Diagnosing vascular cognitive impairment: Current challenges and future perspectives.

Cerebrovascular disease is a major cause of cognitive decline and dementia. This is referred to as vascular cognitive impairment (VCI). Diagnosing VCI is important, among others to optimize treatment to prevent further vascular injury. This narrative review addresses challenges in current diagnostic approaches to VCI and potential future developments. First we summarize how diagnostic criteria for VCI evolved over time. We then highlight challenges in diagnosing VCI in clinical practice: assessment of severity of vascular brain injury on brain imaging is often imprecise and the relation between vascular lesion burden and cognitive functioning shows high intersubject variability. This can make it difficult to establish causality in individual patients. Moreover, because VCI is essentially an umbrella term, it lacks specificity on disease mechanisms, prognosis, and treatment. We see the need for a fundamentally different approach to diagnosing VCI, which should be more dimensional, including multimodal quantitative assessment of injury, with more accurate estimation of cognitive impact, and include biological definitions of disease that can support further development of targeted treatment. Recent developments in the field that can form the basis of such an approach are discussed.

White matter damage as a consequence of vascular dysfunction in a spontaneous mouse model of chronic mild chronic hypoperfusion with eNOS deficiency.

Vascular cognitive impairment and dementia (VCID) is the second most common form of dementia after Alzheimer's disease (AD). Currently, the mechanistic insights into the evolution and progression of VCID remain elusive. White matter change represents an invariant feature. Compelling clinical neuroimaging and pathological evidence suggest a link between white matter changes and neurodegeneration. Our prior study detected hypoperfused lesions in mice with partial deficiency of endothelial nitric oxide (eNOS) at very young age, precisely matching to those hypoperfused areas identified in preclinical AD patients. White matter tracts are particularly susceptible to the vascular damage induced by chronic hypoperfusion. Using immunohistochemistry, we detected severe demyelination in the middle-aged eNOS-deficient mice. The demyelinated areas were confined to cortical and subcortical areas including the corpus callosum and hippocampus. The intensity of demyelination correlated with behavioral deficits of gait and associative recognition memory performances. By Evans blue angiography, we detected blood-brain barrier (BBB) leakage as another early pathological change affecting frontal and parietal cortex in eNOS-deficient mice. Sodium nitrate fortified drinking water provided to young and middle-aged eNOS-deficient mice completely prevented non-perfusion, BBB leakage, and white matter pathology, indicating that impaired endothelium-derived NO signaling may have caused these pathological events. Furthermore, genome-wide transcriptomic analysis revealed altered gene clusters most related to mitochondrial respiratory pathways selectively in the white matter of young eNOS-deficient mice. Using eNOS-deficient mice, we identified BBB breakdown and hypoperfusion as the two earliest pathological events, resulting from insufficient vascular NO signaling. We speculate that the compromised BBB and mild chronic hypoperfusion trigger vascular damage, along with oxidative stress and astrogliosis, accounting for the white matter pathological changes in the eNOS-deficient mouse model. We conclude that eNOS-deficient mice represent an ideal spontaneous evolving model for studying the earliest events leading to white matter changes, which will be instrumental to future therapeutic testing of drug candidates and for targeting novel/specific vascular mechanisms contributing to VCID and AD.

Vascular contributions to cognitive impairment/dementia in diabetes: role of endothelial cells and pericytes.

Vascular contributions to cognitive impairment/dementia (VCID) are a leading cause of dementia, a known neurodegenerative disorder characterized by progressive cognitive decline. Although diabetes increases the risks of stroke and the development of cerebrovascular disease, the cellular and vascular mechanisms that lead to VCID in diabetes are yet to be determined. A growing body of research has identified that cerebrovascular cells within the neurovascular complex display an array of cellular responses that impact their survival and reparative properties, which plays a significant role in VCID development. Specifically, endothelial cells and pericytes are the primary cell types that have gained much attention in dementia-related studies due to their molecular and phenotypic heterogeneity. In this review, we will discuss the various morphological subclasses of endothelial cells and pericytes as well as their relative distribution throughout the cerebrovasculature. Furthermore, the use of diabetic and stroke animal models in preclinical studies has provided more insight into the impact of sex differences on cerebral vascularization in progressive VCID. Understanding how cellular responses and sex differences contribute to endothelial cell and pericyte survival and function will set the stage for the development of potential preventive therapies for dementia-related disorders in diabetes.

Behavioral and Psychological Symptoms of Dementia in Different Dementia Disorders: A Large-Scale Study of 10,000 Individuals.

BACKGROUND: The majority of individuals with dementia will suffer from behavioral and psychological symptoms of dementia (BPSD). These symptoms contribute to functional impairment and caregiver burden. OBJECTIVE: To characterize BPSD in Alzheimer's disease (AD), vascular dementia (VaD), mixed (Mixed) dementia, Parkinson's disease dementia (PDD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and unspecified dementia in individuals residing in long-term care facilities. METHODS: We included 10,405 individuals with dementia living in long-term care facilities from the Swedish registry for cognitive/dementia disorders (SveDem) and the Swedish BPSD registry. BPSD was assessed with the Neuropsychiatric Inventory - Nursing Home Version (NPI-NH). Multivariate logistic regression models were used to evaluate the associations between dementia diagnoses and different BPSDs. RESULTS: The most common symptoms were aberrant motor behavior, agitation, and irritability. Compared to AD, we found a lower risk of delusions (in FTD, unspecified dementia), hallucinations (FTD), agitation (VaD, PDD, unspecified dementia), elation/euphoria (DLB), anxiety (Mixed, VaD, unspecified dementia), disinhibition (in PDD), irritability (in DLB, FTD, unspecified dementia), aberrant motor behavior (Mixed, VaD, unspecified dementia), and sleep and night-time behavior changes (unspecified dementia). Higher risk of delusions (DLB), hallucinations (DLB, PDD), apathy (VaD, FTD), disinhibition (FTD), and appetite and eating abnormalities (FTD) were also found in comparison to AD. CONCLUSION: Although individuals in our sample were diagnosed with different dementia disorders, they all exhibited aberrant motor behavior, agitation, and irritability. This suggests common underlying psychosocial or biological mechanisms. We recommend prioritizing these symptoms while planning interventions in long-term care facilities.

Intelligent Algorithm-Based Quantitative Electroencephalography in Evaluating Cerebral Small Vessel Disease Complicated by Cognitive Impairment.

To analyze the application value of artificial intelligence model based on Visual Geometry Group- (VGG-) 16 combined with quantitative electroencephalography (QEEG) in cerebral small vessel disease (CSVD) with cognitive impairment, 72 patients with CSVD complicated by cognitive impairment were selected as the research subjects. As per Diagnostic and Statistical Manual (5th Edition), they were divided into the vascular dementia (VD) group of 34 cases and vascular cognitive impairment with no dementia (VCIND) group of 38 cases. The two groups were analyzed for the clinical information, neuropsychological test results, and monitoring results of QEEG based on intelligent algorithms for more than 2 hours. The accuracy rate of VGG was 84.27% and Kappa value was 0.7, while that of modified VGG (nVGG) was 88.76% and Kappa value was 0.78. The improved VGG algorithm obviously had higher accuracy. The test results found that the QEEG identified 8 normal, 19 mild, 10 moderate, and 0 severe cases in the VCIND group, while in the VD group, the corresponding numbers were 4, 13, 11, and 7; in the VCIND group, 7 cases had the normal QEEG, 11 cases had background changes, 9 cases had abnormal waves, and 11 cases had in both background changes and abnormal waves, and in the VD group, the corresponding numbers were 5, 2, 5, and 22, respectively; in the VCIND group, QEEG of 18 patients had no abnormal waves, QEEG of 11 patients had a few abnormal waves, and QEEG of 9 patients had many abnormal waves, and QEEG of 0 people had a large number of abnormal waves, and in the VD group, the corresponding numbers were 7, 6, 12, and 9. The above data were statistically different between the two groups (P < 0.05). Hence, QEEG based on intelligent algorithms can make a good assessment of CSVD with cognitive impairment, which had good clinical application value.

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.

Temporal Changes in Cognitive Function in Early Recovery Phase of the Stroke.

OBJECTIVES: Only a few studies longitudinally evaluated all cognitive domains after acute stroke. The purpose was to study the changes in cognitive function after acute stroke. MATERIALS AND METHODS: Cognitive assessment, using Thai mental state examination (TMSE) and Montreal Cognitive Assessment (MOCA), was performed at the acute stroke, and at 3 and 6 months after stroke. Cognitive domains were evaluated by MOCA subcategory score. TMSE and MOCA were compared at different stages of stroke and in among those with normal cognition (NC), vascular mild cognitive impairment (VMCI) and vascular dementia (VAD). RESULTS: 138 patients were included. At 6 months, 32 patients (23%) had NC. VMCI and VAD were diagnosed in 76 patients (55%), and 30 patients (22%), respectively. Total scores of TMSE and MOCA were higher at 3 months as compared to at the acute stroke (TMSE; 24.85 vs 23.01, p-value <0.001, MOCA; 19.30 vs 16.49, p-value <0.001), and higher TMSE, but not MOCA, at 6 months as compared to at 3 months (TMSE; 25.35 vs 24.85, p-value= 0.021, MOCA; 19.04 vs 19.30, p-value= 0.058). Changes in total scores at early stroke were highest in NC. VMCI and VAD patients had cognitive impairment in all cognitive domains. CONCLUSIONS: Cognitive impairment was highest at the acute stroke and improved during early recovery. The greatest rate of improvement occurred within 3 months. Improvement was found in all cognitive domains.

Treatment with edaravone improves the structure and functional changes in the hippocampus after chronic cerebral hypoperfusion in rat.

This study aimed to find out cellular and electrophysiological effects of the edaravone (EDR) administration following induction of vascular dementia (VaD) via bilateral-carotid vessel occlusion (2VO). The rats were randomly divided into control, sham, 2VO + V (vehicle), and 2VO + EDR groups. EDR was administered once a day from day 0-28 after surgery. The passive-avoidance, Morris water-maze, and open-field tests were used for evaluation of memory, locomotor, and anxiety. The field-potential recording was used for assessment of electrophysiological properties of the hippocampus; and after sacrificing, the cerebral hemispheres were removed for stereological study and evaluation of MDA levels. The long-term potentiation (LTP), paired-pulse ratio (PPR), and input-output (I/O) curves were evaluated as indexes for long-term and short-term synaptic plasticity, and basal-synaptic transmission (BST), respectively. The 2VO led to increases in MDA level with considerable neuronal loss and decreases in the volume of the hippocampus, along with a reduction in the BST and LTP induction which was associated with a decrement in PPR and ultimate loss in memory with higher anxiety behavior. However, administration of EDR caused a decline in MDA and prevented the neural loss and volume of the hippocampus, rescued BST and LTP depression, improved memory and anxiety without any effects on PPR. Therefore, most likely through the improvement of MDA level, and the hippocampal cell number and volume, EDR leads to recovery of synaptic plasticity and behavioral performance. Because of the LTP rescue, without recovery of PPR, it is likely that the EDR improved LTP through the post-synaptic neurons.

Distinctive Alterations of Functional Connectivity Strength between Vascular and Amnestic Mild Cognitive Impairment.

Widespread structural and functional alterations have been reported in the two highly prevalent mild cognitive impairment (MCI) subtypes, amnestic MCI (aMCI) and vascular MCI (VaMCI). However, the changing pattern in functional connectivity strength (FCS) remains largely unclear. The aim of the present study is to detect the differences of FCS and to further explore the detailed resting-state functional connectivity (FC) alterations among VaMCI subjects, aMCI subjects, and healthy controls (HC). Twenty-six aMCI subjects, 31 VaMCI participants, and 36 HC participants underwent cognitive assessments and resting-state functional MRI scans. At first, one-way ANCOVA and post hoc analysis indicated significant decreased FCS in the left middle temporal gyrus (MTG) in aMCI and VaMCI groups compared to HC, especially in the VaMCI group. Then, we selected the left MTG as a seed to further explore the detailed resting-state FC alterations among the three groups, and the results indicated that FC between the left MTG and some frontal brain regions were significantly decreased mainly in VaMCI. Finally, partial correlation analysis revealed that the FC values between the left MTG and left inferior frontal gyrus were positively correlated with the cognitive performance episodic memory and negatively related to the living status. The present study demonstrated that different FCS alterations existed in aMCI and VaMCI. These findings may provide a novel insight into the understanding of pathophysiological mechanisms underlying different MCI subtypes.

Emerging Concepts in Vascular Dementia: A Review.

OBJECTIVE: Vascular dementia (VaD) is the second most common cause of dementia and a major health concern worldwide. A comprehensive review on VaD is warranted for better understanding and guidance for the practitioner. We provide an updated overview of the epidemiology, pathophysiological mechanisms, neuroimaging patterns as well as current diagnostic and therapeutic approaches. MATERIALS AND METHODS: A narrative review of current literature in VaD was performed based on publications from the database of PubMed, Scopus and Google Scholar up to January, 2021. RESULTS: VaD can be the result of ischemic or hemorrhagic tissue injury in a particular region of the brain which translates into clinically significant cognitive impairment. For example, a cerebral infarct in the speech area of the dominant hemisphere would translate into clinically significant impairment as would involvement of projection pathways such as the arcuate fasciculus. Specific involvement of the angular gyrus of the dominant hemisphere, with resultant Gerstman's syndrome, could have a pronounced effect on functional ability despite being termed a "minor stroke". Small vessel cerebrovascular disease can have a cumulate effect on cognitive function over time. It is unfortunately well recognized that "good" functional recovery in acute ischemic or haemorrhagic stroke, including subarachnoid haemorrhage, does not necessarily translate into good cognitive recovery. The victim may often be left unable to have gainful employment, drive a car safely or handle their affairs independently. CONCLUSIONS: This review should serve as a compendium of updated information on VaD and provide guidance in terms of newer diagnostic and potential therapeutic approaches.

Efficacy of tanshinone IIA and mesenchymal stem cell treatment of learning and memory impairment in a rat model of vascular dementia.

OBJECTIVE: To investigate the efficacy of administration of tanshinone Ⅱ A (TSA) combined with mesenchymal stem cells (MSCs) for the treatment of learning and memory impairment caused by vascular dementia (VaD) and to determine the underlying mechanism. METHODS: Modified four-vessel occlusion was used to establish a VaD model in rats, and their spatial learning and memory capacity was assessed by the Morris water maze. The rats were randomized into MSCs, TSA, MSCs combined with TSA, vehicle and sham groups. Histological changes were determined by hematoxylin and eosin staining, and the hippocampal neuron apoptosis ratio was assessed by flow cytometry. Western blotting was performed to detect Bcl-2 and Bax expression. The reactive oxidative species (ROS) levels and the activity of total superoxide dismutase (T-SOD), an antioxidant enzyme in the rat hippocampus, were determined. RESULTS: TSA combined with MSCs treatment administered by intravenous injection in the tail significantly attenuated cognitive deficits in the VaD model compared with the vehicle group (P < 0.01), and its protective effect on cognitive function was greater than that obtained by treatment with MSCs or TSA alone. Furthermore, TSA combined with MSCs treatment achieved synergistic effects in suppressing neuronal apoptosis in the rat hippocampus caused by global brain ischemia via up-regulating the expression of Bcl-2, an anti-apoptosis protein, and decreasing the expression of Bax, a pro-apoptotic protein. In addition, TSA combined with MSCs treatment attenuated ROS production and enhanced T-SOD activity in the rat hippocampus, and the antioxidant effect was greater than that of treatment with MSCs or TSA alone. CONCLUSION: TSA combined with MSCs treatment improved the spatial learning and memory capacity in a VaD model via suppressing neuronal apoptosis and antioxidant activity in the hippocampus, and this improvement was greater with combined treatment than with treatment with MSCs or TSA alone.

Targeting Transcription Factor Nrf2 (Nuclear Factor Erythroid 2-Related Factor 2) for the Intervention of Vascular Cognitive Impairment and Dementia.

Vascular cognitive impairment and dementia (VCID) is an age-related, mild to severe mental disability due to a broad panel of cerebrovascular disorders. Its pathobiology involves neurovascular dysfunction, blood-brain barrier disruption, white matter damage, microRNAs, oxidative stress, neuroinflammation, and gut microbiota alterations, etc. Nrf2 (Nuclear factor erythroid 2-related factor 2) is the master regulator of redox status and controls the transcription of a panel of antioxidative and anti-inflammatory genes. By interacting with NF-κB (nuclear factor-κB), Nrf2 also fine-tunes the cellular oxidative and inflammatory balance. Aging is associated with Nrf2 dysfunction, and increasing evidence has proved the role of Nrf2 in mitigating the VCID process. Based on VCID pathobiologies and Nrf2 studies from VCID and other brain diseases, we point out several hypothetical Nrf2 targets for VCID management, including restoration of endothelial function and neurovascular coupling, preservation of blood-brain barrier integrity, reduction of amyloidopathy, promoting white matter integrity, and mitigating oxidative stress and neuroinflammation. Collectively, the Nrf2 pathway could be a promising direction for future VCID research. Targeting Nrf2 would shed light on VCID managing strategies.

GJ-4 ameliorates memory impairment in focal cerebral ischemia/reperfusion of rats via inhibiting JAK2/STAT1-mediated neuroinflammation.

ETHNOPHARMACOLOGICAL RELEVANCE: Gardenia jasminoides J. Ellis (Fructus Gardenia) is a traditional Chinese medicine with diverse pharmacological functions, such as anti-inflammation, anti-depression, as well as improvement of cognition and ischemia brain injury. GJ-4 is a natural extract from Gardenia jasminoides J. Ellis (Fructus Gardenia) and has been proved to improve memory impairment in Alzheimer's disease (AD) mouse model in our previous studies. AIM OF THE STUDY: This study aimed to evaluate the therapeutic effects of GJ-4 on vascular dementia (VD) and explore the potential mechanisms. MATERIAL AND METHODS: In our experiment, a focal cerebral ischemia and reperfusion rat model was successfully developed by the middle cerebral artery occlusion and reperfusion (MCAO/R). GJ-4 (10 mg/kg, 25 mg/kg, 50 mg/kg) and nimodipine (10 mg/kg) were orally administered to rats once a day for consecutive 12 days. Learning and memory behavioral performance was assayed by step-down test and Morris water maze test. The neurological scoring test was performed to evaluate the neurological function of rats. 2,3,5-Triphenyltetrazolium chloride (TTC) staining and Nissl staining were respectively employed to determine the infarct condition and neuronal injury of the brain. Iba1 immunohistochemistry was used to show the activation of microglia. Moreover, the synaptic damage and inflammatory level were detected by Western blot. RESULTS: GJ-4 could significantly improve memory impairment, cerebral infraction, as well as neurological deficits of VD rats induced by MCAO/R. Further research indicated VD-induced neuronal injury was alleviated by GJ-4. In addition, GJ-4 could protect synapse of VD rats by upregulating synaptophysin (SYP) expression, post synaptic density 95 protein (PSD95) expression, and downregulating N-Methyl-D-Aspartate receptor 1 (NMDAR1) expression. Subsequent investigation of the underlying mechanisms identified that GJ-4 could suppress neuroinflammatory responses, supported by inhibited activation of microglia and reduced expression of inflammatory proteins, which ultimately exerted neuroprotective effects on VD. Further mechanistic study indicated that janus kinase 2 (JAK2)/signal transducer and activator of transcription 1 (STAT1) pathway was inhibited by GJ-4 treatment. CONCLUSION: These results suggested that GJ-4 might serve as a potential drug to improve VD. In addition, our study indicated that inhibition of neuroinflammation might be a promising target to treat VD.

Marinoid J, a phenylglycoside from Avicennia marina fruit, ameliorates cognitive impairment in rat vascular dementia: a quantitative iTRAQ proteomic study.

CONTEXT: Fruit of Avicennia marina (Forsk.) Vierh. (Acanthaceae) is used as a Chinese herb. Studies have found that it contains marinoid J, a novel phenylethanoid glycoside (PG) compound, but its neuroprotective functions are largely unknown. OBJECTIVE: This study evaluated the effects of marinoid J on vascular dementia (VD) and determined its potential mechanisms of action. MATERIALS AND METHODS: The VD model was established by the ligation of the bilateral common carotid artery in Sprague-Dawley rats, who received daily intragastrically administration of saline, marinoid J (125 or 500 mg/kg body weight/d), or oxiracetam (250 mg/kg body weight/d) for 14 days (20 rats in each group). The Morris water maze (MWM) was used to evaluate cognitive performance. The hippocampus was subjected to histological and proteomic analyses. RESULTS: Marinoid J shortened the escape latency of VD rats (31.07 ± 3.74 s, p < 0.05). It also decreased malondialdehyde (MDA) (27.53%) and nitric oxide (NO) (20.41%) while increasing superoxide dismutase (SOD) (11.26%) and glutathione peroxidase (GSH-Px) (20.38%) content in hippocampus tissues. Proteomic analysis revealed 45 differentially expressed proteins (DEPs) in marinoid J-treated VD rats, which included angiotensin-converting enzyme (ACE), keratin 18 (KRT18), cluster of differentiation 34 (CD34), and synaptotagmin II (SYT2). CONCLUSIONS: Marinoid J played a role in protecting hippocampal neurons by regulating a set of proteins that influence oxidative stress and apoptosis, this effect may thereby alleviate the symptoms of VD rats. Thus, pharmacological manipulation of marinoid J may offer a novel opportunity for VD treatment.

Improvement of autophagy dysfunction as a potential mechanism for environmental enrichment to protect blood-brain barrier in rats with vascular cognitive impairment.

Vascular cognitive impairment (VCI) is the second most common cause of dementia after Alzheimer's disease, and the cognitive impairment is one of the common effects of VCI. Unfortunately, it lacks effective therapeutic treatments at present. In our previous study, environmental enrichment (EE), as an early intervention for lifestyle modification, can ameliorate cognitive impairment by attenuating hippocampal blood-brain barrier (BBB) injury in chronic cerebral hypoperfusion (CCH) rats. However, the underlying mechanism remains unclear. Here, we found CCH rats in the standard environment (SE) developed cognitive impairment and BBB damage, which were significantly alleviated with the EE intervention. Meantime, EE improved the autophagy dysfunction caused by CCH in the hippocampus of rats, suggesting that the effect of EE on cognitive function and BBB may be related to the improvement of autophagy pathway.

Dramatic Performance by a Professional Actor for the Treatment of Patients with Behavioral and Psychological Symptoms of Dementia.

Behavioral and psychological symptoms of dementia (BPSD) challenge caregivers, leading to caregiver burden and subsequent nursing home or inpatient placement in a psychiatric hospital for dementia. Favorable positive emotions should be an important goal for the treatment of negative emotions of BPSD. Arts are one of the most profound areas to stimulate favorable emotions. We have asked a professional actor, who was not involved in the daily care and regular rehabilitations, to give a dramatic performance by reading selected stories as if the patients with BPSD felt to be in the audiences of a theater. We wondered whether a dramatic performance by the actor might be a way to respond to the complex needs of inpatients with BPSD, especially focused on favorable emotions. New inpatients (Alzheimer's disease, vascular dementia, or dementia with Lewy bodies) were randomly assigned to a control group (n = 20) and a dramatic performance group (n = 14) in Sendai Tomizawa Hospital, a psychiatric hospital for dementia, in Japan. Dramatic performances were performed for one and half hours once per week for 3 months. Neuropsychiatric Inventory for BPSD decreased in both groups and delightful emotional index (DEI) for favorable emotions increased in the intervention group but not in the control group after 3 months. At 3 months, there was an increase of DEI in intervention group compared with control group. We conclude that dramatic performance may be one of the appropriate interventions in patients with BPSD, as it appears to help in their favorable emotional state.

Astaxanthin protects cognitive function of vascular dementia.

OBJECTIVE: The purpose of this study was to evaluate the effect of astaxanthin (AST) on cognition function, inflammatory response and oxidative stress in vascular dementia (VD) mice. METHOD: VD mice model was established by left unilateral common carotid arteries occlusion (LUCCAO). Following LUCCAO, AST was intragastrically administered for 30 days. Object recognition test and morris water maze test were used to evaluate cognitive function. Hematoxylin and eosin staining was performed to observe the hippocampal neuron structure. Enzyme-linked immunosorbent assay kit and bicinchoninic acid kit were respectively adopted to measure IL-1ß and IL-4 protein expression and superoxide dismutase (SOD) activity and malondialdehyde (MDA) content in hippocampus and prefrontal cortex. RESULTS: AST improved the discrimination ability of VD mice. The escape latency and path length of VD mice treated with AST were dramatically reduced. Besides, AST 200 mg/kg enhanced crossing platform time and the number of times crossing the platform quadrant, and alleviated the morphological impairment in VD mice. Moreover, we found that AST inhibited IL-1ß expression and MDA content, whereas promoted IL-4 expression and SOD activity in a dose-dependent manner. CONCLUSION: AST could improve cognitive impairment and hippocampal neurons in VD mice, which may be related to suppression of inflammatory response and oxidative stress.

Pathological Correlations of Neuropsychiatric Symptoms in Institutionalized People with Dementia.

BACKGROUND: Comprehensive clinicopathological studies of neuropsychiatric symptoms (NPS) in dementia are lacking. OBJECTIVE: To describe the pathological correlations of NPS in a sample of institutionalized people with dementia. METHODS: We studied 59 people who were consecutively admitted to a nursing home and donated their brain. Correlations between pathological variables and NPS upon admission (n = 59) and at one-year follow-up assessment (n = 46) were explored and confirmed using bivariate and multivariate statistical methods. RESULTS: Mean (SD) age at admission was 83.2 (6.4) years and mean (SD) age at demise was 85.4 (6.6); 73% of the subjects were female and 98% presented advanced dementia. The most frequent etiological diagnosis was Alzheimer's disease (AD; 74.6% clinical diagnosis, 67.8% pathological diagnosis). The pathological diagnosis of AD was associated with aggression (ß est 0.31), depression (ß est 0.31), anxiety (ß est 0.38), and irritability (ß est 0.28). Tau stage correlated with aggressive symptoms (ß est 0.32) and anxiety (ßest 0.33). Coexistence of AD and Lewy body pathology was associated with depression (ß est 0.32), while argyrophilic grains were associated with eating symptoms (ß est 0.29). Predictive models were achieved for apathy, including cognitive performance, basal ganglia ischemic lesions, and sex as predictors (R2 0.38) and for sleep disorders, including pathological diagnosis of AD and age at demise (R2 0.18) (all p-values <0.05, unadjusted). CONCLUSION: AD was the main pathological substrate of NPS in our sample of very elderly people with advanced dementia. However, correlations were mild, supporting a model of focal/asymmetric rather than diffuse brain damage, along with relevance of environmental and other personal factors, in the genesis of those symptoms.

Elevated Levels of Serum Neurofilament Light Chain Associated with Cognitive Impairment in Vascular Dementia.

OBJECTIVE: Vascular dementia (VaD) is a progressive neurodegenerative disease with cognitive decline caused by cerebrovascular factors. Despite the great progress made in the past decade, VaD still lacks effective treatments and peripheral blood biomarkers. In this study, we tested the level of peripheral blood neurofilament light chain (NfL) in VaD patients and explored its relationship with cognitive impairment. METHOD: A total of 176 study subjects including 80 normal controls (NC) and 96 VaD patients were included in our study. Upon admission, we collected clinical and biochemical characteristics of all research subjects. We also evaluate the Montreal cognitive assessment scale (MoCA) scores of all subjects. The serum NfL level was measured by the single-molecule array (Simoa) method. RESULTS: The years of education in the NC group and VaD group were (11.65 ± 3.04) years and (10.53 ± 3.87) years, respectively. Compared with VaD patients, the NC group has a higher level of education (p = 0.037). Furthermore, the results of Simoa indicated that VaD subjects had higher serum NfL levels compared with the NC group [(8.49 ± 2.37) pg/ml vs. (19.26 ± 4.71) pg/ml, p < 0.001]. In terms of other clinical and biochemical characteristics, there was no significant difference between VaD and NC. The Spearman correlation analysis indicated that educational years have a significant positive correlation with MoCA scores (r = 0.238, p = 0.041), while age and serum NfL levels have a significantly negative correlation with MoCA scores (age: r = -0.213, p = 0.040; NfL: r = -0.395, p = 0.027). However, further multiple regression analysis showed that only serum NfL level might serve as an independent risk factor for cognitive decline in VaD (ß = 0.317, p = 0.021). CONCLUSION: The serum NfL levels in VaD subjects are significantly elevated, which may be used as a potential peripheral blood marker for predicting cognitive impairment in patients with VaD.

Amyloid-PET and 18F-FDG-PET in the diagnostic investigation of Alzheimer's disease and other dementias.

Various biomarkers are available to support the diagnosis of neurodegenerative diseases in clinical and research settings. Among the molecular imaging biomarkers, amyloid-PET, which assesses brain amyloid deposition, and 18F-fluorodeoxyglucose (18F-FDG) PET, which assesses glucose metabolism, provide valuable and complementary information. However, uncertainty remains regarding the optimal timepoint, combination, and an order in which these PET biomarkers should be used in diagnostic evaluations because conclusive evidence is missing. Following an expert panel discussion, we reached an agreement on the specific use of the individual biomarkers, based on available evidence and clinical expertise. We propose a diagnostic algorithm with optimal timepoints for these PET biomarkers, also taking into account evidence from other biomarkers, for early and differential diagnosis of neurodegenerative diseases that can lead to dementia. We propose three main diagnostic pathways with distinct biomarker sequences, in which amyloid-PET and 18F-FDG-PET are placed at different positions in the order of diagnostic evaluations, depending on clinical presentation. We hope that this algorithm can support diagnostic decision making in specialist clinical settings with access to these biomarkers and might stimulate further research towards optimal diagnostic strategies.