing body of evidence indicates that atherosclerosis is correlated with cerebral small vessel disease and contributes to cognitive decline. This study aimed to explore the characteristics and contributions of intracranial hemodynamics and carotid atherosclerosis to cognitive dysfunction in subjects with subcortical ischemic vascular dementia (SIVD). Notably, 44 patients with SIVD, 30 patients with Alzheimer’s disease (AD), and 30 healthy controls (HCs) were recruited from our longitudinal MRI study for AD and SIVD (ChiCTR1900027943). The cerebral mean flow velocity (MFV) and pulsatility index (PI) of both anterior and posterior circulations, artery plaque, and lumen diameter in carotid arteries were investigated using transcranial Doppler and carotid ultrasound, respectively. Their correlations with cognitive function were analyzed in patients with dementia. Decreased MFV and increased PI were found in patients with SIVD and AD. Patients with SIVD showed lower MFV and higher PI in the bilateral posterior cerebral arteries compared to patients with AD. Increases in lumen diameter, number of arteries with plaque, and total carotid plaque score were found in patients with SIVD. The Mini-Mental State Examination score was positively correlated with the MFV and negatively correlated with the PI of most major cerebral arteries, while it was negatively correlated with the lumen diameter of the common carotid artery, number of arteries with plaque, and total carotid plaque score in patients with dementia. There were also correlations between these parameters of some arteries and memory and executive function. Our results provide additional evidence suggesting that the pathological changes in macrovascular structure and function are correlated with cognitive impairment in dementia patients with SIVD and to a lesser extent AD.

Imaging Markers of Subcortical Vascular Dementia in Patients With Multiple-Lobar Cerebral Microbleeds.

Background and Purpose: Small vessel disease (SVD) imaging markers are related to ischemic and hemorrhage stroke and to cognitive dysfunction. This study aimed to clarify the relationship between SVD imaging markers and subcortical vascular dementia in severe SVD burden.Methods: A total of 57 subjects with multiple lobar cerebral microbleeds (CMBs) and four established SVD imaging markers were enrolled from the dementia and stroke registries of a single center. Visual rating scales that are used to semi-quantify SVD imaging changes were analyzed individually and compositely to make correlations with cognitive domains and subcortical vascular dementia.Results: Dementia group had higher subcortical and total white matter hyperintensities (WMHs) and SVD composite scores than non-dementia group. Individual imaging markers correlated differently with one another and had distinct cognitive correlations. After adjusting for demographic factors, multivariate logistic regression indicated associations of subcortical WMHs (odds ratio [OR] 2.03, CI 1.24–3.32), total WMHs (OR 1.43, CI 1.09–1.89), lacunes (OR 1.18, CI 1.02–1.35), cerebral amyloid angiopathy-SVD scores (OR 2.33, CI 1.01–5.40), C1 scores (imaging composite scores of CMB and WMH) (OR 1.41, CI 1.09–1.83), and C2 scores (imaging composite scores of CMB, WMH, perivascular space, and lacune) (OR 1.38, CI 1.08–1.76) with dementia.Conclusions: SVD imaging markers might have differing associations with cognitive domains and dementia. They may provide valuable complementary information in support of personalized treatment planning against cognitive impairment, particularly in patients with a heavy SVD load.

Evaluation of cerebrovascular hemodynamics in vascular dementia patients with a new individual computational fluid dynamics algorithm

BackgroundCerebral hemodynamic disorders are involved in the occurrence and progression of vascular dementia (VaD), but the methods to detect hemodynamics remainmultifarious and uncertain nowadays. We aim to exploit a computational fluid dynamics (CFD) approach by static and dynamic parameters, which can be used to detect individual cerebrovascular hemodynamics quantitatively. MethodsA patient-specific CFD model was constructed with geometrical arteries on the magnetic resonance angiography (MRA) and hemodynamic parameters on ultrasound Doppler, by which, the structural and simulated hemodynamic indexes could be obtained, mainly including the cerebral arterial volume (CAV), the number of visible arterial outlets, the total cerebral blood flow (tCBF) index and the total cerebrovascular resistance (tCVR) index. The hemodynamics were detected in subcortical vascular dementia (SVaD) patients (n = 38) and cognitive normal controls (CNCs; n = 40). ResultsCompared with CNCs, the SVaD patients had reduced outlets, CAV and tCBF index (all P ≤ 0.001), increased volume of white matter hyperintensity (WMH) and tCVR index (both P ≤ 0.01). The fewer outlets (OR = 0.77), higher Hachinski ischemic score (HIS) (OR = 3.65), increased tCVR index (OR = 1.98) and volume of WMH (OR = 1.12) were independently associated with SVaD. All hemodynamic parameters could differentiate the SVaD patinets and CNCs, especially the composite index calculated by outlets, tCVR index and HIS (AUC = 0.943). Fewer outlets and more WMH increased the odds of SVaD, which were partly mediated by the tCBF index (14.4% and 13.0%, respectively). ConclusionThe reduced outlets, higher HIS and tCVR index may be independent risk factors for the SVaD, and a combination of these indexes can differentiate SVaD patients and CNCs reliably. The tCBF index potentially mediates the relationships between hemodynamic indexes and SVaD. Although all simulated indexes only represented the true hemodynamics indirectly, this CFD model can provide patient-specific hemodynamic alterations non-invasively and conveniently.

Experimental Rodent Models of Vascular Dementia: A Systematic Review.

Vascular Dementia (VaD) occurs due to cerebrovascular insufficiency, which leads to decreased blood circulation to the brain, thereby resulting in mental disabilities. The main causes of Vascular Cognitive Impairment (VCI) are severe hypoperfusion, stroke, hypertension, large vessel disease (cortical), small Vessel Disease (subcortical VaD), strategic infarct, hemorrhage (microbleed), Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), and Cerebral Amyloid Angiopathy (CAA), which leads to decreased cerebrovascular perfusion. Many metabolic disorders such as Diabetes Mellitus (DM), dyslipidemia, and hyperhomocysteinemia are also related to VaD. The rodent experimental models provide a better prospective for the investigation of the molecular mechanism of new drugs. A plethora of experimental models are available that mimic the pathological conditions and lead to VaD. This review article updates the current knowledge on the basis of VaD, risk factors, pathophysiology, mechanism, advantages, limitations, and the modification of various available rodent experimental models.

Validity and reliability of the medial temporal lobe atrophy scale in a memory clinic population

BackgroundVisual rating of medial temporal lobe atrophy (MTA) is often performed in conjunction with dementia workup. Most prior studies involved patients with known or probable Alzheimer’s disease (AD). This study investigated the validity and reliability of MTA in a memory clinic population.MethodsMTA was rated in 752 MRI examinations, of which 105 were performed in cognitively healthy participants (CH), 184 in participants with subjective cognitive impairment, 249 in subjects with mild cognitive impairment, and 214 in patients with dementia, including AD, subcortical vascular dementia and mixed dementia. Hippocampal volumes, measured manually or using FreeSurfer, were available in the majority of cases. Intra- and interrater reliability was tested using Cohen’s weighted kappa. Correlation between MTA and quantitative hippocampal measurements was ascertained with Spearman’s rank correlation coefficient. Moreover, diagnostic ability of MTA was assessed with receiver operating characteristic (ROC) analysis and suitable, age-dependent MTA thresholds were determined.ResultsRater agreement was moderate to substantial. MTA correlation with quantitative volumetric methods ranged from -0.20 (p< 0.05) to -0.68 (p < 0.001) depending on the quantitative method used. Both MTA and FreeSurfer are able to distinguish dementia subgroups from CH. Suggested age-dependent MTA thresholds are 1 for the age group below 75 years and 1.5 for the age group 75 years and older.ConclusionsMTA can be considered a valid marker of medial temporal lobe atrophy and may thus be valuable in the assessment of patients with cognitive impairment, even in a heterogeneous patient population.

COVID-19 Lockdown Effect on Not Institutionalized Patients with Dementia and Caregivers.

SARS-COV-2 is a severe medical condition. Old patients are very vulnerable, but they have been studied only as institutionalized patients. During the lock-down, little attention is dedicated to old, demented patients who lived at home. This study wants to examine their behavioral reactions by video-phone follow-up. We conducted a longitudinal study in subcortical vascular dementia (sVAD) patients. We enrolled 221 sVAD, not institutionalized patients. We divided sVAD patients into low-medium grade sVAD (A) and severe sVAD (B), based on neuroimaging severity degree and executive alterations. At baseline, at the end of lock-down, and two months later, global behavioral symptoms were recorded for each patient. We found significantly higher scores of general behavioral deterioration, anxiety, delusions, hallucinations and apathy after controlling for sVAD severity. The direct consequence was a drastic increment of psychotropic drugs prescribed and employed during the lock-down. Moreover, caregivers’ stress has been evaluated, together with their anxiety and depression levels. During the lock-down, their scores increased and reflected a severe worsening of their behavior. Our data demonstrate that social isolation induces a severe perception of loneliness and abandonment; these fears can exacerbate behavior disturbances in old-aged frail persons. Thus, these can be considered as indirect victims of SARS-COV-2.

Transcriptome Profiling of Mouse Corpus Callosum After Cerebral Hypoperfusion.

White matter damage caused by cerebral hypoperfusion is a major hallmark of subcortical ischemic vascular dementia (SIVD), which is the most common subtype of vascular cognitive impairment and dementia (VCID) syndrome. In an aging society, the number of SIVD patients is expected to increase; however, effective therapies have yet to be developed. To understand the pathological mechanisms, we analyzed the profiles of the cells of the corpus callosum after cerebral hypoperfusion in a preclinical SIVD model. We prepared cerebral hypoperfused mice by subjecting 2-month old male C57BL/6J mice to bilateral carotid artery stenosis (BCAS) operation. BCAS-hypoperfusion mice exhibited cognitive deficits at 4 weeks after cerebral hypoperfusion, assessed by novel object recognition test. RNA samples from the corpus callosum region of sham- or BCAS-operated mice were then processed using RNA sequencing. A gene set enrichment analysis using differentially expressed genes between sham and BCAS-operated mice showed activation of oligodendrogenesis pathways along with angiogenic responses. This database of transcriptomic profiles of BCAS-hypoperfusion mice will be useful for future studies to find a therapeutic target for SIVD.

Association of the Irregular 3-Dimensional Shape of White Matter Hyperintensities with Cognitive Function

Introduction: The irregular shapes of white matter hyperintensities (WMHs) are associated with poor cognitive function, diabetes, or lacunes. However, the association between the WMH shape and dementia remains understudied. We investigated the association between the calculated shape index of WMH and the diagnosis of dementia and cognitive function. Methods: The inverse sphericity index (ISI_WMH) and volume of WMHs (VOL_WMH) were compared among 82 participants with normal cognition, 82 with Alzheimer’s dementia (AD), and 82 with subcortical vascular dementia (SVD). We examined the associations of ISI_WMH and VOL_WMH with the modified Hachinski Ischemic Score (mHIS), diagnosis of AD and SVD, and cognitive test scores, using linear, multinomial, or hierarchical linear regression models. Results: The mHIS was associated with both ISI_WMH (β = 0.326, p < 0.001) and VOL_WMH (β = 0.299, p < 0.001). Both ISI_WMH and VOL_WMH were associated with the SVD diagnosis (odds ratio [OR] = 2.685, p = 0.002, ISI_WMH; OR = 2.597, p = 0.005, VOL_WMH), but not with AD. The SVD diagnosis was better explained when the multinomial regression model included both ISI_WMH and VOL_WMH instead of VOL_WMH alone (χ² = 20.768, df = 2, p < 0.001). The Trail Making Test-D (TMT-D) scores of the SVD patients were associated with both ISI_WMH (β = 0.308) and VOL_WMH (β = 0.293). Conclusion: An irregular WMH shape may be associated with the high cerebrovascular component of cognitive impairment and the diagnosis and low cognitive flexibility of SVD, which may improve the prediction of SVD diagnosis when used in combination with WMH volume.

Case Report on a Misdiagnosed Case of Subcortical Vascular Dementia – the Importance of Sound Knowledge of Psychiatry With Proper History Taking

Psychiatric symptoms at presentation may often be missed, if not suspected or specifically explored. A missed psychiatric diagnosis may lead to dire consequences in terms of poor quality of life and function for the patient, affecting overall quality of healthcare provided. This lady presented with depressive symptoms after multiple strokes and was initially diagnosed as post stroke depression. However, after it was observed that she did not show any improvement in symptoms despite being on antidepressants, subsequent further investigations revealed a history more suggestive of subcortical vascular dementia. Consequently, detailed neuropsychological and neuropsychiatric assessments, including NUCOG, and relevant investigations including MRI brain scans were performed suggesting a diagnosis of vascular dementia. This case illustrates that an insufficiently thorough assessment and treatment process results in unnecessary morbidity, prolongs duration of illness, and increases social and occupational dysfunction to the patient. Hence, it further underscores the need to perform a thorough history, physical examination and relevant investigations to ensure organic etiologies are ruled out in clients with relevant sociodemographic and clinical risk factors.

The role of NOTCH3 variants in Alzheimer's disease and subcortical vascular dementia in the Chinese population

Aims NOTCH3 gene mutations predominantly cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, a common etiology of subcortical vascular dementia (SVaD). Besides, there may be a pathogenic link between NOTCH3 variants and Alzheimer's disease (AD). We aimed to study the role of NOTCH3 variants in AD and SVaD patients.MethodsWe recruited 763 patients with dementia (667 AD and 96 SVaD) and 365 healthy controls from the Southern Han Chinese population. Targeted capture sequencing was performed on NOTCH3 coding and adjacent intron regions to detect the pathogenic variants in AD and SVaD. The relationship between common or rare NOTCH3 variants and AD was further analyzed using Plink1.9.ResultsFive known pathogenic variants (p.R182C, p.C201S, p.R544C, p.R607C, and p.R1006C) and two novel likely pathogenic variants (p.C201F and p.C1061F) were detected in 16 SVaD patients. Additionally, no pathogenic or likely pathogenic variants were found in AD patients. NOTCH3 was not associated with AD in either single‐variant association analysis or gene‐based association analysis.ConclusionOur findings broaden the mutational spectrum of NOTCH3 and validate the pathogenic role of NOTCH3 mutations in SVaD, but do not support the notion that NOTCH3 variation influences the risk of AD.

Triptolide protects against white matter injury induced by chronic cerebral hypoperfusion in mice.

White matter injury is the major pathological alteration of subcortical ischemic vascular dementia (SIVD) caused by chronic cerebral hypoperfusion. It is characterized by progressive demyelination, apoptosis of oligodendrocytes and microglial activation, which leads to impairment of cognitive function. Triptolide exhibits a variety of pharmacological activities including anti-inflammation, immunosuppression and antitumor, etc. In this study, we investigated the effects of triptolide on white matter injury and cognitive impairments in mice with chronic cerebral hypoperfusion induced by the right unilateral common carotid artery occlusion (rUCCAO). We showed that triptolide administration alleviated the demyelination, axonal injury, and oligodendrocyte loss in the mice. Triptolide also improved cognitive function in novel object recognition test and Morris water maze test. In primary oligodendrocytes following oxygen-glucose deprivation (OGD), application of triptolide (0.001-0.1 nM) exerted concentration-dependent protection. We revealed that the protective effect of triptolide resulted from its inhibition of oligodendrocyte apoptosis via increasing the phosphorylation of the Src/Akt/GSK3β pathway. Moreover, triptolide suppressed microglial activation and proinflammatory cytokines expression after chronic cerebral hypoperfusion in mice and in BV2 microglial cells following OGD, which also contributing to its alleviation of white matter injury. Importantly, mice received triptolide at the dose of 20 μg·kg-1·d-1 did not show hepatotoxicity and nephrotoxicity even after chronic treatment. Thus, our results highlight that triptolide alleviates whiter matter injury induced by chronic cerebral hypoperfusion through direct protection against oligodendrocyte apoptosis and indirect protection by inhibition of microglial inflammation. Triptolide may have novel indication in clinic such as the treatment of chronic cerebral hypoperfusion-induced SIVD.

Quantitative Assessment Method of Force Tracking Capabilities for Detection of Motor Intentional Disorders

Early detection of motor intentional disorders associated with dysfunction in the action–intention system of the brain is clinically important to provide timely intervention. This study developed a force tracking system that can record forces exerted by the index finger while tracking 5 N, 10 N, 15 N, and 20 N of target forces varying over time. The force tracking system quantified force control measures (initiation time IT; development time, DT, maintenance error, ME; termination time, TT; tracking error, TE) for the individual and overall force control phases. This study evaluated the effectiveness of the force tracking system for a normal control group (n = 12) and two patient groups diagnosed with subcortical vascular mild cognitive impairment (svMCI, n = 11) and subcortical vascular dementia (SVaD, n = 13). Patients with SVaD showed significantly worse force control capabilities in IT (0.84 s) and ME (1.71 N) than those with svMCI (0.64 s in IT, and 1.38 N in ME). Patients with svMCI had significantly worse capabilities in IT, ME, and TE (3.80 N) than the control group (0.49 s in IT, 0.78 N in ME, and 3.07 N in TE). The prevalence rates of force control capabilities lower than the 99% confidence interval of the control group ranged from 17% to 62% for the two patient groups. The force tracking system can sensitively quantify the severity of the force control deficiencies caused by dysfunction in the action–intention system of the brain.