Hippocampus under Pressure: Molecular Mechanisms of Development of Cognitive Impairments in SHR Rats.

Data from clinical trials and animal experiments demonstrate relationship between chronic hypertension and development of cognitive impairments. Here, we review structural and biochemical alterations in the hippocampus of SHR rats with genetic hypertension, which are used as a model of essential hypertension and vascular dementia. In addition to hypertension, dysfunction of the hypothalamic-pituitary-adrenal system observed in SHR rats already at an early age may be a key factor of changes in the hippocampus at the structural and molecular levels. Global changes at the body level, such as hypertension and neurohumoral dysfunction, are associated with the development of vascular pathology and impairment of the blood-brain barrier. Changes in multiple biochemical glucocorticoid-dependent processes in the hippocampus, including dysfunction of steroid hormones receptors, impairments of neurotransmitter systems, BDNF deficiency, oxidative stress, and neuroinflammation are accompanied by the structural alterations, such as cellular signs of neuroinflammation micro- and astrogliosis, impairments of neurogenesis in the subgranular neurogenic zone, and neurodegenerative processes at the level of synapses, axons, and dendrites up to the death of neurons. The consequence of this is dysfunction of hippocampus, a key structure of the limbic system necessary for cognitive functions. Taking into account the available results at various levels starting from the body and brain structure (hippocampus) levels to molecular one, we can confirm translational validity of SHR rats for modeling mechanisms of vascular dementia.

Cognitive trajectories preluding the onset of different dementia entities: a descriptive longitudinal study using the NACC database.

OBJECTIVE: To describe the 10-year preclinical cognitive trajectories of older, non-demented individuals towards the onset of the four most prevalent types of dementia, i.e., Alzheimer's disease(AD), Lewy body(LBD), vascular(VD) and frontotemporal dementia(FTD). METHODS: Our analysis focused on data from older (≥ 60years) NACC (National Alzheimer's Coordinating Center) participants. Four distinct presymptomatic dementia groups (AD-LBD-VD-FTD) and a comparison group of cognitively unimpaired(CU) participants were formed. Comprehensive cognitive assessments involving verbal episodic memory, semantic verbal fluency, confrontation naming, mental processing speed - attention and executive function - cognitive flexibility were conducted at baseline and on an approximately yearly basis. Descriptive analyses (adjusted general linear models) were performed to determine and compare the yearly cognitive scores of each group throughout the follow-up. Exploratory analyses were conducted to estimate the rates of cognitive decline. RESULTS: There were 3343 participants who developed AD, 247 LBD, 108 FTD, 155 VD and 3398 composed the CU group. Participants with AD performed worse on episodic memory than those with VD and LBD for about 3 to 4 years prior to dementia onset (the FTD group documented an intermediate course). Presymptomatic verbal fluency and confrontation naming trajectories differentiated quite well between the FTD group and the remaining dementia entities. Participants with incident LBD and VD performed worse than those with AD on executive functions and mental processing speed-attention since about 5 years prior to the onset of dementia, and worse than those with FTD more proximally to the diagnosis of the disorder. CONCLUSIONS: Heterogeneous cognitive trajectories characterize the presymptomatic courses of the most prevalent dementia entities.

The low and high doses administration of lutein improves memory and synaptic plasticity impairment through different mechanisms in a rat model of vascular dementia.

BACKGROUND AND AIM: Vascular dementia (VD) is a common type of dementia. This study aimed to evaluate the effects of low and high doses of lutein administration in bilateral-carotid vessel occlusion (2VO) rats. EXPERIMENTAL PROCEDURE: The rats were divided into the following groups: the control, sham-, vehicle (2VO+V) groups, and two groups after 2VO were treated with lutein 0.5 (2VO+LUT-o.5) and 5mg/kg (2VO+LUT-5). The passive-avoidance and Morris water maze were performed to examine fear and spatial memory. The field-potential recording was used to investigate the properties of basal synaptic transmission (BST), paired-pulse ratio (PPR), as an index for measurement of neurotransmitter release, and long-term potentiation (LTP). The hippocampus was removed to evaluate hippocampal cells, volume, and MDA level. RESULT: Treatment with low and high doses improves spatial memory and LTP impairment in VD rats, but only the high dose restores the fear memory, hippocampal cell loss, and volume and MDA level. Interestingly, low-dose, but not high-dose, increased PPR. However, BST recovered only in the high-dose treated group. CONCLUSIONS: Treatment with a low dose might affect neurotransmitter release probability, but a high dose affects postsynaptic processes. It seems likely that low and high doses improve memory and LTP through different mechanisms.

[Comparative characteristics of neuropsychological and neurometabolic changes in patients with Alzheimer's disease and vascular cognitive impairment]. / Sravnitel'naya kharakteristika neiropsikhologicheskikh i neirometabolicheskikh pokazatelei u patsientov s bolezn'yu Al'tsgeimera i sosudistymi kognitivnymi rasstroistvami.

OBJECTIVE: To investigate the pattern and connections of neuropsychological and metabolic indices in patients with cognitive disorders of Alzheimer's and vascular (subcortical-cortical) types of different severity. MATERIAL AND METHODS: A total of 177 patients were examined, including 85 patients with Alzheimer's disease (AD) and 92 patients with vascular cognitive impairment (VCI). All patients underwent complex neuropsychological examination; 18F-FDG PET was performed in 17 patients with AD and 15 patients with VCI. RESULTS: The greatest changes in patients with AD were noted in the mnestic sphere, and the indicators significantly differed from the results of the study of patients with VCI already at the pre-dementia stage. Neurodynamic and dysregulatory disorders prevailed in patients with VCI. Patients with AD showed bilateral symmetrical reduction of metabolic activity in the cortex of parietal and temporal lobes, often in combination with marked hypometabolism in the hippocampal region. In patients with VCI, there were areas of decreased brain tissue metabolism of different localization and size, mainly in the projection of the basal ganglia and in the prefrontal and parietal cortex, as well as in the cingulate gyrus, which indirectly confirms the mechanism of disconnection of subcortical and cortical structures. In AD, impaired metabolic activity in the hippocampal region correlated with impaired temporal and spatial orientation (ρ=-0.54, p<0.05), memory impairment (ρ=-0.71, p<0.005). Hypometabolism of the parietal lobe cortex was associated with total MMSE score (ρ=-0.8, p<0.001), 10-word test (ρ=-0.89, p<0.001 and ρ=-0.82, p<0.001), visual-spatial impairment (ρ=-0.64, p<0.01), categorical association test (ρ=-0.73, p<0.005). In patients with VCI, dysregulatory disorders correlated with hypometabolism in the thalamic projection (ρ=-0.56, p<0.05), prefrontal cortex (ρ=-0.64, p<0.05) and in the cingulate gyrus (anterior regions) (ρ=-0.53, p<0.05). CONCLUSION: The results indicate the presence of differences in cognitive impairment and cerebral metabolism in patients with AD and VCI.

Modulation of the Circadian Rhythm and Oxidative Stress as Molecular Targets to Improve Vascular Dementia: A Pharmacological Perspective.

The circadian rhythms generated by the master biological clock located in the brain's hypothalamus influence central physiological processes. At the molecular level, a core set of clock genes interact to form transcription-translation feedback loops that provide the molecular basis of the circadian rhythm. In animal models of disease, a desynchronization of clock genes in peripheral tissues with the central master clock has been detected. Interestingly, patients with vascular dementia have sleep disorders and irregular sleep patterns. These alterations in circadian rhythms impact hormonal levels, cardiovascular health (including blood pressure regulation and blood vessel function), and the pattern of expression and activity of antioxidant enzymes. Additionally, oxidative stress in vascular dementia can arise from ischemia-reperfusion injury, amyloid-beta production, the abnormal phosphorylation of tau protein, and alterations in neurotransmitters, among others. Several signaling pathways are involved in the pathogenesis of vascular dementia. While the precise mechanisms linking circadian rhythms and vascular dementia are still being studied, there is evidence to suggest that maintaining healthy sleep patterns and supporting proper circadian rhythm function may be important for reducing the risk of vascular dementia. Here, we reviewed the main mechanisms of action of molecular targets related to the circadian cycle and oxidative stress in vascular dementia.

Deciphering mitochondrial dysfunction: Pathophysiological mechanisms in vascular cognitive impairment.

Vascular cognitive impairment (VCI) encompasses a range of cognitive deficits arising from vascular pathology. The pathophysiological mechanisms underlying VCI remain incompletely understood; however, chronic cerebral hypoperfusion (CCH) is widely acknowledged as a principal pathological contributor. Mitochondria, crucial for cellular energy production and intracellular signaling, can lead to numerous neurological impairments when dysfunctional. Recent evidence indicates that mitochondrial dysfunction-marked by oxidative stress, disturbed calcium homeostasis, compromised mitophagy, and anomalies in mitochondrial dynamics-plays a pivotal role in VCI pathogenesis. This review offers a detailed examination of the latest insights into mitochondrial dysfunction within the VCI context, focusing on both the origins and consequences of compromised mitochondrial health. It aims to lay a robust scientific groundwork for guiding the development and refinement of mitochondrial-targeted interventions for VCI.

Montelukast Ameliorates 2K1C-Hypertension Induced Endothelial Dysfunction and Associated Vascular Dementia.

BACKGROUND: Declined kidney function associated with hypertension is a danger for cognitive deficits, dementia, and brain injury. Cognitive decline and vascular dementia (VaD) are serious public health concerns, which highlights the urgent need for study on the risk factors for cognitive decline. Cysteinyl leukotriene (CysLT1) receptors are concerned with regulating cognition, motivation, inflammatory processes, and neurogenesis. OBJECTIVE: This research aims to examine the consequence of montelukast (specific CysLT1 antagonist) in renovascular hypertension 2-kidney-1-clip-2K1C model-triggered VaD in experimental animals. METHODS: 2K1C tactics were made to prompt renovascular hypertension in mature male rats. Morris water maze was employed to measure cognition. Mean arterial pressure (MAP), serum nitrite levels, aortic superoxide content, vascular endothelial activity, brain's oxidative stress (diminished glutathione, raised lipid peroxides), inflammatory markers (IL-10, IL-6, TNF-α), cholinergic activity (raised acetylcholinesterase), and cerebral injury (staining of 2, 3, 5- triphenylterazolium chloride) were also examined. RESULTS: Montelukast in doses of 5.0 and 10.0 mg kg-1 was used intraperitoneally as the treatment drug. Along with cognitive deficits, 2K1C-operated rats showed elevated MAP, endothelial dysfunction, brain oxidative stress, inflammation, and cerebral damage with diminished serum nitrite/nitrate. Montelukast therapy significantly and dose-dependently mitigated the 2K1Chypertension- provoked impaired behaviors, biochemistry, endothelial functions, and cerebral infarction. CONCLUSION: The 2K1C tactic caused renovascular hypertension and associated VaD, which was mitigated via targeted regulation of CysLT1 receptors by montelukast administration. Therefore, montelukast may be taken into consideration for the evaluation of its complete potential in renovascular-hypertension-induced VaD.

Age of Symptom Onset and Longitudinal Course of Sporadic Alzheimer's Disease, Frontotemporal Dementia, and Vascular Dementia: A Systematic Review and Meta-Analysis.

BACKGROUND: Understanding how the age of dementia symptom onset affects the longitudinal course of dementia can assist with prognosis and care planning. OBJECTIVE: To synthesize evidence regarding the relationship of age of symptom onset with the longitudinal course of sporadic Alzheimer's disease (AD), vascular dementia (VaD), and frontotemporal dementia (FTD). METHODS: We searched Medline, CINAHL, Embase, PsycINFO, PubMed, and Scopus for longitudinal studies that examined the impact of sporadic AD, VaD, or FTD symptom onset age on measures of cognition, function, or behavioral symptoms. Studies that examined age at diagnosis only were excluded. Quantitative meta-analysis was conducted where studies reported sufficient data for pooling. RESULTS: Thirty studies met all inclusion criteria (people with AD (n = 26), FTD (n = 4)) though no studies examined VaD. Earlier onset of AD was associated with more rapid annual cognitive decline (estimate = -0.07; 95% CI -0.14 to 0.00; p = 0.045). Most studies that stratified their sample reported that younger AD onset (usually < 65 years) was associated with more rapid cognitive decline. Other evidence was inconclusive. CONCLUSION: Younger people with AD appear to have a poorer prognosis in terms of faster cognitive decline than older people with AD. More research is required to determine the impact of symptom onset age in VaD and FTD, and on functional decline in all dementias.

Blood Pressure Levels and Risks of Dementia: a Nationwide Study of 4.5 Million People.

There are inconsistent results on the impacts of controlling blood pressure (BP) on the risk of dementia. We investigated the association between BP and risk of dementia subtypes by antihypertensive treatment and comorbidities. Using the Korean National Health Insurance Service-Health Screening Database from 2009 to 2012, a total of 4 522 447 adults aged 60+ years without a history of dementia were analyzed and followed up for a mean of 5.4 years. Individuals were classified according to their baseline systolic BP (SBP) and diastolic BP; SBP 130 to <140 mm Hg and diastolic BP 80 to <90 mm Hg were used as reference groups. The risk of overall dementia and probable Alzheimer disease was significantly higher in the SBP≥160 and lower SBP groups. These U-shaped associations were consistent regardless of antihypertensive use or comorbidities. The risk of probable vascular dementia (VaD) was not higher among lower SBP groups and increased gradually as SBP increased. Although there was a linear association between SBP and the risk of probable VaD in individuals not taking antihypertensives or without comorbidities, there was a U-shaped association in individuals taking antihypertensives or with comorbidities. Patterns of association between diastolic BP and risk of probable Alzheimer disease or probable VaD were similar to those with SBP, except for the risk of probable VaD in individuals taking antihypertensives. In conclusion, risks of probable Alzheimer disease and probable VaD were different among lower BP groups. Although the risk of dementia appears higher in people with lower BP receiving antihypertensives, this finding may be affected by comorbidities.

The neuroprotective properties and therapeutic potential of epidermal neural crest stem cells transplantation in a rat model of vascular dementia.

INTRODUCTION: The incidence rate of senile dementia is rising, and there is no definite cure for it yet. Cell therapy, as a new investigational approach, has shown promising results. Hair bulges with abundant easily accessible neural stem cells permit autologous implantation in irreversible neurodegenerative disorders. METHODS: Fifty rats were randomly divided into 5 groups of control, sham-operation, two-common carotid vessel-occlusion rats that received vehicle (2VO + V), 2VO rats that received 1 × 106 epidermal stem cells (2VO + ESC1), and 2VO rats that received 2.5 × 106 epidermal stem cells (2VO + ESC2) in 300 µl PBS intravenously on days 4, 9, and 14 after surgery. The epidermal neural crest stem cells (EPI-NCSCs) were isolated from hair follicles of rat whiskers. The open-field, passive avoidance, and Morris water maze were used as behavioral tests. The basal-synaptic transmission, long-term potentiation (LTP), and short-term synaptic plasticity were evaluated by field-potential recording of the CA1 hippocampal area. RESULTS: 30 days after the first transplantation in the 2VO + ESC1 group, functional recovery was prominent in anxiety and fear memory compared to the 2VO + ESC2 group, while LTP induction was recovered in both groups of grafted animals without improvement in basal synaptic transmission. These positive recoveries may be related to the release of different neurotrophic factors from grafted cells that can stimulate endogenous neurogenesis and synaptic plasticity. CONCLUSIONS: Our results showed that EPI-NCSCs implantation could rescue LTP and cognitive disability in 2VO rats, while transplantation of 1 million cells showed better performance relative to 2.5 million cells.

Chronic Renin-Angiotensin System Activation Induced Neuroinflammation: Common Mechanisms Underlying Hypertension and Dementia?

Hypertension is a major risk factor for the pathogenesis of vascular dementia and Alzheimer's disease. Chronic activation of the renin-angiotensin system (RAS) contributes substantially to neuroinflammation. We propose that neuroinflammation arising from chronic RAS activation can initiate and potentiate the onset of hypertension and related dementia. Neuroinflammation induced by chronic activation of the RAS plays a key role in the pathogenesis of dementia. Increased levels of pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and transforming growth factor (TGF)-ß have been reported in brain tissue of vascular dementia patients and animal models of vascular dementia induced by either angiotensin II infusion or transverse aortic coarctation. It is proposed that neuronal cell death and synaptic dysfunction induced by neuroinflammation lead to cognitive impairment in dementia. The neuroprotective RAS pathway, regulated by angiotensin-converting enzyme 2 (ACE2) which converts angiotensin II into angiotensin-(1-7), can attenuate hypertension and dementia. Furthermore, the use of anti-hypertensive medications in preventing dementia or cognitive decline in hypertensive patients and animal models of dementia have mostly been beneficial. Current evidence suggests a strong link between RAS induced neuroinflammation and the onset of hypertension and dementia, which warrants further investigation. Strategies to counteract an overactive RAS and enhance the neuroprotective arm of the RAS may help prevent or improve cognitive impairment associated with hypertension.

DL-3-n-butylphthalide suppressed autophagy and promoted angiogenesis in rats with vascular dementia by activating the Shh/Ptch1 signaling pathway.

DL-3-n-butylphthalide (NBP) has neuroprotective effect on chronic cerebral hypoperfusion animals. Here, we explored the role and underlying mechanism of NBP on autophagy and angiogenesis in rats with vascular dementia (VD). Adult male Sprague-Dawley (SD) rats were subjected to permanent bilateral occlusion of the common carotid arteries (2VO) to establish VD model. These rats were randomly divided into five groups: sham, model, NBP120 (120 mg/kg), Shh siRNA (50 nM), and NBP120 + Shh siRNA groups. Our results showed that NBP treatment attenuated memory damage in rats with VD, as demonstrated by Morris water maze tests. Immunofluorescence (IF) assay revealed that NBP induced neuronal process length and neuronal activity in hippocampus, which were reversed by Shh silencing. Furthermore, NBP treatment also reduced the expression of autophagy marker proteins B-cell lymphoma-2 interacting protein 1 (Beclin 1) and microtubule-associated protein 1 light chain 3 (LC3), which were further enhanced by Shh silencing. Meanwhile, NBP promoted the angiogenesis, which was accompanied by upregulated vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF)-1, and Angiopoietin (Ang) expression in the hippocampus. And Shh siRNA co-treatment blocked the angiogenesis induced by NBP. Altogether, our results established that NBP treatment suppressed autophagy and improved angiogenesis and neurobehavioral recovery in VD rats partly by activating the Shh/Ptch1 signaling pathway.

Differential restoration of functional hyperemia by antihypertensive drug classes in hypertension-related cerebral small vessel disease.

Dementia resulting from small vessel diseases (SVDs) of the brain is an emerging epidemic for which there is no treatment. Hypertension is the major risk factor for SVDs, but how hypertension damages the brain microcirculation is unclear. Here, we show that chronic hypertension in a mouse model progressively disrupts on-demand delivery of blood to metabolically active areas of the brain (functional hyperemia) through diminished activity of the capillary endothelial cell inward-rectifier potassium channel, Kir2.1. Despite similar efficacy in reducing blood pressure, amlodipine, a voltage-dependent calcium-channel blocker, prevented hypertension-related damage to functional hyperemia whereas losartan, an angiotensin II type 1 receptor blocker, did not. We attribute this drug class effect to losartan-induced aldosterone breakthrough, a phenomenon triggered by pharmacological interruption of the renin-angiotensin pathway leading to elevated plasma aldosterone levels. This hypothesis is supported by the finding that combining losartan with the aldosterone receptor antagonist eplerenone prevented the hypertension-related decline in functional hyperemia. Collectively, these data suggest Kir2.1 as a possible therapeutic target in vascular dementia and indicate that concurrent mineralocorticoid aldosterone receptor blockade may aid in protecting against late-life cognitive decline in hypertensive patients treated with angiotensin II type 1 receptor blockers.

Vascular contributions to cognitive impairment and dementia: the emerging role of 20-HETE.

The accumulation of extracellular amyloid-ß (Aß) and intracellular hyperphosphorylated τ proteins in the brain are the hallmarks of Alzheimer's disease (AD). Much of the research into the pathogenesis of AD has focused on the amyloid or τ hypothesis. These hypotheses propose that Aß or τ aggregation is the inciting event in AD that leads to downstream neurodegeneration, inflammation, brain atrophy and cognitive impairment. Multiple drugs have been developed and are effective in preventing the accumulation and/or clearing of Aß or τ proteins. However, clinical trials examining these therapeutic agents have failed to show efficacy in preventing or slowing the progression of the disease. Thus, there is a need for fresh perspectives and the evaluation of alternative therapeutic targets in this field. Epidemiology studies have revealed significant overlap between cardiovascular and cerebrovascular risk factors such as hypertension, diabetes, atherosclerosis and stroke to the development of cognitive impairment. This strong correlation has given birth to a renewed focus on vascular contributions to AD and related dementias. However, few genes and mechanisms have been identified. 20-Hydroxyeicosatetraenoic acid (20-HETE) is a potent vasoconstrictor that plays a complex role in hypertension, autoregulation of cerebral blood flow and blood-brain barrier (BBB) integrity. Multiple human genome-wide association studies have linked mutations in the cytochrome P450 (CYP) 4A (CYP4A) genes that produce 20-HETE to hypertension and stroke. Most recently, genetic variants in the enzymes that produce 20-HETE have also been linked to AD in human population studies. This review examines the emerging role of 20-HETE in AD and related dementias.

Revealing the Influences of Sex Hormones and Sex Differences in Atrial Fibrillation and Vascular Cognitive Impairment.

The impacts of sex differences on the biology of various organ systems and the influences of sex hormones on modulating health and disease have become increasingly relevant in clinical and biomedical research. A growing body of evidence has recently suggested fundamental sex differences in cardiovascular and cognitive function, including anatomy, pathophysiology, incidence and age of disease onset, symptoms affecting disease diagnosis, disease severity, progression, and treatment responses and outcomes. Atrial fibrillation (AF) is currently recognized as the most prevalent sustained arrhythmia and might contribute to the pathogenesis and progression of vascular cognitive impairment (VCI), including a range of cognitive deficits, from mild cognitive impairment to dementia. In this review, we describe sex-based differences and sex hormone functions in the physiology of the brain and vasculature and the pathophysiology of disorders therein, with special emphasis on AF and VCI. Deciphering how sex hormones and their receptor signaling (estrogen and androgen receptors) potentially impact on sex differences could help to reveal disease links between AF and VCI and identify therapeutic targets that may lead to potentially novel therapeutic interventions early in the disease course of AF and VCI.

Prevalence and incidence of possible vascular dementia among Mexican older adults: Analysis of the Mexican Health and Aging Study.

INTRODUCTION: Vascular dementia is the second most common cause of dementia. Physical disability and cognitive impairment due to stroke are conditions that considerably affect quality of life. We estimated the prevalence and incidence of possible vascular dementia (PVD) in older adults using data from the Mexican Health and Aging Study (MHAS 2012 and 2015 waves). METHODS: The MHAS is a representative longitudinal cohort study of Mexican adults aged ≥50 years. Data from 14, 893 participants from the 2012 cohort and 14,154 from the 2015 cohort were analyzed to estimate the prevalence and incidence of PVD. Self-respondents with history of stroke were classified as PVD if scores in two or more cognitive domains in the Cross-Cultural Cognitive Examination were ≥ 1.5 standard deviations below the mean on reference norms and if limitations in ≥ 1 instrumental activities of daily living were present. For proxy respondents with history of stroke, we used a score ≥3.4 on the Informant Questionnaire on Cognitive Decline in the Elderly. Crude and standardized rates of prevalent and incident PVD were estimated. RESULTS: Prevalence of PVD was 0.6% (95% CI, 0.5-0.8) (0.5 with age and sex- standardization). Rates increased with age reaching 2.0% among those aged 80 and older and decreased with educational attainment. After 3.0 years of follow-up, 87 new cases of PVD represented an overall incident rate of 2.2 (95% CI, 1.7-2.6) per 1,000 person-years (2.0 with age and sex- standardization). Incidence also increased with advancing age reaching an overall rate of 9.4 (95% CI, 6.3-13.6) per 1,000 person-years for participants aged >80 years. Hypertension and depressive symptoms were strong predictors of incident PVD. CONCLUSION: These data provide new estimates of PVD prevalence and incidence in the Mexican population. We found that PVD incidence increased with age. Males aged 80 years or older showed a greater incidence rate when compared to females, which is comparable to previous estimates from other studies.

Autophagy in vascular dementia and natural products with autophagy regulating activity.

Chronic Cerebral Hypoperfusion(CCH)-induced vascular dementia(VD) is a common neurodegenerative disease which seriously affects the patient's quality of life. Therefore, it is critical to find an effective treatment of VD. Autophagy is a natural regulated mechanism that can remove dysfunctional proteins and organelles, however, over-activation or under-activation can of autophagy can induce the apoptosis of cells. Although autophagy plays a role in the central nervous system is unquestionable, the effects of autophagy in the ischemic brain are still controversial. Some autophagy regulators have been tested, suggesting that both activation and inhibition of autophagy can improve the cognitive function. This article reviews the role of autophagy in CCH-induced VD to discuss whether autophagy has the potential to become a target for drug development and provides several potential compounds for treating vascular dementia.

Cerebrospinal Fluid Sulfatide Levels Lack Diagnostic Utility in the Subcortical Small Vessel Type of Dementia.

BACKGROUND: Sulfatides (STs) in cerebrospinal fluid (CSF), as well as magnetic resonance imaging (MRI)-detected white matter hyperintensities (WMHs), may reflect demyelination. Here, we investigated the diagnostic utility of CSF ST levels in the subcortical small vessel type of dementia (SSVD), which is characterized by the presence of brain WMHs. OBJECTIVE: To study the diagnostic utility of CSF ST levels in SSVD. METHODS: This was a mono-center, cross-sectional study of SSVD (n = 16), Alzheimer's disease (n = 40), mixed dementia (n = 27), and healthy controls (n = 33). Totally, 20 ST species were measured in CSF by liquid chromatography-mass spectrometry (LC-MS/MS). RESULTS: CSF total ST levels, as well as CSF levels of hydroxylated and nonhydroxylated ST species, did not differ across the study groups. In contrast, CSF neurofilament light chain (NFL) levels separated the patient groups from the controls. CSF total ST level correlated with CSF/serum albumin ratio in the total study population (r = 0.64, p < 0.001) and in all individual study groups. Furthermore, CSF total ST level correlated positively with MRI-estimated WMH volume in the total study population (r = 0.30, p < 0.05), but it did not correlate with CSF NFL level. CONCLUSION: Although there was some relation between CSF total ST level and WMH volume, CSF ST levels were unaltered in all dementia groups compared to the controls. This suggests that CSF total ST level is a poor biomarker of demyelination in SSVD. Further studies are needed to investigate the mechanisms underlying the marked correlation between CSF total ST level and CSF/serum albumin ratio.

Contribution of Graph Theory Applied to EEG Data Analysis for Alzheimer's Disease Versus Vascular Dementia Diagnosis.

BACKGROUND: Most common progressive brain diseases in the elderly are Alzheimer's disease (AD) and vascular dementia (VaD). They present with relatively similar clinical symptoms of cognitive decline, but the underlying pathophysiological mechanisms are different. OBJECTIVE: The aim is to explore the brain connectivity differences between AD and VaD patients compared to mild cognitive impairment (MCI) and normal elderly (Nold) subjects applying graph theory, in particular the Small World (SW) analysis. METHODS: 274 resting state EEGs were analyzed in 100 AD, 80 MCI, 40 VaD, and 54 Nold subjects. Graph theory analyses were applied to undirected and weighted networks obtained by lagged linear coherence evaluated by eLORETA tool. RESULTS: VaD and AD patients presented more ordered low frequency structure (lower value of SW) than Nold and MCI subjects, and more random organization (higher value of SW) in low and high frequency alpha rhythms. Differences between patients have been found in high frequency alpha rhythms in VaD (higher value of SW) with respect to AD, and in theta band with a trend which is more similar to MCI and Nold than to AD. MCI subjects presented a network organization which is intermediate, in low frequency bands, between Nold and patients. CONCLUSION: Graph theory applied to EEG data has proved very useful in identifying differences in brain network patterns in subjects with dementia, proving to be a valid tool for differential diagnosis. Future studies will aim to validate this method to diagnose especially in the early stages of the disease and at single subject level.