Subcortical Dementia Research Articles

HIV-Associated Neurocognitive Disorder (HAND) and Alzheimer's Disease Pathogenesis: Future Directions for Diagnosis and Treatment.

HIV-associated neurocognitive disorder (HAND) and Alzheimer's disease (AD) are two neurocognitive disorders with overlapping clinical presentations and pathophysiology. The two have been thought to be two separate entities. However, the introduction and widespread use of antiretroviral therapy (ART) has altered the clinical manifestations of HAND, shifting from a pattern of subcortical dementia to one more akin to cortical dementia, resembling AD. Thus, the line between the two disease entities is not clear-cut. In this review, we discuss the concept of Alzheimer's disease-like dementia (ADLD) in HIV, which describes this phenomenon. While the mechanisms of HIV-associated ADLD remain to be elucidated, potential mechanisms include HIV-specific pathways, including epigenetic imprinting from initial viral infection, persistent and low viral load (which can only be detected by ultra-sensitive PCR), HIV-related inflammation, and putative pathways underlying traditional AD risk factors. Importantly, we have shown that HIV-specific microRNAs (miRs) encapsulated in extracellular vesicles (EV-miRs) play an important role in mediating the detrimental effects in the cardiovascular system. A useful preclinical model to study ADLD would be to expose AD mice to HIV-positive EVs to identify candidate EV-miRs that mediate the HIV-specific effects underlying ADLD. Characterization of the candidate EV-miRs may provide novel therapeutic armamentaria for ADLD.

Distinct patterns of white matter hyperintensity and cortical thickness of CSF1R-related leukoencephalopathy compared with subcortical ischemic vascular dementia.

CSF1R-related leukoencephalopathy is a type of autosomal dominant leukodystrophy caused by mutations in the colony stimulating factor 1 receptor (CSF1R) gene. Subcortical ischemic vascular dementia (SIVaD), which is caused by cerebral small vessel disease, is similar to CSF1R-related leukoencephalopathy in that it mainly affects subcortical white matter. In this study, we compared the patterns of white matter hyperintensity (WMH) and cortical thickness in CSF1R-related leukoencephalopathy with those in SIVaD. Fourteen patients with CSF1R-related leukoencephalopathy and 129 with SIVaD were retrospectively recruited from three tertiary medical centers. We extracted and visualized WMH data using voxel-based morphometry to compare the WMH distributions between the two groups. Cortical thickness was measured using a surface-based method. Statistical maps of differences in cortical thickness between the two groups were generated using a surface model, with age, sex, education, and intracranial volume as covariates. Predominant distribution of WMH in the CSF1R-related leukoencephalopathy group was in the bilateral frontal and parietal areas, whereas the SIVaD group showed diffuse WMH involvement in the bilateral frontal, parietal, and temporal areas. Compared with the SIVaD group, the CSF1R-related leukoencephalopathy group showed more severe corpus callosum atrophy (CCA) and widespread cortical thinning. To our knowledge, this is the first study using the automated MR measurement to capture WMH, cortical thinning, and CCA with signal changes in CSF1R-related leukoencephalopathy. It provides new evidence regarding differences in the patterns of WMH distribution and cortical thinning between CSF1R-related leukoencephalopathy and SIVaD.

Role of the vessel morphology on the lenticulostriate arteries hemodynamics during atrial fibrillation: A CFD-based multivariate regression analysis

Background and objectiveAtrial fibrillation (AF) is the most common cardiac arrhythmia, inducing accelerated and irregular beating. Beside well-known disabling symptoms - such as palpitations, reduced exercise tolerance, and chest discomfort - there is growing evidence that an alteration of deep cerebral hemodynamics due to AF increases the risk of vascular dementia and cognitive impairment, even in the absence of clinical strokes. The alteration of deep cerebral circulation in AF represents one of the least investigated among the possible mechanisms. Lenticulostriate arteries (LSAs) are small perforating arteries mainly departing from the middle cerebral artery (MCA) and susceptible to small vessel disease, which is one of the mechanisms of subcortical vascular dementia development. The purpose of this study is to investigate the impact of different LSAs morphologies on the cerebral hemodynamics during AF. MethodsBy combining a computational fluid dynamics (CFD) analysis of LSAs with 7T high-resolution magnetic resonance imaging (MRI), we performed different CFD-based multivariate regression analyses to detect which geometrical and morphological vessel features mostly affect AF hemodynamics in terms of wall shear stress. We exploited 17 cerebral 7T-MRI derived LSA vascular geometries extracted from 10 subjects and internal carotid artery data from validated 0D cardiovascular-cerebral modeling as inflow conditions. ResultsOur results revealed that few geometrical variables - namely the size of the MCA and the bifurcation angles between MCA and LSA - are able to satisfactorily predict the AF impact. In particular, the present study indicates that LSA morphologies exhibiting markedly obtuse LSA-MCA inlet angles and small MCA size downstream of the LSA-MCA bifurcation may be more prone to vascular damage induced by AF. ConclusionsThe present MRI-based computational study has been able for the first time to: (i) investigate the net impact of LSAs vascular morphologies on cerebral hemodynamics during AF events; (ii) detect which combination of morphological features worsens the hemodynamic response in the presence of AF. Awaiting necessary clinical confirmation, our analysis suggests that the local hemodynamics of LSAs is affected by their geometrical features and some LSA morphologies undergo greater hemodynamic alterations in the presence of AF.

Immunological Profile and Markers of Endothelial Dysfunction in Elderly Patients with Cognitive Impairments.

The process of aging is accompanied by a dynamic restructuring of the immune response, a phenomenon known as immunosenescence. Further, damage to the endothelium can be both a cause and a consequence of many diseases, especially in elderly people. The purpose of this study was to carry out immunological and biochemical profiling of elderly people with acute ischemic stroke (AIS), chronic cerebral circulation insufficiency (CCCI), prediabetes or newly diagnosed type II diabetes mellitus (DM), and subcortical ischemic vascular dementia (SIVD). Socio-demographic, lifestyle, and cognitive data were obtained. Biochemical, hematological, and immunological analyses were carried out, and extracellular vesicles (EVs) with endothelial CD markers were assessed. The greatest number of significant deviations from conditionally healthy donors (HDs) of the same age were registered in the SIVD group, a total of 20, of which 12 were specific and six were non-specific but with maximal differences (as compared to the other three groups) from the HDs group. The non-specific deviations were for the MOCA (Montreal Cognitive Impairment Scale), the MMSE (Mini Mental State Examination) and life satisfaction self-assessment scores, a decrease of albumin levels, and ADAMTS13 (a Disintegrin and Metalloproteinase with a Thrombospondin Type 1 motif, member 13) activity, and an increase of the VWF (von Willebrand factor) level. Considering the significant changes in immunological parameters (mostly Th17-like cells) and endothelial CD markers (CD144 and CD34), vascular repair was impaired to the greatest extent in the DM group. The AIS patients showed 12 significant deviations from the HD controls, including three specific to this group. These were high NEFAs (non-esterified fatty acids) and CD31 and CD147 markers of EVs. The lowest number of deviations were registered in the CCCI group, nine in total. There were significant changes from the HD controls with no specifics to this group, and just one non-specific with a maximal difference from the control parameters, which was α1-AGP (alpha 1 acid glycoprotein, orosomucoid). Besides the DM patients, impairments of vascular repair were also registered in the CCCI and AIS patients, with a complete absence of such in patients with dementia (SIVD group). On the other hand, microvascular damage seemed to be maximal in the latter group, considering the biochemical indicators VWF and ADAMTS13. In the DM patients, a maximum immune response was registered, mainly with Th17-like cells. In the CCCI group, the reaction was not as pronounced compared to other groups of patients, which may indicate the initial stages and/or compensatory nature of organic changes (remodeling). At the same time, immunological and biochemical deviations in SIVD patients indicated a persistent remodeling in microvessels, chronic inflammation, and a significant decrease in the anabolic function of the liver and other tissues. The data obtained support two interrelated assumptions. Taking into account the primary biochemical factors that trigger the pathological processes associated with vascular pathology and related diseases, the first assumption is that purine degradation in skeletal muscle may be a major factor in the production of uric acid, followed by its production by non-muscle cells, the main of which are endothelial cells. Another assumption is that therapeutic factors that increase the levels of endothelial progenitor cells may have a therapeutic effect in reducing the risk of cerebrovascular disease and related neurodegenerative diseases.

Symptomatology of Idiopathic Normal Pressure Hydrocephalus

Idiopathic normal pressure hydrocephalus causes a triad of gait disturbance, dementia, and urinary incontinence in the elderly. All these symptoms may manifest as age-related functional decline or from neurological and non-neurological diseases common in the elderly. In idiopathic normal pressure hydrocephalus, characterized by ataxic-ataxic gait, subcortical dementia, and urge urinary incontinence, it is clinically important to consider these characteristic features. This overview describes the symptomatology of idiopathic normal pressure hydrocephalus.

A Case of Personality and Behavioral Changes with Frontotemporal and Cerebellar Atrophy on MRI with Corresponding Hypometabolism on FDG‐PET

Background. The differential diagnosis of a patient with cognitive, behavioral, and motor symptoms is broad. There is much overlap between neurocognitive disorders due to frontotemporal dementia and other subcortical dementia. A less known diagnosis, cerebellar cognitive affective syndrome (CCAS), should also be considered. Case History. A 29‐year‐old female presented with ataxia and left‐sided weakness. CSF showed oligoclonal bands, and MRI showed multiple white matter lesions with some atrophy. She was diagnosed with multiple sclerosis (MS). At age 35, she developed frontal lobe symptoms and executive dysfunction; she was diagnosed with MS with bipolar disorder. Neuropsychological evaluation at that time showed significant deficits in multiple cognitive domains. Subsequent MRI showed progressive frontotemporal atrophy, and FDG‐PET uncovered hypometabolism in the frontotemporal lobes and cerebellum. At age 38, her behavior worsened with aggression, and she was started on olanzapine. She responded well with decreased agitation and improved motivation and attention. Compared with previous scans, most recent MRI and FDG‐PET showed interval increase in cerebellar atrophy with increase in hypometabolism in the cerebellum, respectively. Conclusion. Based on cerebellar, affective, and subcortical cognitive examination findings, our diagnosis is probable CCAS. The cerebellum should be considered as a possible etiology of frontal subcortical cognitive impairment.

Radiological Evaluation of Huntington’s Disease: A Case Report

Huntington’s Disease (HD) is a rare neurodegenerative condition inherited in an autosomal dominant pattern, where Gamma Amino Butyric Acid-ergic (GABAergic) neurons in the basal ganglia progressively deteriorate. Symptoms include subcortical dementia, behavioural changes, midlife psychosis, and involuntary choreoathetosis movements. Imaging techniques like Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) show shrinkage of the caudate nucleus and putamen, alongside enlarged lateral ventricles. Diagnosis is confirmed through molecular analysis identifying the hallmark amplified Cytosine Adenine Guanine (CAG) triplet. The case report describes a 57-year-old female diagnosed with HD, presenting symptoms of accidental falls caused by involuntary jerky movements, along with behavioural changes and cognitive decline over three years. Initial Non Contrast Computed Tomography (NCCT) of the brain revealed bilateral basal ganglia and diffuse cerebral atrophy. Quantitative analysis indicated a decreased frontal horn width to intercaudate distance (FH/CC) ratio of 1.24 and an increased Intercaudate distance to inner table width (CC/IT) ratio of 0.30. Multivoxel Magnetic Resonance Spectroscopy (MRS) showed reduced N-Acetyl Alanine (NAA) and creatine (Cr) levels with an NAA/Cr ratio of 0.84. Magnetic Resonance Tractography and Diffusion Tensor Imaging (DTI) revealed elevated Fractional Anisotropy (FA) and diffusivity in the basal ganglia, and reduced FA with increased diffusivity in white matter tracts. Genetic analysis by Polymerase Chain Reaction (PCR) confirmed HD. Newer MRI like DTI allows early identification of disease and better assessment of disease progression and response to therapy. A multidisciplinary approach involving neurologists, psychiatrists, and other healthcare professionals is essential. Genetic counseling and psychosocial support are crucial for patients and their families. Early and accurate identification of HD is vital for timely interventions and improved symptom control.

In vivo Braak staing using 18F‐MK‐6240 PET in Alzheimer’s disease

AbstractBackgroundThis study aimed to identify the distribution of [18F]MK‐6240 PET retention and classified according to Braak staging in Alzheimer’s disease (AD). We also evaluated the relationship between [18F]MK‐6240 PET retention and cognitive functions and neurodegeneration.MethodWe enrolled 194 participants including 70 CU (cognitively unimpaired elderly participants older than 60 years old), 56 MCI, 60 probable AD, and 8 patients who had dementia other than AD (subcortical vascular dementia (n = 3), semantic variant primary progressive aphasia (n = 2), frontotemporal dementia (n = 2), corticobasal syndrome (n = 1)). All participants underwent 3T MRI, [18F]MK‐6240, and [18F]Flutemetamol (FLUTE) PET scans, APOE genotyping, and detailed neuropsychological tests. Braak staging was defined as the stages where regional SUVR of ROIs composing each Braak stage > = 1.3. We assessed the Braak staging in the subjects. Correlation analyses between global retention of MK‐6240 PET and neuropsychological test results or neurodegeneration were performed using linear regression.ResultThe proportion of amyloid positivity was 11.4% in CU, 45.5% in MCI, and 83.3% in probable AD. Among probable AD (n = 60), 12 patients were classified to other dementia after amyloid PET and tau PET confirmation. Main Braak stage was Braak 0 in CU, Braak III/IV in amyloid (+) MCI, Braak V/VI in AD dementia. In CU an patents with AD spectrum, global retention of MK‐6240 PET was significantly correlated with MMSE, CDR SOB, language, visuospatial function, memory and frontal/executive functions. In addition, global retention of MK‐6240 PET was correlated with the MRI markers for neurodegeneration, that is, mean cortical thickness and hippocampal volumes.Conclusion [ 18F]MK‐6240 PET successfully identified the Braak staging and associated with amyloid pathology and clinical phenotype in patients with AD. MK‐6240 PET also correlated with cognitive functions and neurodegeneration. MK6240 is a promising tau PET tracer with the potential to be sensitive surrogate markers of AD.

Changes in iron load in specific brain areas lead to neurodegenerative diseases of the central nervous system

The causes of neurodegenerative diseases remain largely elusive, increasing their personal and societal impacts. To reveal the causal effects of iron load on Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis and multiple sclerosis, we used Mendelian randomisation and brain imaging data from a UK Biobank genome-wide association study of 39,691 brain imaging samples (predominantly of European origin). Using susceptibility-weighted images, which reflect iron load, we analysed genetically significant brain regions. Inverse variance weighting was used as the main estimate, while MR Egger and weighted median were used to detect heterogeneity and pleiotropy. Nine clear associations were obtained. For AD and PD, an increased iron load was causative: the right pallidum for AD and the right caudate, left caudate and right accumbens for PD. However, a reduced iron load was identified in the right and left caudate for multiple sclerosis, the bilateral hippocampus for mixed vascular dementia and the left thalamus and bilateral accumbens for subcortical vascular dementia. Thus, changes in iron load in different brain regions have causal effects on neurodegenerative diseases. Our results are crucial for understanding the pathogenesis and investigating the treatment of these diseases.

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

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. To explore the neurovascular correlates of Cbl/folate/Hcy in Alzheimer's disease (AD) and subcortical ischemic vascular dementia (SIVD). 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. 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. 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.

55 Tracking Cognitive Change in Huntington’s Disease with the Mini Mental State Exam and the Montreal Cognitive Assessment

Objective:To assess the utility of the Mini Mental State Exam (MMSE) and Montreal Cognitive Assessment (MoCA) for tracking cognitive changes Huntington’s Disease.Participants and Methods:Currently, the most frequently used brief assessment of global cognitive functioning is the MMSE. Although the MMSE is helpful for distinguishing individuals without significant cognitive impairment from those with dementia, it is not particularly sensitive to more subtle cognitive deficits. The MoCA is another brief cognitive screening tool that has been shown to be more sensitive to mild impairment and may have greater usefulness in subcortical dementias because of its more extensive assessment of executive function. Although the MoCA appears to have high sensitivity and specificity in a variety of neurological populations, there is currently little known about its efficacy in tracking cognitive decline in individuals with HD. We used a mixed effects model to analyze MMSE and MoCA scores collected prospectively during 5 years of follow-up for 163 patients with HD seen at one academic HDSA Center of Excellence. Baseline mean age for the HD cohort was 51.35 years, mean education 14.46 years, and a mean CAG repeat length 43.95. Mean follow-up time was 3.33 years.Results:Mean MMSE and MoCA scores at baseline were 25.13 (SD=1.66) and 22.76 (SD=3.70) respectively. At baseline, age and gender were not associated with MMSE and MoCA scores, while years of education were. Neither age nor gender predicted rate of decline for the MoCA while years of education predicted rate of decline for the MMSE. For the MMSE, each year of education predicted on average 0.51 points higher score at enrollment; for the MoCA, each year of education predicted on average 0.79 points higher score at enrollment. The mean rates of decline on the MMSE was 0.48 points per year (p<.001) while that on the MoCA was only 0.31 points annually (p<.001) in the first five years of observation.Conclusions:The MMSE and MoCA decline significantly over time in an unselected HD population. The smaller rate of decline in the MoCA may be due, in part, to the greater variability in baseline, MoCA (SD=3.70) vs MMSE (SD=1.66) scores in our HD cohort. Unlike cortical dementias, such as Alzheimer’s disease (AD), where declines of 2-3 points per year have been described for the MMSE and MoCA, much lower annual rates of decline have been reported in subcortical dementias such as Parkinson’s disease. To our knowledge, this is the first report of rate of cognitive decline on the MMSE and MoCA in HD: such information is vital for adequately preparing patients and families for future needs, in addition to planning for interventional/treatment trials in HD.

Independent effect of Aβ burden on cognitive impairment in patients with small subcortical infarction

BackgroundThe effect of amyloid-β (Aβ) on cognitive impairment in patients with small subcortical infarction remains controversial, although a growing body of evidence shows a substantial overlap between Alzheimer’s disease (AD) and subcortical ischemic vascular dementia, another form of cerebral small vessel disease (cSVD). Therefore, we investigated the relationships between Aβ positivity and the development of post-stroke cognitive impairment (PSCI) in patients with small subcortical infarction.MethodsWe prospectively recruited 37 patients aged ≥ 50 years, with first-ever small subcortical infarction, who underwent amyloid positron emission tomography, 3 months after stroke at Korea University Guro Hospital. We also enrolled CU participants matched for age and sex with stroke patients for comparison of Aβ positivity. Patients were followed up at 3 and 12 months after the stroke to assess cognitive decline. Logistic and linear mixed-effect regression analyses were performed to identify the effect of Aβ positivity on PSCI development and long-term cognitive trajectories.ResultsAt 3 months after stroke, 12/37 (32.4%) patients developed PSCI, and 11/37 (29.7%) patients had Aβ deposition. Aβ positivity (odds ratio [OR] = 72.2, p = 0.024) was predictive of PSCI development regardless of cSVD burden. Aβ positivity (β = 0.846, p = 0.014) was also associated with poor cognitive trajectory, assessed by the Clinical Dementia Rating-Sum of Box, for 1 year after stroke.ConclusionsOur findings highlight that Aβ positivity is an important predictor for PSCI development and cognitive decline over 1 year. Furthermore, our results provide evidence that anti-AD medications may be a strategy for preventing cognitive decline in patients with small subcortical infarctions.

Brain-derived neurotrophic factor gene polymorphism affects cognitive function and neurofilament light chain level in patients with subcortical ischaemic vascular dementia.

To investigate the effects of brain-derived neurotrophic factor (BDNF) gene polymorphism on cognitive function, neuroimaging and blood biological markers in patients with subcortical ischaemic vascular dementia (SIVD). A total of 81 patients with SIVD were included. According to their BDNF gene polymorphism, the participants were divided into the Val/Val (n = 26), Val/Met (n = 35), and Met/Met (n = 20) groups. A comprehensive neuropsychological evaluation and multimodal brain MRI scan were performed. MRI markers for small vessel disease were visually rated or quantitatively analysed. Moreover, 52 patients were further evaluated with blood marker assays, including amyloid beta (Aβ), phosphorylated tau at threonine-181 (P-tau181), glial fibrillary acidic protein (GFAP), total tau (T-tau) and neurofilament light chain (NfL). There were no significant differences in demographics, disease duration or MRI markers of small vessel disease between the three groups. Compared with the Val/Val and Val/Met groups, the Met/Met group showed worse performance in the verbal fluency test and higher levels of plasma NfL. The rs6265 polymorphism of the BDNF gene is associated with semantic language fluency in patients with SIVD. The Met genotype may be a risk factor for cognitive impairment and neuronal injury.

Pursuing Dementia in People Living with HIV: Prevalence and Associated Factors

Introduction: The human immunodeficiency virus (HIV) is the leading cause of neurocognitive impairment in people over 40. The development of highly active antiretroviral therapy (HAART), the comprehension of disease pathogenesis, and the constant search for better life quality in people living with HIV have led to the HIV disease chronic evolution. Hence, it has been common to observe chronic diseases such as HIV-associated neurocognitive disorder (HAND). Unfortunately, the practitioner’s unfamiliarity with HAND screening and treatment has contributed to poor patient care. Methods: We evaluated 134 patients living with HIV and performed two tracking tests, the Mini-mental, which evaluates cortical dementia, and the International HIV Dementia Scale, which evaluates subcortical dementia. Results: We observed dementia associated with HIV (HAD) in 29 patients (prevalence of 21.6%; CI 95%: 15.0 – 29.6). The independent factors related to HAD in this study, with statistical significance, were age (RPaj 1.05; CI 1.00 – 1.09; p=0.033), TCD4+ nadir (RPaj 0.998; CI 95% 0.996 – 0.999; p=0.03), and more than two years of detectable HIV viral load (RPaj 2.35; CI 95% 1.27 – 4.33; p=0.006). Discussion: The prevalence of dementia related to HIV in our study was similar to the Brazilian and International data. Early diagnosis and treatment are fundamental for preventing HAND development, especially in older patients.

Method of differential diagnosis of mild cognitive impairment of various origins: cross sectional study

INTRODUCTION:The differential diagnosis of mild cognitive impairment (MCI), due to the high prevalence in the population and the rapid increase in incidence, is an urgent task. The most common causes leading to the development of cognitive impairment are Alzheimer’s disease (AD), cerebrovascular pathology, and their combination. AD usually manifests as an amnestic type of mild cognitive impairment (aMCI) at the pre-dementia stage. Subcortical vascular mild cognitive impairment (svMCI) is considered as the prodromal stage of subcortical vascular dementia. According to the results of pathomorphological studies, it was found that subfields of the hippocampal formation are selective vulnerability to AD, ischemia/hypoxia, and aging.Currently, using the FreeSurfer 6.0 software, it is possible to obtain quantitative indicators of the hippocampal formation subfieldsin vivo.The current trend in medicine is the development and implementation of new diagnostic solutions based on artificial intelligence and machine learning. One of the machine learning algorithms is binary logistic regression, which we used in the course of the study for the differential diagnosis of MCI of various origins.OBJECTIVE:To develop a method for the differential diagnosis of mil cognitive impairment of various origins.MATERIALS AND METHODS:The study included patients with the syndrome of mild cognitive impairment who were examined in the department of geriatric psychiatry of the V.M.Bekhterev National Medical Research Center for Psychiatry and Neurology, from which two groups were formed: group 1 — patients with aMCI, group 2 — patients with svMCI. Conditionally healthy volunteers, comparable in age, sex and level of education, made up the 3rdgroup (control). MRI examination was performed using a Excelart Vantage Atlas XGV magnetic resonance imaging system (Toshiba, Japan) with a magnetic field strength of 1.5 T, followed by MR morphometry of the subfields of the hippocampal formation.Statistics:Statistical analysis was carried out using data that was converted from a database in Microsoft Excel to the statistical package IBM SPSS 21. To develop a differential diagnosis method, based on the data obtained, the binary regression method and ROC analysis were used.RESULTS:Based on the obtained MR-morphometry data, a method was developed using the binary logistic regression equation. The value of p≥0.5 makes it possible to classify the patient to the aMCI group, and the value of p<0.5 — to the svMCI. The sensitivity of the method is 90%, the specificity is 80%, and the accuracy is 85%.DISCUSSION:Using binary logistic regression, the selection of variants of sets of variables (quantitative indicators) was carried out, for which ROC curves were constructed. The selection criterion was the area under the ROC curve — the AUC criterion (Area Under the Curve). The largest area under the curve (AUC=0.824) in the differential diagnosis of aMCI from svMCI was determined for the combination of the volume of the left subiculum and the thickness of the right entorhinal cortex.Since patients in the aMCI group have a significantly lower number of vascular foci than in the svMCI group (p<0.05), at the next stage, one more variable, the volume fraction, was added to the selected combination of two variables (volume of the left subiculum and thickness of the right entorhinal cortex) hypointense foci. When conducting an ROC analysis with a combination of three variables, an increase in AUC to 0.892 was noted. Further, using a combination of three variables and a binary logistic regression equation, a method for differential diagnosis of aMCI from svMCI was developed.CONCLUSION:The method of differential diagnosis based on binary logistic regression using MR morphometry data allows to distinguish patients with aMCI from patients with svMCI with high sensitivity and specificity.

Astragaloside IV ameliorates cognitive impairment and protects oligodendrocytes from antioxidative stress via regulation of the SIRT1/Nrf2 signaling pathway

Subcortical ischemic vascular dementia (SIVD), which is caused by chronic cerebral hypoperfusion, is a common subtype of vascular dementia, accompanied by white matter damage and cognitive impairment. Currently, there are no effective treatments for this condition. Oxidative stress is a key factor in the pathogenesis of white matter damage. Astragaloside IV (AS-IV), one of the main active components of astragaloside, has antioxidant properties and promotes cognitive improvement; however, its effect on SIVD and its potential mechanism remain unknown. We aimed to clarify whether AS-IV had a protective effect against SIVD injury caused by right unilateral common carotid artery occlusion and the underlying mechanism. The results showed that AS-IV treatment improved cognitive function and white matter damage, inhibited oxidative stress and glial cells activation, and promoted the survival of mature oligodendrocytes after chronic cerebral hypoperfusion. Moreover, the protein expression levels of NQO1, HO-1, SIRT1 and Nrf2 were increased by AS-IV treatment. However, pre-treatment with EX-527, a SIRT1-specific inhibitor, eliminated the beneficial effects of AS-IV. These results demonstrate that AS-IV plays a neuroprotective role in SIVD by suppressing oxidative stress and increasing the number of mature oligodendrocytes via the modulation of SIRT1/Nrf2 signaling. Our results support AS-IV as a potential therapeutic agent for SIVD.

The Importance of Neuro-Imaging in Patients with Symptomatic Presentation of Both Cortical and Subcortical Dementia

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A neuropsychological profile and its correlation with neuroimaging markers in patients with subcortical ischaemic vascular dementia.

Cognitive and neuroimaging assessments are still the main clinical practice methods for screening and diagnosing vascular dementia (VaD) patients. This study aimed to establish the neuropsychological characteristics of mild-to-moderate subcortical ischaemic vascular dementia (SIVD) patients, find an optimal cognitive marker for differentiating them from Alzheimer's disease (AD) patients, and explore the correlation between cognitive function and total small vessel disease (SVD) burden. SIVD (n=60) and AD (n=30) patients and cognitively unimpaired healthy controls (HCs; n=30) were recruited from our longitudinal MRI AD and SIVD study (ChiCTR1900027943) and received a comprehensive neuropsychological assessment and a multimodal MRI scan. Cognitive performance and MRI SVD markers were compared between groups. Combined cognitive scores were established for differentiating between SIVD and AD patients. Correlations between cognitive function and total SVD scores were analysed in dementia patients. SIVD patients showed poorer performance in information processing speed and better performance in memory, language, and visuospatial function than AD patients, although all cognitive domains were impaired in both groups compared with HCs. Combined cognitive scores showed an area under the curve of 0.727 (95%CI 0.62-0.84, p<0.001) for differentiating SIVD and AD patients. Auditory Verbal Learning Test recognition scores were negatively correlated with total SVD scores in SIVD patients. Our results suggested that neuropsychological assessments, specifically combined tests including episodic memory, information processing speed, language and visuospatial ability, are useful in the clinical differentiation between SIVD and AD patients. Moreover, cognitive dysfunction was partly correlated with MRI SVD burden in SIVD patients.

Otras formas de demencia: demencia vascular, demencia con cuerpos de Lewy y demencia frontotemporal

Vascular dementia is the second cause of dementia after Alzheimer's disease. It is a heterogeneous entity with highly variable symptoms based on the location of vascular damage and the type of vessel affected. It is classified as multi-infarct dementia, subcortical dementia, and strategic infarct dementia. Lewy body dementia is the second most common degenerative dementia and is characterized by cognitive impairment with parkinsonism that does not respond well to treatment, fluctuations in level of consciousness and cognition, hallucinations, and hypersensitivity to neuroleptics. Frontotemporal dementia is most common in those younger than 60 years. The behavioral variant is the most frequent and is characterized by inappropriate social behavior, lack of inhibition, personality disorder, apathy, and eating disorders. The second group comprises progressive primary aphasia which, in turn, has a nonfluent variant and a semantic variant. Lastly, included in the group of frontotemporal dementia is progressive supranuclear paralysis and corticobasal degeneration, given that together with parkinsonism, they tend to entail cognitive disorder in the behavioral variant or primary progressive aphasia.

Fo-Shou-San Ameliorates Chronic Cerebral Hypoperfusion-Induced Cognitive Impairment in Mice by Regulating NRF2/HO-1 Pathway Against Ferroptosis

Fo-Shou-San (FSS) is a traditional Chinese medicine (TCM) decoction that can effectively treat vascular dementia (VD). In the face of unclear pharmacological mechanisms, we set out to validate that FSS treats chronic cerebral hypoperfusion (CCH)-induced cognitive impairment in mice. CCH animal model caused by permanent right unilateral common carotid arteries occlusion (rUCCAO) was established to verify that FSS could treat subcortical ischemic vascular dementia (SIVD). We performed novel object recognition test and Morris water maze test, observed morphological changes via HE and Nissl staining, and detected hippocampus apoptosis by TUNEL staining and oxidative stress by biochemical assays. Ferroptosis-related markers and NRF2/HO-1 signaling-related expressions were examined via qPCR and immunofluorescence staining. We found that FSS ameliorated cognitive disorders, and lessened oxidative stress by decreasing MDA and GSH-PX while increasing the reduced glutathione (GSH)/oxidized glutathione disulfide (GSSG) ratio, which are associated with ferroptosis. Additionally, FSS reduced expression of SLC7A11, GPX4, ROX and 4HNE, as vital markers of ferroptosis. Further, FSS regulated NRF2/HO-1 signaling by downregulating NRF2 and HO-1. Our study suggests that FSS may ameliorate chronic cerebral hypoperfusion-induced cognitive deficits through regulation of the NRF2/HO-1 pathway against ferroptosis. Taken together, our study highlights the neuroprotective efficacy of FSS.