The AHA/ASA & DSM-V diagnostic criteria for vascular cognitive impairment identify cases with predominant vascular pathology.

BACKGROUND: There are major challenges in determining the aetiology of vascular cognitive impairment (VCI) clinically, especially in the presence of mixed pathologies, such as vascular and amyloid. Most recently, two criteria (American Heart Association/American Stroke Association [AHA/ASA] and Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [DSM-V]) have been proposed for the clinical diagnosis of VCI but have not as yet been validated using neuroimaging. AIMS: This study aims to determine whether the AHA/ASA and DSM-V criteria for VCI can distinguish between cases with predominantly vascular pathology and cases with mixed pathology. METHODS: 186 subjects were recruited from a cross-sectional memory clinic-based study at the National University Hospital, Singapore. All subjects underwent clinical and neuropsychological assessment, MRI and [11C] PiB PET scans. Diagnosis of the etiological subtypes of VCI [probable vascular mild cognitive impairment (VaMCI), possible VaMCI, non-VaMCI, probable vascular dementia (VaD), possible VaD, non-VaD] were performed following AHA/ASA and DSM-V criteria. Brain amyloid burden was determined for each subject with standardised uptake value ratio (SUVR) values ≥ 1.5 classified as amyloid positive. RESULTS: Using κ statistics, both criteria had excellent agreement for probable VaMCI, probable VaD, and possible VaD (κ=1.00), and good for possible VaMCI (κ=0.71). Using the AHA/ASA criteria, the amyloid positivity of probable VaMCI (3.8%) and probable VaD (15%) was significantly lower compared to possible VaMCI (26.7%), non-VaMCI (33.3%), possible VaD (73.3%) and non-VaD (76.2%) )(p<0.001). Similarly, using the DSM-V criteria the amyloid positivity of probable VaMCI (3.8%) and probable VaD (15%) were significantly lower compared to possible VaMCI (26.3%), non-VaMCI (32.1%), possible VaD (73.3%) and non-VaD (76.2%)(p<0.001). In both criteria, there was good agreement in differentiating individuals with non-VaD and possible VaD, with significantly higher (p<0.001) global [11C]-PiB SUVR, from individuals with probable VaMCI and probable VaD, who had predominant vascular pathology. CONCLUSIONS: The AHA/ASA and DSM-V criteria for VCI can identify VCI cases with little to no concomitant amyloid pathology, hence supporting the utility of AHA/ASA and DSM-V criteria in diagnosing patients with predominant vascular pathology.

Predictors of post stroke cognitive impairment: VITATOPS cognition substudy.

INTRODUCTION: Post stroke cognitive impairment (PSCI) is a common complication of ischemic stroke. PSCI can involve different depending on clinical and stroke related characteristics. The aim of this study is to determine the factors associated with impairments in specific cognitive domains. METHODS: The Vitamins to Prevent Stroke (VITATOPS) trial is a large, multinational randomised controlled trial. In this substudy, consecutive patients admitted for ischaemic stroke or transient ischaemic attack (TIA) at a tertiary hospital in Singapore were included. PSCI was defined as impairment of any of the six cognitive subgroups - visuoconstruction, attention, verbal memory, language, visual memory and visuomotor function - that were assessed annually for up to five years. Univariate and multivariate Cox proportional hazard models were used to determine factors associated with impairments in each of these cognitive domains. RESULTS: A total of 736 patients were included in this study, of which 173 (23.5 %) developed cognitive impairment. Out of the six cognitive domains, the greatest proportion of patients had an impairment in visuoconstruction (26.4 %) followed by attention (19.8 %), verbal memory (18.3 %), language (17.5 %), visual memory (17.3 %) and visuomotor function (14.8 %). Patients with posterior circulation cerebral infarction (POCI) as the index stroke subtype had higher rates of cognitive impairment. Further subgroup analyses show that Indian race and advanced age were predictive of language impairment, whilst fewer years of education and POCI were predictive of verbal memory impairment. POCI was predictive of visual memory impairment, and advanced age and POCI were predictive of visuomotor function impairment. CONCLUSION: We identified visuoconstruction and attention domains to be the most affected in our Asian cohort of PSCI. Advanced age, lower levels of education, posterior circulation strokes and concomitant comorbidities such as peripheral artery disease are independent predictors of PSCI.

Longitudinal associations between ß-amyloid and cortical thickness in mild cognitive impairment.

How beta-amyloid accumulation influences brain atrophy in Alzheimer's disease remains contentious with conflicting findings. We aimed to elucidate the correlations of regional longitudinal atrophy with cross-sectional regional and global amyloid in individuals with mild cognitive impairment and no cognitive impairment. We hypothesized that greater cortical thinning over time correlated with greater amyloid deposition, particularly within Alzheimer's disease characteristic regions in mild cognitive impairment, and weaker or no correlations in those with no cognitive impairment. 45 patients with mild cognitive impairment and 12 controls underwent a cross-sectional [11C]-Pittsburgh Compound B PET and two retrospective longitudinal structural imaging (follow-up: 23.65 ± 2.04 months) to assess global/regional amyloid and regional cortical thickness, respectively. Separate linear mixed models were constructed to evaluate relationships of either global or regional amyloid with regional cortical thinning longitudinally. In patients with mild cognitive impairment, regional amyloid in the right banks of the superior temporal sulcus was associated with longitudinal cortical thinning in the right medial orbitofrontal cortex (P = 0.04 after False Discovery Rate correction). In the mild cognitive impairment group, greater right banks amyloid burden and less cortical thickness in the right medial orbitofrontal cortex showed greater visual and verbal memory decline over time, which was not observed in controls. Global amyloid was not associated with longitudinal cortical thinning in any locations in either group. Our findings indicate an increasing influence of amyloid on neurodegeneration and memory along the preclinical to prodromal spectrum. Future multimodal studies that include additional biomarkers will be well-suited to delineate the interplay between various pathological processes and amyloid and memory decline, as well as clarify their additive or independent effects along the disease deterioration.

Ischemic Stroke and Savings in Time to Achieve Functional Recovery: Experience from NeuroAiD.

Despite recent progress with revascularisation interventions after acute ischemic stroke, many patients remain disabled after stroke. Using data from a multi-centre, randomised, double-blind, placebo-controlled trial of a neuro-repair treatment (NeuroAiD/MLC601) with a long-term follow-up, we analysed the savings in time to functional recovery, measured by a modified Rankin Scale (mRS) score of 0 or 1, in patients receiving a 3-month oral course of MLC601. Analysis of time to recovery was assessed by a log-rank test and hazard ratios (HRs) adjusted for prognosis factors. A total of 548 patients with baseline NIHSS scores 8-14, mRS scores ≥ 2 at day 10 post-stroke, and at least one mRS assessment on or after month 1 were included in the analysis (placebo = 261; MLC601 = 287). Time to functional recovery was significantly shortened for patients receiving MLC601 versus patients receiving placebo (log-rank test: p = 0.039). This result was confirmed by Cox regression adjusting for the main baseline prognostic factors (HR: 1.30 [0.99, 1.70]; p = 0.059) and was more pronounced in patients with additional poor prognosis factors. The Kaplan-Meier plot showed that approximately 40% cumulative incidence of functional recovery was achieved within 6 months after stroke onset in the MLC601 group versus 24 months in the placebo group. The main findings are that MLC601 reduced the time to achieve functional recovery, and a 40% functional recovery rate was achieved 18 months earlier compared to placebo.

Association between Baseline NIHSS Limb Motor Score and Functional Recovery after Stroke: Analysis Based on a Multicountry Dataset.

INTRODUCTION: Motor skills are the domains most often affected by stroke, but a comprehensive assessment of motor function is often impractical in the acute setting. It could be useful to have a brief simple tool allowing the stratification of patients at the time of inclusion in clinical studies. Hence, our primary objective was to evaluate whether the baseline NIH Stroke Scale limb motor score (b-NIHSS-LMS), obtained by summing the four motor items 5a to 6b of the NIHSS, is associated with functional recovery assessed by the modified Rankin Score (mRS). A secondary objective was to apply this new tool in the context of a clinical trial. METHODS: The analysed population considered for this research included subjects from a large published, double-blind, multicentre trial, randomised to receive either a combination of various herbal and non-herbal components (MLC601) or placebo, administered within 72 h after an acute ischaemic stroke of intermediate severity (defined by baseline NIH Stroke Scale [b-NIHSS] score of 8-14). Associations between b-NIHSS-LMS and favourable outcome, i.e., mRS 0-1 at month 3, were evaluated using logistic regression adjusted for baseline covariates and study treatment. RESULTS: The analysis included 533 subjects with an acute ischaemic stroke of intermediate severity assessed at month 3. Analyses showed that b-NIHSS-LMS was independently associated with a favourable outcome (OR 0.84; 95% confidence interval 0.76-0.92; p < 0.0003) at 3 months. Furthermore, in the clinical study considered, a selection of patients based upon a sufficient level of motor impairment at study entry (b-NIHSS-LMS ≥3) would result in the detection of a more pronounced and longer-lasting treatment effect. Indeed, ORs of treatment effect versus placebo in the selected subgroup (b-NIHSS-LMS ≥3) were statistically significant from months 3-24. DISCUSSION/CONCLUSIONS: As an independent association between b-NIHSS-LMS and functional recovery after an acute ischaemic stroke of intermediate severity was established in this study, we suggest that the b-NIHSS-LMS can be used as a stratification factor in large clinical trials to define a target population with poststroke motor impairments.

B-vitamin supplementation on mitigating post-stroke cognition and neuropsychiatric sequelae: A randomized controlled trial.

BACKGROUND AND PURPOSE: A third of stroke patients suffer from post-stroke cognitive decline, depressive symptoms, and anxiety symptoms. B-vitamin supplementation provides a possible safe and affordable treatment to mitigate post-stroke neuropsychiatric sequelae via reducing homocysteine levels. Our study aims to examine the effect of B-vitamin supplementation in the prevention of post-stroke cognitive decline, depressive symptoms, and anxiety symptoms. Our secondary aims were to investigate associations between baseline factors and the three outcomes. METHODS: Patients were recruited as part of a Singaporean substudy of a randomized controlled trial that examined the effect of B-vitamin supplementation on recurrent cardiovascular events. Cognitive decline, depressive symptoms, and anxiety symptoms were assessed with neuropsychological assessments and Hospital Anxiety and Depression Scale 6 monthly. Cox regression analyses were performed to determine treatment efficacy. Logistic regression used to examine factors associated with cognitive decline, depressive symptoms, and anxiety symptoms. RESULTS: A total of 707 were included in the analyses. Survival and hazards ratio analysis showed no treatment effect of B-vitamins on cognitive decline, depressive symptoms, and anxiety symptoms. Cognitive decline was only associated with age. Depressive symptoms were associated with large anterior cerebral infarcts and hyperlipidemia. CONCLUSIONS: Our study showed no benefit of supplementation with B-vitamins for post-stroke cognitive decline, depressive symptoms, or anxiety symptoms. Depressive symptoms were associated with larger anterior cerebral infarcts, which may be reflective of the disability associated with larger infarcts.

Intermittent Fasting Attenuates Hallmark Vascular and Neuronal Pathologies in a Mouse Model of Vascular Cognitive Impairment.

Background - Chronic cerebral hypoperfusion (CCH) is an important pathophysiological mechanism of vascular cognitive impairment (VCI). The heterogeneous effects of CCH complicate establishing single target therapies against VCI and its more severe form, vascular dementia (VaD). Intermittent fasting (IF) has multiple targets and is neuroprotective across a range of disease conditions including stroke, but its effects against CCH-induced neurovascular pathologies remain to be elucidated. We therefore assessed the effect of IF against CCH-associated neurovascular pathologies and investigated its underlying mechanisms. Methods - Male C57BL/6NTac mice were subjected to either ad libitum feeding (AL) or IF (16 hours of fasting per day) for 4 months. In both groups, CCH was experimentally induced by the bilateral common carotid artery stenosis (BCAS) method. Sham operated groups were used as controls. Measures of leaky microvessels, blood-brain barrier (BBB) permeability, protein expression of tight junctions, extracellular matrix components and white matter changes were determined to investigate the effect of IF against CCH-induced neurovascular pathologies. Results - IF alleviated CCH-induced neurovascular pathologies by reducing the number of leaky microvessels, BBB breakdown and loss of tight junctional proteins. In addition, IF mitigated the severity of white matter lesions, and maintained myelin basic protein levels, while concurrently reducing hippocampal neuronal cell death. Furthermore, IF reduced the CCH-induced increase in levels of matrix metalloproteinase (MMP)-2 and its upstream activator MT1-MMP, which are involved in the breakdown of the extracellular matrix that is a core component of the BBB. Additionally, we observed that IF reduced CCH-induced increase in the oxidative stress marker malondialdehyde, and increased antioxidant markers glutathione and superoxide dismutase. Overall, our data suggest that IF attenuates neurovascular damage, metalloproteinase and oxidative stress-associated pathways, and cell death in the brain following CCH in a mouse model of VCI. Conclusion - Although IF has yet to be assessed in human patients with VaD, our data suggest that IF may be an effective means of preventing the onset or suppressing the development of neurovascular pathologies in VCI and VaD.

A deep learning model for detection of Alzheimer's disease based on retinal photographs: a retrospective, multicentre case-control study.

BACKGROUND: There is no simple model to screen for Alzheimer's disease, partly because the diagnosis of Alzheimer's disease itself is complex-typically involving expensive and sometimes invasive tests not commonly available outside highly specialised clinical settings. We aimed to develop a deep learning algorithm that could use retinal photographs alone, which is the most common method of non-invasive imaging the retina to detect Alzheimer's disease-dementia. METHODS: In this retrospective, multicentre case-control study, we trained, validated, and tested a deep learning algorithm to detect Alzheimer's disease-dementia from retinal photographs using retrospectively collected data from 11 studies that recruited patients with Alzheimer's disease-dementia and people without disease from different countries. Our main aim was to develop a bilateral model to detect Alzheimer's disease-dementia from retinal photographs alone. We designed and internally validated the bilateral deep learning model using retinal photographs from six studies. We used the EfficientNet-b2 network as the backbone of the model to extract features from the images. Integrated features from four retinal photographs (optic nerve head-centred and macula-centred fields from both eyes) for each individual were used to develop supervised deep learning models and equip the network with unsupervised domain adaptation technique, to address dataset discrepancy between the different studies. We tested the trained model using five other studies, three of which used PET as a biomarker of significant amyloid ß burden (testing the deep learning model between amyloid ß positive vs amyloid ß negative). FINDINGS: 12 949 retinal photographs from 648 patients with Alzheimer's disease and 3240 people without the disease were used to train, validate, and test the deep learning model. In the internal validation dataset, the deep learning model had 83·6% (SD 2·5) accuracy, 93·2% (SD 2·2) sensitivity, 82·0% (SD 3·1) specificity, and an area under the receiver operating characteristic curve (AUROC) of 0·93 (0·01) for detecting Alzheimer's disease-dementia. In the testing datasets, the bilateral deep learning model had accuracies ranging from 79·6% (SD 15·5) to 92·1% (11·4) and AUROCs ranging from 0·73 (SD 0·24) to 0·91 (0·10). In the datasets with data on PET, the model was able to differentiate between participants who were amyloid ß positive and those who were amyloid ß negative: accuracies ranged from 80·6 (SD 13·4%) to 89·3 (13·7%) and AUROC ranged from 0·68 (SD 0·24) to 0·86 (0·16). In subgroup analyses, the discriminative performance of the model was improved in patients with eye disease (accuracy 89·6% [SD 12·5%]) versus those without eye disease (71·7% [11·6%]) and patients with diabetes (81·9% [SD 20·3%]) versus those without the disease (72·4% [11·7%]). INTERPRETATION: A retinal photograph-based deep learning algorithm can detect Alzheimer's disease with good accuracy, showing its potential for screening Alzheimer's disease in a community setting. FUNDING: BrightFocus Foundation.

Truncated Tau caused by intron retention is enriched in Alzheimer's disease cortex and exhibits altered biochemical properties.

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-ß plaques and Tau tangles in brain tissues. Recent studies indicate that aberrant splicing and increased level of intron retention is linked to AD pathogenesis. Bioinformatic analysis revealed increased retention of intron 11 at the Tau gene in AD female dorsal lateral prefrontal cortex as compared to healthy controls, an observation validated by quantitative polymerase chain reaction using different brain tissues. Retention of intron 11 introduces a premature stop codon, resulting in the production of truncated Tau11i protein. Probing with customized antibodies designed against amino acids encoded by intron 11 showed that Tau11i protein is more enriched in AD hippocampus, amygdala, parietal, temporal, and frontal lobe than in healthy controls. This indicates that Tau messenger RNA with the retained intron is translated in vivo instead of being subjected to nonsense-mediated decay. Compared to full-length Tau441 isoform, ectopically expressed Tau11i forms higher molecular weight species, is enriched in Sarkosyl-insoluble fraction, and exhibits greater protein stability in cycloheximide assay. Stably expressed Tau11i also shows weaker colocalization with α-tubulin of microtubule network in human mature cortical neurons as compared to Tau441. Endogenous Tau11i is enriched in Sarkosyl-insoluble fraction in AD hippocampus and forms aggregates that colocalize weakly with Tau4R fibril-like structure in AD temporal lobe. The elevated level of Tau11i protein in AD brain tissues tested, coupled with biochemical properties resembling pathological Tau species suggest that retention of intron 11 of Tau gene might be an early biomarker of AD pathology.

Prevalence, Clinical Correlates, Cognitive Trajectories, and Dementia Risk Associated With Mild Behavioral Impairment in Asians.

Objective: Mild behavioral impairment (MBI) is characterized as later-life-emergent and persistent neuropsychiatric symptoms (NPS). The symptom persistence criterion of MBI has shown to increase the signal-to-noise ratio of the syndrome, decreasing the likelihood of false-positive NPS. However, the long-term cognitive and prognostic impact of MBI remains to be evaluated against the traditional framework of NPS, especially in Asian cohorts. This study investigated the epidemiologic characteristics of MBI in a prospective clinical cohort of Singaporean elderly.Methods: A total of 304 dementia-free individuals (mean [SD] age = 72.2 [8.0] years, 51.6% female) were recruited between August 2010 and October 2019. All participants underwent annual neuropsychological, neuropsychiatric, and clinical assessments for 4 consecutive years and were diagnosed as having no cognitive impairment (NCI) or cognitive impairment-no dementia (CIND). MBI was ascertained using both baseline and year-1 Neuropsychiatric Inventory assessments. Cognitive Z-scores and Clinical Dementia Rating Sum-of-Boxes (CDR-SoB) scores were calculated.Results: The prevalence of MBI was 14.5% (7.1% of NCI, 12.9% of CIND-mild, and 24.7% of CIND-moderate patients). MBI patients showed poorer cognitive function at baseline (F1,295 = 8.13 [SE = 0.47], P = .005), primarily in memory and executive function domains. MBI was associated with accelerated decline in global cognition (ß = -0.15; 95% CI, -0.23 to -0.07) along with faster increase in CDR-SoB (ß = 0.92; 95% CI, 0.62 to 1.21) as compared to individuals without symptoms or transient NPS. A total of 38.6% of MBI patients developed dementia as compared to 12.3% of non-MBI elderly (χ2 = 19.29, P < .001). MBI increased risk of incident dementia by 2.56-fold as compared to no symptoms or transient NPS, regardless of cognitive impairment.Conclusions: MBI is a neurobehavioral risk factor for dementia, representing a potential target for dementia risk modeling, preventive intervention, and disease management.

Age-Related Eye Diseases in Individuals With Mild Cognitive Impairment and Alzheimer's Disease.

Introduction: Alzheimer's disease (AD) and age-related eye diseases pose an increasing burden as the world's population ages. However, there is limited understanding on the association of AD/cognitive impairment, no dementia (CIND) with age-related eye diseases. Methods: In this cross-sectional, memory clinic-based study of multiethnic Asians aged 50 and above, participants were diagnosed as AD (n = 216), cognitive impairment, no dementia (CIND) (n = 252), and no cognitive impairment (NCI) (n = 124) according to internationally accepted criteria. Retinal photographs were graded for the presence of age-related macular degeneration (AMD) and diabetic retinopathy (DR) using standard grading systems. Multivariable-adjusted logistic regression models were used to determine the associations between neurological diagnosis and odds of having eye diseases. Results: Over half of the adults had at least one eye disease, with AMD being the most common (60.1%; n = 356), followed by DR (8.4%; n = 50). After controlling for age, sex, race, educational level, and marital status, persons with AD were more likely to have moderate DR or worse (OR = 2.95, 95% CI = 1.15-7.60) compared with NCI. In the fully adjusted model, the neurological diagnosis was not associated with AMD (OR = 0.75, 95% CI = 0.45-1.24). Conclusion: Patients with AD have an increased odds of having moderate DR or worse, which suggests that these vulnerable individuals may benefit from specific social support and screening for eye diseases.

Time-restricted feeding modulates the DNA methylation landscape, attenuates hallmark neuropathology and cognitive impairment in a mouse model of vascular dementia.

Objective: Vascular dementia (VaD) is the second most common cause of dementia worldwide. The increasing contribution of lifestyle-associated risk factors to VaD has pointed towards gene-environment interactions (i.e. epigenetics). This study thus aims to investigate the DNA methylation landscape in a chronic cerebral hypoperfusion (CCH) mouse model of VaD. As a nexus between the gene-environment interaction, intermittent fasting (IF) was introduced as a prophylactic intervention. Methods: Bilateral common carotid artery stenosis (BCAS) was used to induce CCH by placing micro-coils of 0.18 mm in each common carotid artery of the mice. The coils were left in the mice for 7, 15 and 30 days to study temporal differences. IF was introduced for 16 h daily for 4 months prior to BCAS. Reduced Representation Bisulfite Sequencing (RRBS) was used to study the DNA methylation landscape. Cognitive impairment was measured using Barnes Maze Test. White matter lesions (WML) and neuronal loss were measured using Luxol fast blue staining and cresyl violet staining respectively. Results: IF mice subjected to CCH displayed significantly better cognitive learning ability and memory, improved neuropathological alterations with reduced WMLs and neuronal loss. Modulation of DNA methylation patterns in the cortex of AL CCH mice was re-modelled and signs of reversal was observed in IF CCH mice across all three timepoints. Conclusions: These findings provide an understanding of how IF may protect the brain against damage caused by CCH and show promise in offering potential beneficial effects in mitigating the neuropathology and cognitive deficits in VaD.

Cerebrovascular disease in suspected non-Alzheimer's pathophysiology and cognitive decline over time.

BACKGROUND: The underlying cause of cognitive decline in individuals who are positive for biomarkers of neurodegeneration (N) but negative for biomarkers of amyloid-beta (A), designated as Suspected non-Alzheimer's pathophysiology (SNAP), remains unclear. We evaluate whether cerebrovascular disease (CeVD) is more prevalent in those with SNAP compared to A-N- and A+N+ individuals and whether CeVD is associated with cognitive decline over time in SNAP patients. METHODS: A total of 216 individuals from a prospective memory clinic cohort (mean [SD] age, 72.7 [7.3] years, 100 women [56.5%]) were included and were diagnosed as no cognitive impairment (NCI), cognitive impairment no dementia (CIND), Alzheimer's dementia (AD) or vascular dementia (VaD). All individuals underwent clinical evaluation and neuropsychological assessment annually for up to 5 years. Carbon 11-labeled Pittsburgh Compound B ([11 C]-PiB) or [18 F]-flutafuranol-positron emission spectrometry imaging was performed to ascertain amyloid-beta status. Magnetic resonance imaging was performed to assess neurodegeneration as measured by medial temporal atrophy ≥2, as well as significant CeVD (sCeVD) burden, defined by cortical infarct count ≥1, Fazekas score ≥2, lacune count ≥2 or cerebral microbleed count ≥2. RESULTS: Of the 216 individuals, 50 (23.1%) A-N+ were (SNAP), 93 (43.1%) A-N-, 36 (16.7%) A+N- and 37 (17.1%) A+N+. A+N+ individuals were significantly older, while A+N+ and SNAP individuals were more likely to have dementia. The SNAP group had a higher prevalence of sCeVD (90.0%) compared to A-N-. Moreover, SNAP individuals with sCeVD had significantly steeper decline in global cognition compared to A-N- over 5 years (p = 0.042). CONCLUSIONS: These findings suggest that CeVD is a contributing factor to cognitive decline in SNAP. Therefore, SNAP individuals should be carefully assessed and treated for CeVD.

A multi-regression framework to improve diagnostic ability of optical coherence tomography retinal biomarkers to discriminate mild cognitive impairment and Alzheimer's disease.

BACKGROUND: Diagnostic performance of optical coherence tomography (OCT) to detect Alzheimer's disease (AD) and mild cognitive impairment (MCI) remains limited. We assessed whether compensating the circumpapillary retinal nerve fiber layer (cpRNFL) thickness for multiple demographic and anatomical factors as well as the combination of macular layers improves the detection of MCI and AD. METHODS: This cross-sectional study of 62 AD (n = 92 eyes), 108 MCI (n = 158 eyes), and 55 cognitively normal control (n = 86 eyes) participants. Macular ganglion cell complex (mGCC) thickness was extracted. Circumpapillary retinal nerve fiber layer (cpRNFL) measurement was compensated for several ocular factors. Thickness measurements and their corresponding areas under the receiver operating characteristic curves (AUCs) were compared between the groups. The main outcome measure was OCT thickness measurements. RESULTS: Participants with MCI/AD showed significantly thinner measured and compensated cpRNFL, mGCC, and altered retinal vessel density (p < 0.05). Compensated RNFL outperformed measured RNFL for discrimination of MCI/AD (AUC = 0.74 vs 0.69; p = 0.026). Combining macular and compensated cpRNFL parameters provided the best detection of MCI/AD (AUC = 0.80 vs 0.69; p < 0.001). CONCLUSIONS AND RELEVANCE: Accounting for interindividual variations of ocular anatomical features in cpRNFL measurements and incorporating macular information may improve the identification of high-risk individuals with early cognitive impairment.

Pathophysiology of blood brain barrier dysfunction during chronic cerebral hypoperfusion in vascular cognitive impairment.

The prevalence of cerebrovascular disease increases with age, placing the elderly at a greater lifetime risk for dementia. Vascular cognitive impairment (VCI) encompasses a spectrum of cognitive deficits from mild cognitive impairment to dementia. VCI and its most severe form, vascular dementia (VaD), is becoming a major public health concern worldwide. As growing efforts are being taken to understand VCI and VaD in animal models and humans, the pathogenesis of the disease is being actively explored. It is postulated that chronic cerebral hypoperfusion (CCH) is a major cause of VCI. CCH activates a molecular and cellular injury cascade that leads to breakdown of the blood brain barrier (BBB) and neurodegeneration. The BBB tightly regulates the movement of substances between the blood and the brain, thereby regulating the microenvironment within the brain parenchyma. Here we illustrate how BBB damage is causal in the pathogenesis of VCI through the increased activation of pathways related to excitotoxicity, oxidative stress, inflammation and matrix metalloproteinases that lead to downstream perivascular damage, leukocyte infiltration and white matter changes in the brain. Thus, CCH-induced BBB damage may initiate and contribute to a vicious cycle, resulting in progressive neuropathological changes of VCI in the brain. This review outlines the molecular and cellular mechanisms that govern BBB breakdown during CCH and highlights the clinical evidence in identifying at-risk VCI patients.

The role of inflammasomes in vascular cognitive impairment.

There is an increasing prevalence of Vascular Cognitive Impairment (VCI) worldwide, and several studies have suggested that Chronic Cerebral Hypoperfusion (CCH) plays a critical role in disease onset and progression. However, there is a limited understanding of the underlying pathophysiology of VCI, especially in relation to CCH. Neuroinflammation is a significant contributor in the progression of VCI as increased systemic levels of the proinflammatory cytokine interleukin-1ß (IL-1ß) has been extensively reported in VCI patients. Recently it has been established that CCH can activate the inflammasome signaling pathways, involving NLRP3 and AIM2 inflammasomes that critically regulate IL-1ß production. Given that neuroinflammation is an early event in VCI, it is important that we understand its molecular and cellular mechanisms to enable development of disease-modifying treatments to reduce the structural brain damage and cognitive deficits that are observed clinically in the elderly. Hence, this review aims to provide a comprehensive insight into the molecular and cellular mechanisms involved in the pathogenesis of CCH-induced inflammasome signaling in VCI.

AIM2 inflammasome mediates apoptotic and pyroptotic death in the cerebellum following chronic hypoperfusion.

Vascular dementia (VaD) is the second most common form of dementia and is caused by vascular pathologies resulting in chronic cerebral hypoperfusion (CCH)- induced brain injury, and ultimately cognitive impairment and memory loss. Several lines of evidence have demonstrated chronic inflammation may be involved in VaD disease progression. It is now recognized that a major contributor to cerebral and systemic chronic inflammation involves the activation of innate immune molecular complexes termed inflammasomes. Whilst previous studies on animal models of VaD have focused on the cortex, hippocampus and striatum, few studies have investigated the effect of CCH on the cerebellum. Emerging studies have found new roles of the cerebellum in cognition, based on its structural interconnectivity with other brain regions and clinical relevance in neuropsychological deficits. In the present study, we conducted our investigation on the cerebellum using a CCH mouse model of VaD following bilateral common carotid artery stenosis (BCAS). This study is the first to characterize an increased expression of inflammasome receptors, adaptor and effector proteins, markers of inflammasome activation, proinflammatory cytokines, and apoptotic and pyroptotic cell death proteins in the cerebellum following CCH. Furthermore, in AIM2 knockout mice, we observed attenuated inflammasome-mediated production of proinflammatory cytokines, apoptosis, and pyroptosis in the cerebellum following CCH. Collectively, our findings provide novel evidence that AIM2 inflammasome activation promotes apoptosis and pyroptosis in the cerebellum following chronic hypoperfusion in a mouse model of VaD.

Hippocampal transcriptome profiling reveals common disease pathways in chronic hypoperfusion and aging.

Vascular dementia (VaD) is a progressive cognitive impairment of vascular etiology. VaD is characterized by cerebral hypoperfusion, increased blood-brain barrier permeability and white matter lesions. An increased burden of VaD is expected in rapidly aging populations. The hippocampus is particularly susceptible to hypoperfusion, and the resulting memory impairment may play a crucial role in VaD. Here we have investigated the hippocampal gene expression profile of young and old mice subjected to cerebral hypoperfusion by bilateral common carotid artery stenosis (BCAS). Our data in sham-operated young and aged mice reveal an age-associated decline in cerebral blood flow and differential gene expression. In fact, BCAS and aging caused broadly similar effects. However, BCAS-induced changes in hippocampal gene expression differed between young and aged mice. Specifically, transcriptomic analysis indicated that in comparison to young sham mice, many pathways altered by BCAS in young mice resembled those already present in sham aged mice. Over 30 days, BCAS in aged mice had minimal effect on either cerebral blood flow or hippocampal gene expression. Immunoblot analyses confirmed these findings. Finally, relative to young sham mice the cell type-specific profile of genes in both young BCAS and old sham animals further revealed common cell-specific genes. Our data provide a genetic-based molecular framework for hypoperfusion-induced hippocampal damage and reveal common cellular signaling pathways likely to be important in the pathophysiology of VaD.

Intermittent fasting attenuates inflammasome-associated apoptotic and pyroptotic death in the brain following chronic hypoperfusion.

Chronic cerebral hypoperfusion (CCH) has been shown to initiate several inflammatory pathways that can contribute to cognitive deficits and memory loss in vascular cognitive impairment (VCI). Multi-protein complexes termed inflammasomes that may be involved in the inflammatory response to CCH has already been shown to contribute to the inflammatory process and cell death following acute cerebral ischemia. Intermittent fasting (IF) has already been shown to decrease inflammasome activation and protect the brain from ischemic stroke; however, its effects during CCH remains unknown. The present study investigated the impact of IF (16 h of food deprivation daily) for four months on inflammasome-mediated cell death in the cerebellum following CCH in a mouse model of VCI using fourteen to sixteen-week-old male C57BL/6NTac mice. Here we demonstrated that IF decreased inflammasome activation, and initiation of apoptotic and pyroptotic cell death pathways as reflected by the reduction (20-30%) in the expression levels of key effector proteins and cell death markers in the cerebellum following CCH. In summary, our results indicate that IF can attenuate the inflammatory response and cell death pathways in the brain following chronic hypoperfusion in a mouse model of VCI.

High burden of cerebral white matter lesion in 9 Asian cities.

Age-related white matter lesion (WML) is considered a manifestation of sporadic cerebral small vessel disease and an important pathological substrate for dementia. Asia is notable for its large population with a looming dementia epidemic. Yet, the burden of WML and its associated risk factors across different Asian societies are unknown. Subjects from 9 Asian cities (Bangkok, Bandung, Beijing, Bengaluru, Hong Kong, Kaohsiung, Manila, Seoul, and Singapore) were recruited (n = 5701) and classified into (i) stroke/transient ischemic attack (TIA), (ii) Alzheimer's disease (AD)/mild cognitive impairment (MCI), or (iii) control groups. Data on vascular risk factors and cognitive performance were collected. The severity of WML was visually rated on MRI or CT. The prevalence of moderate-to-severe WML was the highest in subjects with stroke/TIA (43.3%). Bandung Indonesia showed the highest prevalence of WML, adjusted for age, sex, education, disease groups, and imaging modality. Hypertension and hyperlipidemia were significant risk factors for WML, and WML was negatively associated with MMSE in all groups. WML is highly prevalent in Asia and is associated with increasing age, hypertension, hyperlipidemia, and worse cognitive performance. Concerted efforts to prevent WML will alleviate the huge dementia burden in the rapidly aging Asian societies.