Mild cognitive impairment: a systematic review

MCI is a nosological entity proposed as an intermediate state between normal aging and dementia. The syndrome can be divided into two broad subtypes: amnestic MCI ( aMCI) characterized by reduced memory, and non- amnestic MCI ( naMCI) in which other cognitive functions rather than memory are mostly impaired. aMCI seems to represent an early stage of AD, while the outcomes of the naMCI subtypes appear more heterogeneous - including vascular dementia, frontotemporal dementia or dementia with Lewy bodies- but this aspect is still under debate. MCI in fact represents a condition with multiple sources of heterogeneity, including clinical presentation, etiology, and prognosis. To improve classification and prognosis, there is a need for more sensitive instruments specifically developed for MCI as well as for more reliable methods to determine its progression or improvement. Current clinical criteria for MCI should be updated to include restriction in complex ADL; also the diagnostic and prognostic role of behavioral symptoms and motor dysfunctions should be better defined. A multidisciplinary diagnostic approach including biological and neuroimaging techniques may probably represent the best option to predict the conversion from MCI to dementia. In this review we discuss the most recent aspects related to the epidemiological, clinical, neuropathological, neuroimaging, biochemical and therapeutic aspects of MCI, with specific attention to possible markers of conversion to dementia

Biomarkers of oxidative and nitrosative damage in Alzheimer's disease and mild cognitive impairment

Alzheimer's disease (AD) is the most common type of dementia in the elderly. Products of oxidative and nitrosative stress (OS and NS, respectively) accumulate with aging, which is the main risk factor for AD. This provides the basis for the involvement of OS and NS in AD pathogenesis. OS and NS occur in biological systems due to the dysregulation of the redox balance, caused by a deficiency of antioxidants and/or the overproduction of free radicals. Free radical attack against lipids, proteins, sugars and nucleic acids leads to the formation of bioproducts whose detection in fluids and tissues represents the currently available method for assessing oxidative/nitrosative damage. Post-mortem and in-vivo studies have demonstrated an accumulation of products of free radical damage in the central nervous system and in the peripheral tissues of subjects with AD or mild cognitive impairment (MCI). In addition to their individual role, biomarkers for OS and NS in AD are associated with altered bioenergetics and amyloid-beta (Aβ) metabolism. In this review we discuss the main results obtained in the field of biomarkers of oxidative/nitrosative stress in AD and MCI in humans, in addition to their potential role as a tool for diagnosis, prognosis and treatment efficacy in AD. © 2009 Elsevier Ireland Ltd. All rights reserved

Appendix to "Torque setpoint tracking for parallel hybrid electric vehicles using dynamic input allocation", published on IEEE Transactions on Control Systems Technology

A dynamic allocator is proposed in order to generalize a previously introduced strategy for input redundant plants, which applies to linear plants with multiple and redundant inputs. The theory is extended here to the case of multiple linear actuators, each of them with its own dynamics, acting on a nonlinear plant with strong input redundancy. In the HEV case the two redundant inputs are the ICE and EM torques and the two actuators with different dynamics are the two propulsion systems

Cognitive performance in elderly patients undergoing carotid endarterectomy or carotid artery stenting: A twelve-month follow-up study

Background: It is still a matter of debate if and to what extent carotid endarterectomy (CEA) and carotid artery stenting (CAS) impair cognitive functioning in the elderly. Methods: We conducted a nonrandomized clinical trial on subjects with asymptomatic carotid artery stenosis comparing CEA (n = 28; 24 males and 4 females; 72.6 ± 5.8 years old) with CAS (n = 29; 17 males and 12 females; 75.1 ± 5.7 years old). Cognition, mood and functional status were evaluated by a broad spectrum of tests performed on the day prior to carotid reopening as well as 3 and 12 months after. Results: No significant differences in scores on cognitive tests including the Babcock story recall test and Rey's auditory verbal learning test (memory), category naming test (verbal fluency), trail-making test parts A and B (attention and executive function) and controlled oral word association test (executive functioning) were observed 3 and 12 months after carotid reopening independent of the technique used. Only scores on the copy drawing test (visuospatial and constructional abilities) slightly but significantly (p < 0.05) worsened in the CAS group 12 months after the intervention. No significant differences between the CEA and CAS groups were detected regarding mood and functional status after 3 and 12 months. Conclusions: CEA and CAS seem to be safe procedures in elderly patients in terms of cognitive, mood and functional status in the short and long term. CAS might be preferred for the shorter hospital stay, but further studies with a larger number of old and oldest old subjects with a longer follow-up are needed to better understand the cost-effectiveness of both treatments

Vitamin E for Alzheimer's dementia and mild cognitive impairment

Background: Vitamin E is a dietary compound that functions as an antioxidant scavenging toxic free radicals. Evidence that free radicals may contribute to the pathological processes of cognitive impairment including Alzheimer's disease has led to interest in the use of vitamin E in the treatment of mild cognitive impairment (MCI) and Alzheimer's dementia (AD). Objectives: To assess the efficacy of vitamin E in the treatment of AD and prevention of progression of MCI to dementia. Search methods: The Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (ALOIS), The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS as well as many trials databases and grey literature sources were searched on 25 June 2012 using the terms: "Vitamin E", vitamin-E, alpha-tocopherol. Selection criteria: All unconfounded, double-blind, randomised trials in which treatment with vitamin E at any dose was compared with placebo for patients with AD and MCI. Data collection and analysis: Two review authors independently applied the selection criteria and assessed study quality and extracted and analysed the data. For each outcome measure data were sought on every patient randomised. Where such data were not available an analysis of patients who completed treatment was conducted. It was not possible to pool data between studies owing to a lack of comparable outcome measure. Main results: Only three studies met the inclusion criteria: two in an AD population and one in an MCI population. In the first of the AD studies (Sano 1996) the authors reported some benefit from vitamin E (2000 IU/day) with fewer participants reaching an end point of death, institutionalisation, change to a Clinical Dementia Rating (CDR) of three, or loss of two basic activities of daily living within two years. Of patients completing treatment, 58% (45/77) on vitamin E compared with 74% (58/78) on placebo reached one of the end points (odds ratio (OR) 0.49; 95% confidence interval (CI) 0.25 to 0.96). The second AD treatment study (Lloret 2009) explored the effects of vitamin E (800 IU/day) on cognitive progression in relation to oxidative stress levels. Patients whose oxidative stress markers were lowered by vitamin E showed no significant difference in the percentage change in Mini-Mental State Examination (MMSE) score, between baseline and six months, compared to the placebo group. The primary aim of the MCI study (Petersen 2005) was to investigate the effect of vitamin E (2000 IU/day) on the time to progression from MCI to possible or probable AD. A total of 214 of the 769 participants progressed to dementia, with 212 being classified as having possible or probable AD. There was no significant difference in the probability of progression from MCI to AD between the vitamin E group and the placebo group (hazard ratio 1.02; 95% CI 0.74 to 1.41; P = 0.91). Authors' conclusions: No convincing evidence that vitamin E is of benefit in the treatment of AD or MCI. Future trials assessing vitamin E treatment in AD should not be restricted to alpha-tocopherol

DNA repair modulates the vulnerability of the developing brain to alkylating agents

Neurons of the developing brain are especially vulnerable to environmental agents that damage DNA (i.e., genotoxicants), but the mechanism is poorly understood. The focus of the present study is to demonstrate that DNA damage plays a key role in disrupting neurodevelopment. To examine this hypothesis, we compared the cytotoxic and DNA damaging properties of the methylating agents methylazoxymethanol (MAM) and dimethyl sulfate (DMS) and the mono- and bifunctional alkylating agents chloroethylamine (CEA) and nitrogen mustard (HN2), in granule cell neurons derived from the cerebellum of neonatal wild type mice and three transgenic DNA repair strains. Wild type cerebellar neurons were significantly more sensitive to the alkylating agents DMS and HN2 than neuronal cultures treated with MAM or the half-mustard CEA. Parallel studies with neuronal cultures from mice deficient in alkylguanine DNA glycosylase (Aag[superscript −/−]) or O6-methylguanine methyltransferase (Mgmt[superscript −/−]), revealed significant differences in the sensitivity of neurons to all four genotoxicants. Mgmt−/− neurons were more sensitive to MAM and HN2 than the other genotoxicants and wild type neurons treated with either alkylating agent. In contrast, Aag[superscript −/−] neurons were for the most part significantly less sensitive than wild type or Mgmt[superscript −/−] neurons to MAM and HN2. Aag[superscript −/−] neurons were also significantly less sensitive than wild type neurons treated with either DMS or CEA. Granule cell development and motor function were also more severely disturbed by MAM and HN2 in Mgmt[superscript −/−] mice than in comparably treated wild type mice. In contrast, cerebellar development and motor function were well preserved in MAM-treated Aag[superscript −/−] or MGMT-overexpressing (Mgmt[superscript Tg+]) mice, even as compared with wild type mice suggesting that AAG protein increases MAM toxicity, whereas MGMT protein decreases toxicity. Surprisingly, neuronal development and motor function were severely disturbed in Mgmt[superscript Tg+] mice treated with HN2. Collectively, these in vitro and in vivo studies demonstrate that the type of DNA lesion and the efficiency of DNA repair are two important factors that determine the vulnerability of the developing brain to long-term injury by a genotoxicant.United States. Army Medical Research and Materiel Command (Contract/Grant/Intergovernmental Project Order DAMD 17-98-1-8625)United States. National Institutes of Health (grants CA075576)United States. National Institutes of Health (RO1 C63193)United States. National Institutes of Health (P30 CA043703

RTAIAED: A Real-Time Ambulance in an Emergency Detector with a Pyramidal Part-Based Model Composed of MFCCs and YOLOv8

In emergency situations, every second counts for an ambulance navigating through traffic. Efficient use of traffic light systems can play a crucial role in minimizing response time. This paper introduces a novel automated Real-Time Ambulance in an Emergency Detector (RTAIAED). The proposed system uses special Lookout Stations (LSs) suitably positioned at a certain distance from each involved traffic light (TL), to obtain timely and safe transitions to green lights as the Ambulance in an Emergency (AIAE) approaches. The foundation of the proposed system is built on the simultaneous processing of video and audio data. The video analysis is inspired by the Part-Based Model theory integrating tailored video detectors that leverage a custom YOLOv8 model for enhanced precision. Concurrently the audio analysis component employs a neural network designed to analyze Mel Frequency Cepstral Coefficients (MFCCs) providing an accurate classification of auditory information. This dual-faceted approach facilitates a cohesive and synergistic analysis of sensory inputs. It incorporates a logic-based component to integrate and interpret the detections from each sensory channel, thereby ensuring the precise identification of an AIAE as it approaches a traffic light. Extensive experiments confirm the robustness of the approach and its reliable application in real-world scenarios thanks to its predictions in real time (reaching an fps of 11.8 on a Jetson Nano and a response time up to 0.25 s), showcasing the ability to detect AIAEs even in challenging conditions, such as noisy environments, nighttime, or adverse weather conditions, provided a suitable-quality camera is appropriately positioned. The RTAIAED is particularly effective on one-way roads, addressing the challenge of regulating the sequence of traffic light signals so as to ensure a green signal to the AIAE when arriving in front of the TL, despite the presence of the “double red” periods in which the one-way traffic is cleared of vehicles coming from one direction before allowing those coming from the other side. Also, it is suitable for managing temporary situations, like in the case of roadworks

Plasma based markers of [11C] PiB-PET brain amyloid burden.

PublishedJournal ArticleResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov'tChanges in brain amyloid burden have been shown to relate to Alzheimer's disease pathology, and are believed to precede the development of cognitive decline. There is thus a need for inexpensive and non-invasive screening methods that are able to accurately estimate brain amyloid burden as a marker of Alzheimer's disease. One potential method would involve using demographic information and measurements on plasma samples to establish biomarkers of brain amyloid burden; in this study data from the Alzheimer's Disease Neuroimaging Initiative was used to explore this possibility. Sixteen of the analytes on the Rules Based Medicine Human Discovery Multi-Analyte Profile 1.0 panel were found to associate with [(11)C]-PiB PET measurements. Some of these markers of brain amyloid burden were also found to associate with other AD related phenotypes. Thirteen of these markers of brain amyloid burden--c-peptide, fibrinogen, alpha-1-antitrypsin, pancreatic polypeptide, complement C3, vitronectin, cortisol, AXL receptor kinase, interleukin-3, interleukin-13, matrix metalloproteinase-9 total, apolipoprotein E and immunoglobulin E--were used along with co-variates in multiple linear regression, and were shown by cross-validation to explain >30% of the variance of brain amyloid burden. When a threshold was used to classify subjects as PiB positive, the regression model was found to predict actual PiB positive individuals with a sensitivity of 0.918 and a specificity of 0.545. The number of APOE [Symbol: see text] 4 alleles and plasma apolipoprotein E level were found to contribute most to this model, and the relationship between these variables and brain amyloid burden was explored.Alzheimer's Disease Neuroimaging Initiative (ADNI)Canadian Institutes of Health ResearchFoundation for the National Institutes of HealthNational Institutes of HealthInnoMed, European Union of the Sixth Framework programNational Institutes for Health Research Biomedical Research Centre for Mental Health at the South London and Maudsley National Health Service Foundation TrustInstitute of Psychiatry, King's College Londo

Mitochondrial dysfunction and immune activation are detectable in early Alzheimer's disease blood.

PublishedJournal ArticleResearch Support, Non-U.S. Gov'tAlzheimer's disease (AD), like other dementias, is characterized by progressive neuronal loss and neuroinflammation in the brain. The peripheral leukocyte response occurring alongside these brain changes has not been extensively studied, but might inform therapeutic approaches and provide relevant disease biomarkers. Using microarrays, we assessed blood gene expression alterations occurring in people with AD and those with mild cognitive changes at increased risk of developing AD. Of the 2,908 differentially expressed probes identified between the three groups (p < 0.01), a quarter were altered in blood from mild cognitive impairment (MCI) and AD subjects, relative to controls, suggesting a peripheral response to pathology may occur very early. There was strong evidence for mitochondrial dysfunction with decreased expression of many of the respiratory complex I-V genes and subunits of the core mitochondrial ribosome complex. This mirrors changes previously observed in AD brain. A number of genes encoding cell adhesion molecules were increased, along with other immune-related genes. These changes are consistent with leukocyte activation and their increased the transition from circulation into the brain. In addition to expression changes, we also found increased numbers of basophils in people with MCI and AD, and increased monocytes in people with an AD diagnosis. Taken together this study provides both an insight into the functional response of circulating leukocytes during neurodegeneration and also identifies potential targets such as the respiratory chain for designing and monitoring future therapeutic interventions using blood.InnoMed, European Union of the Sixth Framework programAlzheimer’s Research TrustJohn and Lucille van Geest FoundationNIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation TrustInstitute of Psychiatry Kings College Londo