34 research outputs found
Alleviating the cold-start problem by using demographic data and domain-aware similarity measure
No full textRecommender systems (RS) are a cornerstone for most online businesses that cater to a large customer base such as e-commerce, social network platforms and many others. RS's enable these platforms to provide tailor-made experiences to each of their customers by strategically utilizing users/items rating data or any other available data. Collaborative filtering (CF) techniques are some of the most popular and successful RS models created. However, CF techniques often suffer from the cold start (CS) problem. In particular, they struggle with complete cold start (CCS) situations in which no user/item rating history is available and incomplete cold start (ICS) situations in which only a limited amount of user/item rating history is available. In this paper, we explore two models which utilize novel ideas to combat the CCS and ICS problems. The first model (DCF) focuses on the intelligent use of user demographic data to combat the CCS problem. The second model (PIPCF) focuses on the use of a novel domain-specific similarity measure called Proximity-Impact-Popularity (PIP) to combat the ICS problem. In addition to this, we also propose our own model (DPIP-CF) which combines these two ideas in conjunction with some of our own modifications to combat the CCS and ICS problems simultaneously. We utilize the MovieLens data set which is a commonly available and popular dataset that is often used to test RS's. Through a series of experiments, we demonstrate the strengths of DCF and PIPCF in dealing with the CCS and ICS problems respectively. Finally, we also show that our DPIP-CF model outperforms all other models discussed in this paper and is a viable solution to dealing with the CCS and ICS problems simultaneously.CSE3000 Research ProjectComputer Science and Engineerin
Current perspectives on prevention of vascular cognitive impairment and promotion of vascular brain health
No full text\ua9 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. Introduction: The true global burden of vascular cognitive impairment (VCI) is unknown. Reducing risk factors for stroke and cardiovascular disease would inevitably curtail VCI. Areas Covered: The authors review current diagnosis, epidemiology, and risk factors for VCI. VCI increases in older age and by inheritance of known genetic traits. They emphasize modifiable risk factors identified by the 2020 Lancet Dementia Commission. The most profound risks for VCI also include lower education, cardiometabolic factors, and compromised cognitive reserve. Finally, they discuss pharmacological and non-pharmacological interventions. Expert Opinion: By virtue of the high frequencies of stroke and cardiovascular disease the global prevalence of VCI is expectedly higher than prevalent neurodegenerative disorders causing dementia. Since ~ 90% of the global burden of stroke can be attributed to modifiable risk factors, a formidable opportunity arises to reduce the burden of not only stroke but VCI outcomes including progression from mild to the major in form of vascular dementia. Strict control of vascular risk factors and secondary prevention of cerebrovascular disease via pharmacological interventions will impact on burden of VCI. Non-pharmacological measures by adopting healthy diets and encouraging physical and cognitive activities and urging multidomain approaches are important for prevention of VCI and preservation of vascular brain health
Metabolic syndrome and the immunological affair with the blood-brain barrier
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Author Correction: Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores (Nature Communications, (2021), 12, 1, (3417), 10.1038/s41467-021-22491-8)
No full textThe original version of this Article omitted from the author list the 212th author Patrizia Mecocci, who is from the Institute of Gerontology and Geriatrics, Department of Medicine, University of Perugia, Perugia, Italy. Consequently, the “Sample Contribution” section of Author Contributions was updated to add “P.M” between “P.D.” and “R.C.”. Additionally, the original version of this Article contained the incorrect affiliation for author Patrick Gavin Kehoe, which incorrectly read “German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany”. The correct version replaces this affiliation with “Bristol Medical School (THS), University of Bristol, Southmead Hospital, Bristol, UK”. This has been corrected in both the PDF and HTML versions of the Article. © The Author(s) 2023
Transcriptomic Profiling Reveals Discrete Poststroke Dementia Neuronal and Gliovascular Signatures
No full text\ua9 2022, The Author(s). Poststroke dementia (PSD) is associated with pathology in frontal brain regions, in particular dorsolateral prefrontal cortex (DLPFC) neurons and white matter, remote from the infarct. We hypothesised that PSD results from progressive DLPFC neuronal damage, associated with frontal white matter gliovascular unit (GVU) alterations. We investigated the transcriptomic profile of the neurons and white matter GVU cells previously implicated in pathology. Laser-capture microdissected neurons, astrocytes and endothelial cells were obtained from the Cognitive Function After Stroke cohort of control, PSD and poststroke non-dementia (PSND) human subjects. Gene expression was assessed using microarrays and pathway analysis to compare changes in PSD with controls and PSND. Neuronal findings were validated using NanoString technology and compared with those in the bilateral common carotid artery stenosis (BCAS) mouse model. Comparing changes in PSD compared to controls with changes in PSND compared to controls identified transcriptomic changes associated specifically with dementia. DLPFC neurons showed defects in energy production (tricarboxylic acid (TCA) cycle, adenosine triphosphate (ATP) binding and mitochondria), signalling and communication (MAPK signalling, Toll-like receptor signalling, endocytosis). Similar changes were identified in neurons isolated from BCAS mice. Neuronal findings accompanied by altered astrocyte communication and endothelium immune changes in the frontal white matter, suggesting GVU dysfunction. We propose a pathogenic model in PSD whereby neuronal changes are associated with frontal white matter GVU dysfunction leading to astrocyte failure in supporting neuronal circuits resulting in delayed cognitive decline associated with PSD. Therefore, targeting these processes could potentially ameliorate the dementia seen in PSD
Mutations in NOTCH3 cause the formation and retention of aggregates in the endoplasmic reticulum, leading to impaired cell proliferation
No full textMutations in the human NOTCH3 gene cause cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), but the pathogenic mechanisms of the disorder remain unclear. We investigated the cytotoxic properties of mutant Notch3 using stable cell lines with inducible expression of either wild-type or two mutants p.R133C and p.C185R. We found that both mutants of Notch3 were prone to aggregation and retained in the endoplasmic reticulum (ER). The turnover rates of the mutated Notch3 proteins were strikingly slow, with half-lives greater than 6 days, whereas wild-type Notch3 was rapidly degraded, with a half-life of 0.7 days. The expression of mutant Notch3 also impaired cell proliferation compared with wild-type Notch3. In addition, cell lines expressing mutant Notch3 were more sensitive to proteasome inhibition resulting in cell death. These findings suggest that prolonged retention of mutant Notch3 aggregates in the ER decreases cell growth and increases sensitivity to other stresses. It is also possible that the aggregate-prone property of mutant Notch3 contributes to a pathogenic mechanism underlying CADASIL. \ua9 The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
High vulnerability of medial prefrontal pyramidal neurons in post-stroke, vascular, Alzheimer\u27s disease, and aging-related dementias
No full text\ua9 2026 The Author(s). Alzheimer\u27s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer\u27s Association. INTRODUCTION: The medial prefrontal cortex (mPFC) is critical for executive function, behavioral inhibition, and memory. Its high vulnerability to dementia, compared to other prefrontal regions, remains unclear. METHODS: We analyzed post mortem brain tissue from 118 older subjects, including post-stroke survivors, Alzheimer\u27s disease; vascular, mixed, and frontotemporal dementia (FTD); and cognitively unimpaired controls. Three-dimensional stereology was used to assess pyramidal neuron densities and volumes in mPFC layers III and V. Immunohistochemistry evaluated metabolic dysfunction via cytochrome c oxidase subunit 1 (COX1), cytochrome c oxidase subunit 4 (COX4), and 78 kDa glucose-regulated protein expression. RESULTS: Pyramidal neuron densities were lowered by ≈ 45% and volumes by ≈ 37% within all dementia groups relative to controls, except for FTD densities. COX1 and COX4 mitochondrial markers were consistently reduced across dementias. Neuronal densities declined with age, especially in the sixth decade of life. Other prefrontal areas were less affected. DISCUSSION: The mPFC shows high neuronal vulnerability in dementia, while suggesting a vascular–metabolic mechanism, with implications for targeted therapeutic strategies. Highlights: Severe pyramidal neuron loss and atrophy arose in the medial prefrontal cortex. Neuronal morphometric changes correlated with cognitive status or aging effects. Metabolic changes decreased by the greatest extent in vascular-associated dementias. Metabolic neuronal markers correlated with aging and frontal vascular pathology
Loss with ageing but preservation of frontal cortical capillary pericytes in post-stroke dementia, vascular dementia and Alzheimer’s disease
No full text\ua9 2021, The Author(s). Cerebral pericytes are an integral component of the neurovascular unit, which governs the blood–brain barrier. There is paucity of knowledge on cortical pericytes across different dementias. We quantified cortical pericytes in capillaries in 124 post-mortem brains from subjects with post-stroke dementia (PSD), vascular dementia (VaD), Alzheimer’s disease (AD) and AD-VaD (Mixed) and, post-stroke non-demented (PSND) stroke survivors as well as normal ageing controls. Collagen 4 (COL4)-positive nucleated pericyte soma were identified as protrusions on capillaries of the frontal cortex. The COL4-positive somata or nodule-like cell bodies were also verified by platelet derived growth factor receptor-β (PDGFR-β) immunohistochemistry. The mean (\ub1 SEM) pericyte somata in frontal cortical capillaries in normal young controls (46–65 years of age) was estimated as 5.2 \ub1 0.2 per mm capillary length. This number was reduced by 45% in older controls (> 78 years) to 2.9 \ub1 0.1 per mm capillary length (P < 0.001). We further found that the numbers of pericyte cell bodies per COL4 mm2 area or per mm capillary length were not decreased but rather preserved or increased in PSD, AD and Mixed dementia groups compared to similar age older controls (P < 0.01). Consistent with this, we noted that capillary length densities identified by the endothelial marker glucose transporter 1 or COL4 were not different across the dementias compared to older controls. There was a negative correlation with age (P < 0.001) suggesting fewer pericyte somata in older age, although the % COL4 immunoreactive capillary area was increased in older controls compared to young controls. Using a proven reliable method to quantify COL4-positive nucleated pericytes, our observations demonstrate ageing related loss but mostly preserved pericytes in the frontal cortex of vascular and AD dementias. We suggest there is differential regulation of capillary pericytes in the frontal lobe between the cortex and white matter in ageing-related dementias
Nox2 underpins microvascular inflammation and vascular contributions to cognitive decline
No full text\ua9 The Author(s) 2022. Chronic microvascular inflammation and oxidative stress are inter-related mechanisms underpinning white matter disease and vascular cognitive impairment (VCI). A proposed mediator is nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (Nox2), a major source of reactive oxygen species (ROS) in the brain. To assess the role of Nox2 in VCI, we studied a tractable model with white matter pathology and cognitive impairment induced by bilateral carotid artery stenosis (BCAS). Mice with genetic deletion of Nox2 (Nox2 KO) were compared to wild-type (WT) following BCAS. Sustained BCAS over 12 weeks in WT mice induced Nox2 expression, indices of microvascular inflammation and oxidative damage, along with white matter pathology culminating in a marked cognitive impairment, which were all protected by Nox2 genetic deletion. Neurovascular coupling was impaired in WT mice post-BCAS and restored in Nox2 KO mice. Increased vascular expression of chemoattractant mediators, cell-adhesion molecules and endothelial activation factors in WT mice post-BCAS were ameliorated by Nox2 deficiency. The clinical relevance was confirmed by increased vascular Nox2 and indices of microvascular inflammation in human post-mortem subjects with cerebral vascular disease. Our results support Nox2 activity as a critical determinant of VCI, whose targeting may be of therapeutic benefit in cerebral vascular disease
Trajectories of cognitive change following stroke: Stepwise decline towards dementia in the elderly
No full text\ua9 2022 The Author(s). Published by Oxford University Press on behalf of the Guarantors of Brain. Stroke events increase the risk of developing dementia, 10% for a first-ever stroke and 30% for recurrent strokes. However, the effects of stroke on global cognition, leading up to dementia, remain poorly understood. We investigated: (i) post-stroke trajectories of cognitive change, (ii) trajectories of cognitive decline in those who develop dementia over periods of follow-up length and (iii) risk factors precipitating the onset of dementia. Prospective cohort of hospital-based stroke survivors in North-East England was followed for up to 12 years. In this study, we included 355 stroke survivors of ≥75 years of age, not demented 3 months post-stroke, who had had annual assessments during follow-up. Global cognition was measured annually and characterized using standardized tests: Cambridge Cognition Examination - Revised and Mini-Mental State Examination. Demographic data and risk factors were recorded at baseline. Mixed-effects models were used to study trajectories in global cognition, and logistic models to test associations between the onset of dementia and key risk factors, adjusted for age and sex. Of the 355 participants, 91 (25.6%) developed dementia during follow-up. The dementia group had a sharper decline in Cambridge Cognition Examination - Revised (coeff. = -1.91, 95% confidence interval = -2.23 to -1.59, P < 0.01) and Mini-Mental State Examination (coeff. = -0.46, 95% confidence interval = -0.58 to -0.34, P < 0.01) scores during follow-up. Stroke survivors who developed dementia within 3 years after stroke showed a steep decline in global cognition. However, a period of cognitive stability after stroke lasting 3 years was identified for individuals diagnosed with dementia in 4-6 years (coeff. = 0.28, 95% confidence interval = -3.28 to 3.8, P = 0.88) of 4 years when diagnosed at 7-9 years (coeff. = -3.00, 95% confidence interval = -6.45 to 0.45, P = 0.09); and of 6 years when diagnosed at 10-12 years (coeff. = -6.50, 95% confidence interval = -13.27 to 0.27, P = 0.06). These groups then showed a steep decline in Cambridge Cognition Examination - Revised in the 3 years prior to diagnosis of dementia. Risk factors for dementia within 3 years include recurrent stroke (odds ratio = 3.99, 95% confidence interval = 1.30-12.25, P = 0.016) and previous disabling stroke, total number of risk factors for dementia (odds ratio = 2.02, 95% confidence interval = 1.26-3.25, P = 0.004) and a Cambridge Cognition Examination - Revised score below 80 at baseline (odds ratio = 3.50, 95% confidence interval = 1.29-9.49, P = 0.014). Our unique longitudinal study showed cognitive decline following stroke occurs in two stages, a period of cognitive stability followed by rapid decline before a diagnosis of dementia. This pattern suggests stroke may predispose survivors for dementia by diminishing cognitive reserve but with a smaller impact on cognitive function, where cognitive decline may be precipitated by subsequent events, e.g. another cerebrovascular event. This supports the assertion that the development of vascular dementia can be stepwise even when patients have small stroke lesions
