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BACKGROUND Neuropsychological tests are particularly important for the clinical evaluation and Alzheimer's disease (AD) diagnosis. However, the tests currently employed for neuropsychological assessment have been developed several decades ago, and thus they do not fully exploit the potential provided by modern digital tools. One of the tests most commonly employed to assess attention and executive functions is the Trail Making Test (TMT). OBJECTIVE The aim of this study was to evaluate whether the TMT developed and used for the serious exergame X-Torp (TMTX-Torp) can be used to evaluate cognitive functions such as mental flexibility. METHODS Adjusted multivariate mixed model was used to compare performances in the TMTX-Torp to performances in the standard variant (TMTs) in three populations. 21 participants with AD (78.6y±8.5 y), 27 with mild cognitive impairment (MCI) (76.8y±8.5 y), and 27 healthy (HEC) (71.8y±7.4 y) were included. RESULTS A difference was observed for the TMT A between AD and HEC and for the TMT B between AD and MCI and between AD and HEC. Whatever the variant of the TMT, we found a positive linear correlation between the time to complete the TMTX-Torp and the TMTs for HEC (TMT A: r = 0.75, p

Background: BIOMARKAPD seeks to diminish the barriers associated with the clinical use of cerebrospinal fluid (CSF) biomarker analysis by reducing variation in CSF laboratory methodologies and generating consensus recommendations on their clinical interpretation and application for dementia diagnosis.Objective: To examine the disparity in practitioner attitudes and clinical practice relating to the use of CSF biomarkers for dementia diagnosis across Europe.Methods: Clinical dementia experts were surveyed on the prevalence of national consensus guidelines and analytical reimbursement across Europe, their biomarker platform preferences, lumbar puncture methodologies and application of reference values and cut-offs for CSF analysis.Results: 74% of respondents (total n = 51) use CSF biomarkers in clinical practice and 69% perform lumbar punctures on an outpatient basis. Most use CSF biomarkers to diagnose atypical (84%) and early-onset cases of cognitive impairment (71%) and for the differential diagnosis of other dementias (69%). 82% state they are sufficiently informed about CSF biomarkers yet 61% report a lack of national consensus guidelines on their use for dementia diagnosis. 48% of countries represented do not reimburse clinical CSF analysis costs. 43% report using normal reference ranges derived from publications.Conclusion: Variations in attitude and practice relating to CSF biomarkers, widely recognised as barriers to their clinical acceptance, remain evident within and between countries across Europe, even in expert centres. These shortcomings must be addressed by developing consensus guidelines on CSF-related methodologies and their clinical application, to further their use for the diagnostic evaluation of dementia.

Porphyromonas gingivalis (Pg) is a primary oral pathogen in the widespread biofilm-induced “chronic” multi-systems inflammatory disease(s) including Alzheimer’s disease (AD). It is possibly the only second identified unique example of a biological extremophile in the human body. Having a better understanding of the key microbiological and genetic mechanisms of its pathogenesis and disease induction are central to its future diagnosis, treatment, and possible prevention. The published literature around the role of Pg in AD highlights the bacteria’s direct role within the brain to cause disease. The available evidence, although somewhat adopted, does not fully support this as the major process. There are alternative pathogenic/virulence features associated with Pg that have been overlooked and may better explain the pathogenic processes found in the “infection hypothesis” of AD. A better explanation is offered here for the discrepancy in the relatively low amounts of “Pg bacteria” residing in the brain compared to the rather florid amounts and broad distribution of one or more of its major bacterial protein toxins. Related to this, the “Gingipains Hypothesis”, AD-related iron dyshomeostasis, and the early reduced salivary lactoferrin, along with the resurrection of the Cholinergic Hypothesis may now be integrated into one working model. The current paper suggests the highly evolved and developed Type IX secretory cargo system of Pg producing outer membrane vesicles may better explain the observed diseases. Thus it is hoped this paper can provide a unifying model for the sporadic form of AD and guide the direction of research, treatment, and possible prevention.

Technology has transformed the science and practice of medicine. In this special mini-forum, data using digital neuropsychological technology are reported. All of these papers demonstrate how coupling digital technology with standard paper and pencil neuropsychological tests are able to extract behavior not otherwise obtainable. As digital assessment methods mature, early identification of persons with emergent neurodegenerative and other neurological illness may be possible.

Virtual reality-based neuropsychological assessments proffer the potential to address the limited ecological validity of pen-and-paper measures of memory. To investigate the construct validity of a newly developed virtual reality measure of memory, the Virtual Environment Grocery Store (VEGS), traditional neuropsychological measures of memory and executive functioning were administered to 48 older adults and 55 young adults. Performances on the VEGS memory tasks and the traditional neuropsychological assessments of memory were positively correlated, indicating that memory for VEGS content was similar to memory for traditional paper-and-pencil measures. The older adults performed significantly worse than young adults on the VEGS and the California Verbal Learning Test, but the DKEFS Color-Word Interference failed to differentiate the groups. Furthermore, significant differences were found between groups for the VEGS memory and multitasking measures. The VEGS has the advantage over traditional measures of providing objective measurement of individual components of memory in simulations of everyday activities.

In this paper, we reconstructed the medical history of frontotemporal dementia (FTD) by reviewing the literature and analyzing papers with the highest impact through citation index. Several research studies and groups involved in FTD have been reviewed. An increasing amount of knowledge has been made available in the last 20 years through a large number of publications, leading to a better definition of the genetic and clinical bases of the disease. A total of 1,436 references (articles and reviews), published in 395 journals, were retrieved through the Scopus database. The two highest publication peaks (i.e., largest number of publications) were found in 2000 and 2008. The most cited papers considering both total citation number and the number of citations within the first two years after publication refer to: (i) the genetic bases of FTD, (ii) the clinical criteria that progressively refined the different FTD phenotypes, and (iii) FTD epidemiology. Advanced neuroimaging techniques, genotype-phenotype heterogeneity, and animal models gave us a broader understanding of various aspects of the disorder. These findings confirm the great interest in FTD research. The analysis of the literature might help in guiding future goals in the field.

Background/Objective: Alzheimer’s disease (AD) is a very costly pathology. Total costs of AD result from the sum of direct and indirect costs. Intangible costs represent an additional burden that is difficult to quantify. This paper has reviewed the evaluation of the costs of AD and the methodologies to estimate them, and proposes the use of some tools which may be useful in establishing the financial weight of the disease. Method: A systematic literature search was conducted using the Pubmed and Medline databases as a source of published papers. Results: In AD, direct and indirect costs and their sum (total costs) are very high and tend to increase parallel with the evolution of the pathology. The evolution of AD is characterized by the loss of functional autonomy, the onset of behavioral and sleep disorders, and the development of delusions and hallucinations. This requires more frequent medical examinations and hospitalizations resulting in higher direct costs, which become the relevant weight. None of the papers reviewed investigated intangible cost. Conclusion: The calculation of costs of AD is frequently based on cognitive decline and the degree of dependence of patients. The evaluation of intangible costs (psychological pain of the patient and of the unpaid caregivers’ and their impaired quality of life) is a missing aspect in all reviewed studies. Due to the complexity of AD, it will be necessary to adopt cost evaluation systems including the different dimensions of the problem and its various aspects.

Background: The BetterBrains Randomized Controlled Trial (RCT) will evaluate the effectiveness of an online, person-centered, risk factor management, coaching intervention in community-dwelling, healthy adults at risk of cognitive decline. Multi-component interventions are challenging to evaluate due to program complexity and personalization to individual needs and contexts. This paper describes a multi-level process evaluation conducted alongside the BetterBrains RCT. Objective: To understand how and why the BetterBrains intervention was effective or ineffective at reducing cognitive decline in healthy adults whilst considering the context in which it was implemented. Methods: 1,510 non cognitively-deteriorated community-dwelling adults aged 40–70 years old at risk of cognitive decline will be recruited and randomly assigned to the intervention or control group. All BetterBrains intervention participants, coaches, and the research team will be included in the evaluation. A mixed-methods design will be used, guided by The Framework for Implementation Fidelity and the program logic model. Data will be sourced from interviews, focus groups, surveys, BetterBrains coach notes, participant weekly check-in surveys, and audio recordings of intervention coaching sessions. Quantitative data will be analyzed via descriptive and inferential statistics and qualitative data will be analyzed using content and thematic analysis. Results: The process evaluation will provide information about contextual and influencing factors related to the implementation of BetterBrains and the RCT outcomes. Conclusion: Understanding how BetterBrains was implemented and its associated impacts will inform the translation of the program into community and clinical settings, providing easy access to online, personalized dementia prevention services.

Advances in biomarkers, genetics, and other data used as dementia risk evidence (DRE) are increasingly informing clinical diagnosis and management. The purpose of this Mini-Forum is to provide a solutions-based discussion of the ethical and legal gaps and practical questions about how to use and communicate these data. Investigators often use DRE in research. When participants ask for their personal results, investigators have concerns. Will data that was intended to study groups be valid for individuals? Will sharing data cause distress? Debates around sharing DRE became heated when blood-based amyloid tests and amyloid reducing drugs appeared poised to enable clinicians easily to identify people with elevated brain amyloid and reduce it with a drug. Such an approach would transform the traditional role of DRE from investigational to foundational; however, then the high costs, uncertain clinical benefits and risks of the therapy led to an urgent need for education to support clinical decision making. Further complicating DRE use are direct to consumer genetic testing and increasingly available biomarker testing. Withholding DRE becomes less feasible and public education around responsible use and understanding become vital. A critical answer to these legal and ethical issues is supporting education that clearly delineates known risks, benefits, and gaps in knowledge, and communication to promote understanding among researchers, clinicians, patients, and all stakeholders. This paper provides an overview and identifies general concepts and resource documents that support more informed discussions for individuals and interdisciplinary groups.

In recent years, the association between the activity of platelets and risk of Alzheimer’s disease (AD) risk has been noticed in numerous studies. However, there in no investigations on the role of specific intracellular pathways to explain this connection. The phosphatidylinositol 3 kinase (PI3K)/AKT pathway is one of the main regulators of cell survival which regulates cellular responses to environmental changes. This pathway also regulates the activity of platelets, and its aberrant activity has been linked to platelet dysfunction in different pathologies. On the other hand, the PI3K/AKT pathway regulates amyloid-β (Aβ) production through regulation of amyloid-β protein precursor (AβPP), BACE-1, ADAMs, and γ-secretase. In addition, alterations in the activity of all of these factors in platelets has been shown in AD-related pathologies. Therefore, this paper aims to introduce the PI3K/AKT pathway as a molecular inducer of platelet dysfunction during aging and AD progression.

Background: Early intervention of amnestic mild cognitive impairment (aMCI) may be the most promising way for delaying or even preventing the progression to Alzheimer’s disease. Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that has been recognized as a promising approach for the treatment of aMCI. Objective: In this paper, we aimed to investigate the modulating mechanism of tDCS on the core neurocognitive networks of brain. Methods: We used repeated anodal high-definition transcranial direct current stimulation (HD-tDCS) over the left dorsolateral prefrontal cortex and assessed the effect on cognition and dynamic functional brain network in aMCI patients. We used a novel method called temporal variability to depict the characteristics of the dynamic brain functional networks. Results: We found that true anodal stimulation significantly improved cognitive performance as measured by the Montreal Cognitive Assessment after simulation. Meanwhile, the Mini-Mental State Examination scores showed a clear upward trend. More importantly, we found significantly altered temporal variability of dynamic functional connectivity of regions belonging to the default mode network, central executive network, and the salience network after true anodal stimulation, indicating anodal HD-tDCS may enhance brain function by modulating the temporal variability of the brain regions. Conclusion: These results imply that ten days of anodal repeated HD-tDCS over the LDLPFC exerts beneficial effects on the temporal variability of the functional architecture of the brain, which may be a potential neural mechanism by which HD-tDCS enhances brain functions. Repeated HD-tDCS may have clinical uses for the intervention of brain function decline in aMCI patients.

Vascular cognitive impairment (VCI), including vascular dementia, is the second most common dementia after Alzheimer's disease. Despite its prevalence, the genetic etiology of sporadic VCI is largely unknown. We conducted a systematic review of all published genetic association studies of forms of sporadic VCI prior to 6 July 2012. An initial pool of 229 gene association studies yielded 104 papers (72 polymorphisms from 47 genes) that met inclusion criteria for analysis. Systematic meta-analysis was conducted on 6 polymorphisms (which had 3 or more published case-control cohorts from 69 papers) in the APOE, ACT, ACE, MTHFR, PON1, and PSEN-1 genes. Associations of increased risk for VCI were found for APOE e4 (1.818 (95% CI = 1.611-2.053), p < 0.001; n = 3,554 cases, n = 12,277 controls) and MTHFR rs1801133 (1.323 (95% CI = 1.061-1.650) p = 0.013); n = 659 cases, n = 981 controls). There was marginal evidence of a protective effect for APOE e2 (0.885 (95% CI = 0.783-0.999), p = 0.048; n = 3,320 cases, n = 10,786 controls). This systematic study of all published genetic association studies of sporadic VCI supports MTHFR and APOE as susceptibility genes for VCI. It also shows the utility of meta-analysis as a tool to identify potential candidate genes from numerous individual small-scale studies of diseases where sample recruitment may be limited for a variety of practical reasons.

This review focuses on six key papers published in the mid 2000 s based on work conducted in Cambridge. The first two relate to clinico-pathological studies which established that Alzheimer's disease (AD) is a relatively common cause of focal cortical syndromes, notably progressive aphasia (largely nonfluent), progressive apraxia, and posterior cortical atrophy with complex visual symptoms. Building on these findings, criteria for the progressive aphasias have been developed which define the variant associated with AD (progressive logopenic aphasia). Memory in the dementias has been a major area of interest and one paper discussed here explored the neural basis for episodic and semantic memory failure in AD and semantic dementia. Despite very different memory profiles, the two disorders both cause severe hippocampal hypometabolism and atrophy but differ in the degree of involvement of other memory related structures. This work drew attention to the role of pathology in non-hippocampal structures early in AD. The next two articles deal with the behavioral variant frontotemporal dementia (bvFTD) which we have shown is associated with breakdown in theory of mind, social reasoning, empathy, and emotion processing and contributed towork on the neural basis of social cognition. We also identified a subgroup of bvFTD who fail to progress over many years, termed phenocopy cases, who are differentiated by their lack of atrophy on MRI. The final paper described the application of the Addenbrooke's Cognitive Examination-Revised, which has proven a useful brief assessment tool for the early detection of a range of neurodegenerative disorders including AD and FTD. It also appears to be helpful in predicting those with mild cognitive impairment who will progress to frank dementia.

The conditions of chronic obesity and overweight status are risk factors for lower cognitive performance, cognitive decline, cognitive deficit, and dementia. But lower cognitive performance early in life itself may be a risk factor for an increase in body weight over time. With this in mind, we review important papers in the literature that advance our knowledge of relations between weight and cognitive functioning, with an emphasis on papers that illustrate methodological and theoretical issues of importance. We describe the evolution in research on weight and cognition with respect to two major features: (a) the move backward in time from the diagnosis of dementia to the pre-clinical period of dementia in order to better identify risk factors; and (b) the evolution of studies from an earlier emphasis on obesity-related cardiovascular risk factors as major mediators of relations between obesity and cognition to a more recent emphasis on metabolic variables, lifestyle variables, genotype, and other mechanisms that explain relations among weight change, obesity, and cognition. We conclude that: 1) a complete understanding of the causal links between weight and cognitive functioning requires a lifespan perspective; 2) practically speaking, lifespan research may need to amalgamate and integrate research at different segments of the lifespan until such time that we can include the entire life cycle within a single study of weight and cognition; and 3) we need more studies that examine reciprocal relations between weight and cognition, especially early in life.

Much experimental evidence suggests that age-related brain pathologies are most often mediated by reactive oxygen species primarily originating from mitochondria (mROS). Two papers with such evidence have been recently published in the Journal of Alzheimer's Disease (Stefanova et al., J Alzheimers Dis 21, 476-491, 2010; Lloret et al., J Alzheimers Dis, doi: 10.3233/JAD-2011-110890). In the first paper, it was shown that appearance of a typical behavioral trait of aging in rats (that old animals do not enter an open arm in a maze) was completely reversed by ten weeks treatment of the old rats with the mitochondria-targeted antioxidant SkQ1. In the second article, the authors identified molecular mechanisms by which amyloid-β-induced mROS can mediate hyperphosphorylation of the tau protein, a key event in Alzheimer's disease. Conventional antioxidants prevented such hyperphosphorylation. In this article, I will summarize the present state of the art in this field. I conclude that mitochondria-targeted rechargeable antioxidants are promising as tools to treat brain pathologies developing in elderly humans.

This article reviews the role of amyloid-beta (Abeta) and mitochondria in synaptic damage and cognitive decline found in patients with Alzheimer's disease (AD). Recent molecular, cellular, animal model, and postmortem brain studies have revealed that Abeta and mitochondrial abnormalities are key factors that cause synaptic damage and cognitive decline in AD. Abeta is reported to accumulate in subcellular compartments and to impair the normal function of neurons in AD patients. Further, recent studies using biochemical methods and electron microscopy have revealed that the accumulation of Abeta at nerve terminals affect synaptic activities, including the release of neurotransmitters and synaptic vesicles. Recent studies of the relationship between mitochondria and Abeta in AD patients suggest that in mitochondria, structural changes caused by Abeta result in increased mitochondrial fragmentation, decreased mitochondrial fusion, mitochondrial dysfunction, and synaptic damage. This paper discusses the latest research on Abeta, mitochondria, age-dependent factors of AD in the brain, and synaptic damage in AD. This paper also briefly discusses potential mitochondrial therapeutics in the treatment of patients with AD.

The Commentary by Zatta [9] on our recent publication [4] is error strewn and interwoven with unsubstantiated claims which can only serve to blur the edges not only of the research published in our paper but also the general question of the role of aluminium in Alzheimer’s disease [2]. It is perhaps surprising that someone who has built his scientific reputation on the investigation of the putative role of aluminium in AD should now present such a prejudiced view. The essence of Zatta’s piece is immediately clear from its title. The use of the term ‘Vexata Questio’ implies that putting aluminium and AD together is to act in a malicious, irritating and even trivial manner. He is imploring the reader as to why he/she should have to waste his/her time considering aluminium and AD and not least because of new data [4] which he believes leaves more to the imagination than to the scientific method. His major unsubstantiated criticism is ‘modestly’ reiterated at the end of the Commentary and concerns the scientific method and statistical analyses. The research in our paper has been peer-reviewed and it is unfortunate that Zatta’s Commentary includes unsubstantiated opinions on its validity, opinions which can only serve to seed doubt in the scientific rigour of our findings. Another criticism with which he sought to reject our research was that the mineral water in question would include other constituents which could be responsible for the observed reduction in the body burden of aluminium. When challenged to explain this allusion he now reports in his Commentary that the 8.0 mg/L magnesium in Volvic could be responsible for the observed changes in the excretion of aluminium through an unsupported mechanism which he calls ‘the domino effect’. We have trawled through the literature on both animal and human studies to try to find one example of how drinking water containing 8.0 mg/L magnesium influenced the urinary excretion of aluminium. There are no data to support any such effects and presumably Zatta’s lack of any reference to such shows that he is aware of this. This does not, of course, prevent him from making this statement and using it along with his unsubstantiated criticisms of our scientific method as basis to reject our research. Zatta now turns his attentions to the general subject areas of aluminium, silicon and AD. I found his manner to be condescending and his reference to JD Birchall FRS ill-informed and unnecessary. He also gives the impression that he is unaware that what he calls ‘the old story’ has moved on and, as exemplified by our JAD paper, continues to this day, relying only upon sound science for its substance (see, http:// www.keele.ac.uk/depts/ch/groups/aluminium/publications.htm). However, Zatta’s understanding of the bioinorganic chemistry of silicon is very much an ‘old story’. It has been acknowledged for at least the last twenty years that there are no Si-C, Si-N, Si-O-C . . . etc. bonds in any form of life on Earth [8], though we are still looking for these up to this day, and therefore Zatta’s allusion to silicon being ‘usually bonded to glycoproteins’ is to say the least, ill-informed. The reference to the silicon concentration of blood is similarly out-dated, the lowest

It is now 25 years since the publication of our original paper investigating the association aluminum with Alzheimer's disease. This publication reported on the results of scanning electron microscopy coupled x-ray spectrometry microprobe elemental studies of both neurofibrillary tangle-bearing and tangle-free neurons in the hippocampus of cases of Alzheimer's disease and controls. Peaks related to the presence of aluminum were consistently detected within the tangle-bearing neurons. This paper supported the association of aluminum and Alzheimer's disease on the cellular level of resolution and caused considerable interest and discussion. Subsequent work demonstrated prominent evidence of aluminum accumulation in the tangle-bearing neurons of cases of amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam. This latter observation has now been replicated using five different forms of microanalysis. Finally, using laser microprobe mass analysis, we demonstrated that the abnormally high aluminum-related signal which we originally detected was actually located within the neurofibrillary tangle, itself, and was accompanied by excess concentrations of iron. Although it is unlikely that aluminum represents an etiologic cause of Alzheimer's disease, we believe that this highly reactive element, known to cross-link hyperphosphorylated proteins, may play an active role in the pathogenesis of critical neuropathologic lesion in Alzheimer's disease and other related disorders.

Neuropsychological assessment using the Boston Process Approach (BPA) suggests that an analysis of the strategy or the process by which tasks and neuropsychological tests are completed, and the errors made during test completion convey much information regarding underlying brain and cognition and are as important as overall summary scores. Research over the last several decades employing an analysis of process and errors has been able to dissociate between dementia patients diagnosed with Alzheimer’s disease, vascular dementia associated with MRI-determined white matter alterations, and Parkinson’s disease; and between mild cognitive impairment subtypes. Nonetheless, BPA methods can be labor intensive to deploy. However, the recent availability of digital platforms for neuropsychological test administration and scoring now enables reliable, rapid, and objective data collection. Further, digital technology can quantify highly nuanced data previously unobtainable to define neurocognitive constructs with high accuracy. In this paper, a brief review of the BPA is provided. Studies that demonstrate how digital technology translates BPA into specific neurocognitive constructs using the Clock Drawing Test, Backward Digit Span Test, and a Digital Pointing Span Test are described. Implications for using data driven artificial intelligence-supported analytic approaches enabling the creation of more sensitive and specific detection/diagnostic algorithms for putative neurodegenerative illness are also discussed.

The COVID-19 pandemic has accelerated neurological, mental health disorders, and neurocognitive issues. However, there is a lack of inexpensive and efficient brain evaluation and screening systems. As a result, a considerable fraction of patients with neurocognitive or psychobehavioral predicaments either do not get timely diagnosed or fail to receive personalized treatment plans. This is especially true in the elderly populations, wherein only 16% of seniors say they receive regular cognitive evaluations. Therefore, there is a great need for development of an optimized clinical brain screening workflow methodology like what is already in existence for prostate and breast exams. Such a methodology should be designed to facilitate objective early detection and cost-effective treatment of such disorders. In this paper we have reviewed the existing clinical protocols, recent technological advances and suggested reliable clinical workflows for brain screening. Such protocols range from questionnaires and smartphone apps to multi-modality brain mapping and advanced imaging where applicable. To that end, the Society for Brain Mapping and Therapeutics (SBMT) proposes the Brain, Spine and Mental Health Screening (NEUROSCREEN) as a multi-faceted approach. Beside other assessment tools, NEUROSCREEN employs smartphone guided cognitive assessments and quantitative electroencephalography (qEEG) as well as potential genetic testing for cognitive decline risk as inexpensive and effective screening tools to facilitate objective diagnosis, monitor disease progression, and guide personalized treatment interventions. Operationalizing NEUROSCREEN is expected to result in reduced healthcare costs and improving quality of life at national and later, global scales.

Background: The World Health Organization has estimated that worldwide around 50 million people have dementia. The World Alzheimer Report estimated that between 2 and 10% of all cases of dementia begin before the age of 65. Early and young onset dementias (EYOD) provoke more working, social, family, and economic consequences than late onset dementias. All general studies about costs of dementias show that most of them are indirect or social costs. Despite that, very few studies have been performed in EYOD. Objective: To do a systematic review of literature about indirect or social costs in EYOD to know the state of knowledge and to discover gaps that should be filled. Methods: A systematic review was performed in the main database: Scopus, PsychInfo, Web of Science (Web of Science Core Collection, Medline and SciELO), and CINAHL. Additionally, we looked for reviews in Cochrane and in the International Prospective Register Of Systematic Reviews (PROSPERO). Results: Most of the studies are about costs of dementias in general, but they do no differentiate costs for the case of EYOD. Many studies highlight the increased costs for EYOD but very little included evidence of that. 135 papers were selected. Finally, only two were studies providing data. EYOD reduce the odds to get or maintain a job. Most of the care is provided by informal caregivers. The costs in EYOD are 39.26% higher among EYOD than in late onset. Conclusion: There is a lack of studies about social and indirect costs in EYOD. More evidence is needed.

Alzheimer’s disease (AD) is a common progressive neurodegenerative disease. In recent years, the research on the treatment of AD with Chinese medicine is increasing and the results are optimistic, which may provide some new options for the treatment of AD. Existing animal and clinical studies have found that Danggui Shaoyao San (DSS), which has been used in gynecological diseases, is effective in the treatment of AD. As the main component of DSS, macromolecular polysaccharide plays an indispensable role in the treatment of AD. In addition to anti-inflammatory, anti-neuronal injury, and immune regulation, polysaccharides extracted from Danggui Shaoyao San (p-DSS) also have good activities in hypoglycemia, and participate in the physiological regulation of ubiquitination, iron metabolism, intestinal flora, estrogen, and autophagy. Given that there is little systematic analysis of p-DSS, this paper reviews the possible mechanism of p-DSS in the treatment of AD, so as to provide reference for further research.

Glutamate is the main excitatory neurotransmitter in the brain, and its excitatory neurotoxicity is closely related to the occurrence and development of Alzheimer’s disease. However, increasing evidence shows that in the process of Alzheimer’s disease, glutamate is not only limited to its excitotoxicity as a neurotransmitter but also related to the disorder of its metabolic balance. The balance of glutamate metabolism in the brain is an important determinant of central nervous system health, and the maintenance of this balance is closely related to glutamate uptake, glutamate circulation, intracellular mitochondrial transport, and mitochondrial metabolism. In this paper, we intend to elaborate the key role of mitochondrial glutamate metabolism in the pathogenesis of Alzheimer’s disease and review glutamate metabolism in mitochondria as a potential target in the treatment of Alzheimer’s disease.

Alzheimer’s disease (AD) is the leading cause of cognitive impairment in the elderly. Recent evidence suggests that preventive interventional trials could significantly reduce the risk for development of dementia. Periodontitis is the most common dental disease characterized by chronic inflammation and loss of alveolar bone and perialveolar attachment of teeth. Growing number of studies propose a potential link between periodontitis and neurodegeneration. In the first part of the paper, we overview case-control studies analyzing the prevalence of periodontitis among AD patients and healthy controls. Second, we survey observational libraries and cross-sectional studies investigating the risk of cognitive decline in patients with periodontitis. Next, we describe the current view on the mechanism of periodontitis linked neural damage, highlighting bacterial invasion of neural tissue from dental plaques, and periodontitis induced systemic inflammation resulting in a neuroinflammatory process. Later, we summarize reports connecting the four most common periodontal pathogens to AD pathology. Finally, we provide a practical guide for further prevalence and interventional studies on the management of cognitively high-risk patients with and without periodontitis. In this section, we highlight strategies for risk control, patient information, dental evaluation, reporting protocol and dental procedures in the clinical management of patients with a risk for periodontitis and with diagnosed periodontitis. In conclusion, our review summarizes the current view on the association between AD and periodontitis and provides a research and intervention strategy for harmonized interventional trials and for further case-control or cross-sectional studies.

Background: Early identification of Alzheimer’s disease (AD) may be extremely beneficial for delaying disease progression. Subjective cognitive decline (SCD) may be an early indicator of AD pathology. Not all individuals with SCD will eventually develop AD, making it critical to identify biomarkers during the SCD stage which indicate likely clinical progression. Objective: The present review aims to summarize available data on structural MRI and cerebrospinal fluid (CSF) biomarkers and their association with clinical progression to mild cognitive impairment (MCI) or AD in people with SCD. Methods: Database searches were conducted using Embase and PubMed until June 2020. Longitudinal studies assessing biomarkers in individuals with SCD and assessing clinical progression to MCI/AD were included. Two assessors performed data extraction and assessed the risk of bias in the included studies. Data were synthesized narratively. Results: An initial search identified 1,065 papers; after screening and review 14 studies were included. Sample size of the included studies ranged from 28–674, mean age was 60.0–68.6 years, and 10.2%–52%of participants converted to MCI/AD. Lower levels of CSF Aβ42 were consistently associated with clinical progression. Combination measures identifying an AD-like profile of Aβ42 and tau levels were strongly associated with clinical progression. Biomarkers identified with structural MRI were less conclusive, as some studies found significant associations while others did not. Conclusion: Biomarkers may be able to predict clinical progression in those with cognitive complaints. Aβ42, or combinations of Aβ42 and tau may be useful biomarkers in identifying individuals with SCD who will progress to MCI/AD.

Alzheimer’s disease (AD) is the most common form of dementia with global burden projected to triple by 2050. It incurs significant biopsychosocial burden worldwide with limited treatment options. Aducanumab is the first monoclonal antibody recently approved by the US-FDA for mild AD through the accelerated approval pathway. It is the first molecule to be approved for AD since 2003 and carries with it a therapeutic promise for the future. As the definition of AD has evolved from a pathological entity to a Clinico-biological construct over the years, the amyloid-β (Aβ) pathway has been increasingly implicated in its pathogenesis. The approval of Aducanumab is based on reduction of the Aβ load in the brain, which forms a surrogate marker for this pathway. The research populace has, however, been globally divided by skepticism and hope regarding this approval. Failure to meet clinical endpoints in the trials, alleged transparency issues, cost-effectiveness, potential adverse effects, need for regular monitoring, and critique of ‘amyloid cascade hypothesis’ itself are the main caveats concerning the antibody. With this controversy in background, this paper critically looks at antibody research in AD therapeutics, evidence, and evolution of Aducanumab as a drug and the potential clinical implications of its use in future. While the efficacy of this monoclonal antibody in AD stands as a test of time, based on the growing evidence it is vital to rethink and explore alternate pathways of pathogenesis (oxidative stress, neuroinflammation, cholesterol metabolism, vascular factors, etc.) as possible therapeutic targets that may help elucidate the enigma of this complex yet progressive and debilitating neurodegenerative disorder.

Background: Agraphia is a typical feature in the clinical course of Alzheimer’s disease (AD). Objective: Assess the differences between AD and normal aging as regards kinematographic features of handwriting and elucidate writing deficits in AD. Methods: The study included 23 patients with AD (78.09 years/SD = 7.12; MMSE 21.39/SD = 3.61) and 34 healthy controls (75.56 years/SD = 5.85; MMSE 29.06/SD = 0.78). Both groups performed alphabetical and non-alphabetical writing tasks. The kinematographic assessment included the average number of inversions per stroke (NIV; number of peaks in the velocity profile in a single up or down stroke), percentage of automated segments, frequency (average number of strokes per second), writing pressure, and writing velocity on paper. Results: A total of 14 patients showed overt writing difficulties reflected by omissions or substitutions of letters. AD patients showed less automated movements (as measured by NIV), lower writing velocity, and lower frequency of up-and-down strokes in non-alphabetical as well as in alphabetical writing. In the patient group, Spearman correlation analysis between overt writing performance and NIV was significant. That means patients who had less errors in writing a sentence showed a higher automaticity in handwriting. The correctness of alphabetical writing and some kinematographic measures in writing non-alphabetical material reached excellent diagnostic values in ROC analyses. There was no difference in the application of pressure on the pen between patients and controls. Conclusion: Writing disorders are multi-componential in AD and not strictly limited to one processing level. The slow and poorly automated execution of motor programs is not bound to alphabetical material.

Accumulating evidence suggests that the adiponectin (APN) paradox might be involved in promoting aging-associated chronic diseases such as Alzheimer’s disease (AD). In human brain, APN regulation of the evolvability of amyloidogenic proteins (APs), including amyloid-β (Aβ) and tau, in developmental/reproductive stages, might be paradoxically manifest as APN stimulation of AD through antagonistic pleiotropy in aging. The unique mechanisms underlying APN activity remain unclear, a better understanding of which might provide clues for AD therapy. In this paper, we discuss the possible relevance of activin, a member of transforming growth factor β (TGFβ) superfamily of peptides, to antagonistic pleiotropy effects of APN. Notably, activin, a multiple regulator of cell proliferation and differentiation, as well as an endocrine modulator in reproduction and an organizer in early development, might promote aging-associated disorders, such as inflammation and cancer. Indeed, serum activin, but not serum TGFβ increases during aging. Also, activin/TGFβ signal through type II and type I receptors, both of which are transmembrane serine/threonine kinases, and the serine/threonine phosphorylation of APs, including Aβ42 serine 8 and αS serine 129, may confer pathological significance in neurodegenerative diseases. Moreover, activin expression is induced by APN in monocytes and hepatocytes, suggesting that activin might be situated downstream of the APN paradox. Finally, a meta-analysis of genome-wide association studies demonstrated that two SNPs relevant to the activin/TGFβ receptor signaling pathways conferred risk for major aging-associated disease. Collectively, activin might be involved in the APN paradox of AD and could be a significant therapeutic target.

Alzheimer’s disease (AD) is a heterogeneous disease with different subtypes. Studying AD subtypes from brain structure, neuropathology, and cognition are of great importance for AD heterogeneity research. Starting from the study of constructing AD subtypes based on the features of T1-weighted structural magnetic resonance imaging, this paper introduces the major connections between the subtype definition and analysis strategies, including brain region-based subtype definition, and their demographic, neuropathological, and neuropsychological characteristics. The advantages and existing problems are analyzed, and reasonable improvement schemes are prospected. Overall, this review offers a more comprehensive view in the field of atrophy subtype in AD, along with their advantages, challenges, and future prospects, and provide a basis for improving individualized AD diagnosis.

Our research team recently published two relevant papers. In one study, we have seen the acute effect of low-dose ionizing irradiation (LDIR) did not reduce the amyloid-β (Aβ) protein concentration in brain tissue, yet significantly improved synaptic degeneration and neuronal loss in the hippocampus and cerebral cortex. Surprisingly, in another study, we could see late effect that the LDIR-treated mice showed significantly improved learning and memory skills compared with those in the sham group. In addition, Aβ concentrations were significantly decreased in brain tissue. Furthermore, the pro-inflammatory cytokine tumor necrosis factor-α was decreased and the anti-inflammatory cytokine transforming growth factor-β was increased in the brain tissue of 5xFAD mice treated with LDIR. Definitive clinical results for the safety and efficacy of LDIR have not yet been published and, despite the promising outcomes reported during preclinical studies, LDIR can only be applied to patients with Alzheimer’s disease dementia when clinical results are made available. In addition, in the case of LDIR, additional large-scale clinical studies are necessary to determine the severity of Alzheimer’s disease dementia, indications for LDIR, the total dose to be irradiated, fraction size, and intervals of LDIR treatment. The purpose of this review is to summarize the mechanism of LDIR based on existing preclinical results in a way that is useful for conducting subsequent clinical research.

Mobile technologies are becoming ubiquitous in the world, changing the way we communicate and provide patient care and services. Some of the most compelling benefits of mobile technologies are in the areas of disease prevention, health management, and care delivery. For all the advances that are occurring in mobile health, its full potential for older adults is only starting to emerge. Yet, existing mobile health applications have design flaws that may limit usability by older adults. The aim of this paper is to review barriers and identify knowledge gaps where more research is needed to improve the accessibility of mobile health use in aging populations. The same observations might apply to those who are not elderly, including individuals suffering from severe mental or medical illnesses.

In a broad sense, the concept of social stigmatization (from the Greek word “stigma”, or sign) refers to the attitude of social disapproval and the negative reception of a specific group of people due to the characteristic features of this group. The problem of stigma affects many people, and it is also present in medicine and affects people with dementia. Social stigma of people with dementia is a worldwide problem. The severity of this phenomenon depends on several factors, including gender, age, level of education, religiosity, cultural differences, and the severity of cognitive disorders. Stigmatization can have numerous negative consequences. It leads to rejection, discrimination, and exclusion of stigmatized people from participation in various areas of social life. It also affects close relatives. The main goal of this review paper is to present the problem of stigma among people with dementia, discuss the results of represented research that deals with this issue, to approximate the elements that make up this process, and to present the negative consequences of stigma. Detailed knowledge of this phenomenon provides opportunity to reduce the extent of stigma and improve the quality of life people suffering from dementia. It is worth emphasizing the role of an individual approach to the patient and the need to educate the public about dementia.

Alzheimer’s disease (AD) is an irreversible neurodegenerative disease characterized by brain function disorder and chronic cognitive function impairment. The onset of AD is complex and is mostly attributed to interactions between genetic factors and environmental factors. Lifestyle, dietary habits, and food consumption are likely to play indispensable functions in aged-related neurodegenerative diseases in elderly people. An increasing number of epidemiological studies have linked dietary fatty acid factors to AD, raising the point of view that fatty acid metabolism plays an important role in AD initiation and progression as well as in other central nervous system disorders. In this paper, we review the effects of the consumption of various dietary fatty acids on AD onset and progression and discuss the detrimental and beneficial effects of some typical fatty acids derived from dietary patterns on the pathology of AD. We outline these recent advances, and we recommend that healthy dietary lifestyles may contribute to preventing the occurrence and decreasing the pathology of AD.

Background: Mild traumatic brain injury (mTBI) is a putative risk factor for dementia; however, despite having apparent face validity, the evidence supporting this hypothesis remains inconclusive. Understanding the role of mTBI as a risk factor is becoming increasingly important given the high prevalence of mTBI, and the increasing societal burden of dementia. Objective: Our objective was to use the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) format to determine if an association exists between mTBI and dementia and related factors, and to quantify the degree of risk. Methods: In this format, two authors conducted independent database searches of PubMed, PsycInfo, and CINAHL using three search blocks to find relevant papers published between 2000 and 2020. Relevant studies were selected using pre-defined inclusion/exclusion criteria, and bias scoring was performed independently by the two authors before a subset of studies was selected for meta-analysis. Twenty-one studies met the inclusion criteria for this systematic review. Results: The meta-analysis yielded a pooled odds ratio of 1.96 (95% CI 1.698–2.263), meaning individuals were 1.96 times more likely to be diagnosed with dementia if they had a prior mTBI. Most studies examining neuropsychiatric and neuroimaging correlates of dementia found subtle, persistent changes after mTBI. Conclusion: These results indicate that mTBI is a risk factor for the development of dementia and causes subtle changes in performance on neuropsychiatric testing and brain structure in some patients.

COVID-19 is a severe infectious disease that has claimed >150,000 lives and infected millions in the United States thus far, especially the elderly population. Emerging evidence has shown the virus to cause hemorrhagic and immunologic responses, which impact all organs, including lungs, kidneys, and the brain, as well as extremities. SARS-CoV-2 also affects patients’, families’, and society’s mental health at large. There is growing evidence of re-infection in some patients. The goal of this paper is to provide a comprehensive review of SARS-CoV-2-induced disease, its mechanism of infection, diagnostics, therapeutics, and treatment strategies, while also focusing on less attended aspects by previous studies, including nutritional support, psychological, and rehabilitation of the pandemic and its management. We performed a systematic review of >1,000 articles and included 425 references from online databases, including, PubMed, Google Scholar, and California Baptist University’s library. COVID-19 patients go through acute respiratory distress syndrome, cytokine storm, acute hypercoagulable state, and autonomic dysfunction, which must be managed by a multidisciplinary team including nursing, nutrition, and rehabilitation. The elderly population and those who are suffering from Alzheimer’s disease and dementia related illnesses seem to be at the higher risk. There are 28 vaccines under development, and new treatment strategies/protocols are being investigated. The future management for COVID-19 should include B-cell and T-cell immunotherapy in combination with emerging prophylaxis. The mental health and illness aspect of COVID-19 are among the most important side effects of this pandemic which requires a national plan for prevention, diagnosis and treatment.

Alzheimer’s disease (AD) is the most common neurodegenerative disease and is characterized by preclinical, pre-dementia, and dementia phases. Progression of the disease leads to cognitive decline and is associated with loss of functional independence, personality changes, and behavioral disturbances. Current guidelines for AD diagnosis include the use of neuroimaging tools as biomarkers for identifying and monitoring pathological changes. Various imaging modalities, namely magnetic resonance imaging (MRI), fluorodeoxyglucose-positron emission tomography (FDG-PET) and PET with amyloid-beta tracers are available to facilitate early accurate diagnoses. Enhancing diagnosis in the early stages of the disease can allow for timely interventions that can delay progression of the disease. This paper will discuss the characteristic findings associated with each of the imaging tools for patients with AD, with a focus on FDG-PET due to its established accuracy in assisting with the differential diagnosis of dementia and discussion of other methods including MRI. Diagnostically-relevant features to aid clinicians in making a differential diagnosis will also be pointed out and multimodal imaging will be reviewed. We also discuss the role of quantification software in interpretation of brain imaging. Lastly, to guide evaluation of patients presenting with cognitive deficits, an algorithm for optimal integration of these imaging tools will be shared. Molecular imaging modalities used in dementia evaluations hold promise toward identifying AD-related pathology before symptoms are fully in evidence. The work describes state of the art functional and molecular imaging methods for AD. It will also overview a clinically applicable quantitative method for reproducible assessments of such scans in the early identification of AD.

Mild cognitive impairment (MCI) exhibits a high risk of progression to Alzheimer's disease (AD), and it is commonly deemed as the precursor of AD. It is important to find effective and robust ways for the early diagnosis of MCI. In this paper, a random forest-based method combining multiple morphological metrics was proposed to identify MCI from normal controls (NC). Voxel-based morphometry, deformation-based morphometry, and surface-based morphometry were utilized to extract morphological metrics such as gray matter volume, Jacobian determinant value, cortical thickness, gyrification index, sulcus depth, and fractal dimension. An initial discovery dataset (56 MCI/55 NC) from the ADNI were used to construct classification models and the performances were testified with 10-fold cross validation. To test the generalization of the proposed method, two extra validation datasets including longitudinal ADNI data (30 MCI/16 NC) and collected data from Xuanwu Hospital (27 MCI/32 NC) were employed respectively to evaluate the performance. No matter whether testing was done on the discovery dataset or the extra validation datasets, the accuracies were about 80% with the combined morphological metrics, which were significantly superior to single metric (accuracy: 45% ∼76%) and also displayed good generalization across datasets. Additionally, gyrification index and cortical thickness derived from surface-based morphometry outperformed other features in MCI identification, suggesting they were some key morphological biomarkers for early MCI diagnosis. Combining the multiple morphological metrics together resulted in a significantly better and reliable identification model, which may be helpful to assist in the clinical diagnosis of MCI.

Neurocognitive disorders create important challenges for patients, their families, and clinicians who provide their health care. Early/timely detection in daily clinical practice allows for diagnosis and adequate treatment, psychosocial support, education, and engagement in shared decision-making related to health care, life planning, involvement in research, and financial matters. However, neurocognitive disorders, when present, are not detected or not diagnosed and not documented, in more than half of patients seen by primary care physicians. The aim of this paper is to highlight the strategies and the perspectives to improve the early/timely detection of neurocognitive disorders in daily clinical practice.

This paper presents an overview of the literature studies on the sources of ultrafine particles (UFPs), nanomaterials (NMs), and nanoparticles (NPs) occurring in indoor (occupational and residential) and outdoor environments. Information on the relevant emission factors, particle concentrations, size, and compositions is provided, and health relevance of UFPs and NPs is discussed. Particular attention is focused on the fraction of particles that upon inhalation deposit on the olfactory bulb, because these particles can possibly translocate to brain and their possible role in neurodegenerative diseases is an important issue emerging in the recent literature.

TREM2 (triggering receptor expressed on myeloid cells 2) gene variants were reported to increase the risk of Alzheimer's disease (AD) and even other neurodegenerative diseases (frontotemporal dementia (FTD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS)), but so far, no definite conclusion has been drawn. The aim of our systematic review and meta-analysis was to investigate the role of TREM2 variants in neurodegenerative diseases. A total of 39 papers (including 26 case-control studies and 13 case reports) were retrieved from PubMed, MEDLINE, EMBASE, and the Cochrane library in this study. A fixed effect model was used to pool results in the analysis. Three variants in TREM2 (rs75932628 (R47H), rs2234255 (H157Y), and rs143332484 (R62H)) were significantly associated with AD risk, but the similar associations between rs104894002 (Q33X), rs2234253 (T96K), rs142232675 (D87N), rs2234256 (L211P), and AD were not proven. Rs75932628 also increased risk of PD in North Americans and FTD, but not PD in Europeans or ALS. In the systematic review, 12 biallelic TREM2 mutations (e.g., rs104894002, rs201258663 (T66M), and rs386834144, etc.) have been described to cause Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy (PLOSL) in 14 families. And homozygous mutations also have been reported to cause FTD without typical bone phenotypes in 7 families. This study demonstrates that multiple variants in TREM2 have association with the onset of AD, FTD, and PD in North Americans and also play a key role in the phenotypes of the rare familial genetic disorder.

Developing novel agents for unexplored targets to combat Alzheimer's disease (AD) represents an urgent task due to its increasing prevalence worldwide. The present paper summarizes the latest studies emerged in the past few years investigating the associations between the "forgotten organ" gut microbiota and AD from the following two aspects: 1) the associations between gut microbiota and AD development by animal models and human studies; and 2) the effects of gut microbiota modulation-based intervention for AD. Then, we propose future perspectives in two promising research areas: 1) developing gut microbiota modulation-based intervention; and 2) developing gut microbiota-associated diagnostic biomarkers for AD. Knowledge gaps and potential barriers to overcome towards these two goals are also discussed.

Alzheimer’s disease (AD), the most common neurodegenerative dementia, leads to memory dysfunction due to widespread neuronal loss associated with aggregation of amyloidogenic proteins (APs), while schizophrenia (SCZ) represents a major psychiatric disorder characterized by delusions, hallucinations, and other cognitive abnormalities, the underlying mechanisms of which remain obscure. Although AD and SCZ partially overlap in terms of psychiatric symptoms and some aspects of cognitive impairment, the causal relationship between AD and SCZ is unclear. Based on the similarity of APs with yeast prion in terms of stress-induced protein aggregation, we recently proposed that evolvability of APs might be an epigenetic phenomenon to transmit stress information of parental brain to cope with the stressors in offspring. Although amyloid evolvability may be beneficial in evolution, AD might be manifested during parental aging as the mechanism of antagonistic pleiotropy phenomenon. Provided that accumulating evidence implicates stress as an important factor in SCZ, the main objective of this paper is to better understand the possible connection of AD and SCZ through amyloid evolvability. Hypothetically, the delivery of information of stress by APs may be less efficient under the decreased evolvability conditions such as disease-modifying treatment, leading to SCZ in offspring. Conversely, the increased evolvability conditions including gene mutations of APs are supposed to be beneficial for offspring, but might lead to AD in parents. Collectively, AD and SCZ might transgenerationally interfere with each other through amyloid evolvability, and this could explain why both AD and SCZ have not been selected out through evolution.

Alzheimer's disease (AD) is a common, devastating disease which carries a heavy economic burden. Accelerated efforts to identify presymptomatic stages of AD and biomarkers to classify the disease are urgent needs. Currently, no biomarkers can perfectly discriminate individuals into multiple disease categories of AD (no cognitive impairment, mild cognitive impairment, and dementia). Although many biomarkers for diagnosis and their various features are being studied, we lack advanced statistical methods which can fully utilize biomarkers to classify AD accurately, thereby facilitating evaluation of putative markers both alone and in combination. In this paper, we propose two approaches: 1) a forward addition procedure in which we adapt an additive logistic regression model to the setting for disease with ordered multiple categories. Using this approach, we select and combine multiple cross-sectional biomarkers to improve diagnostic accuracy, and 2) a method by extending the Neyman-Pearson Lemma to the ordered three disease categories to construct optimal cutoff points to distinguish multiple disease categories. We evaluate the robustness of the proposed model using a simulation study. Then we apply these two methods to data from the Religious Orders Study to examine the feasibility of combining biomarkers, and compare the diagnostic accuracy between the proposed methods and existing methods including model-based methods (ordinal logistic regression and quadratic discriminant analysis), a tree-based method CART, and the Youden index method. The two proposed methods facilitate evaluations of biomarkers for conditions with graded, rather than binary, classifications. The evaluation of the performance of different approaches provides guidance of how to choose approaches to address research questions.

Alzheimer's disease (AD) is an insidious and progressive neurodegenerative disease. The main pathological features of AD are the formation of amyloid-β deposits in the anterior cerebral cortex and hippocampus as well as the formation of intracellular neurofibrillary tangles. Thus far, accumulating evidence shows that glycation is closely related to AD. As a final product resulting from the crosslinking of a reducing sugar or other reactive carbonyls and a protein, the advanced glycation end products have been found to be associated with the formation of amyloid-β and neurofibrillary tangles in AD. As a saccharification inhibitor, the glyoxalase system and its substrate methylglyoxal (MG) were certified to be associated with AD onset and development. As an active substance of AGEs, MG could cause direct or indirect damage to nerve cells and tissues. MG is converted to D-lactic acid after decomposition by the glyoxalase system. Under normal circumstances, MG metabolism is in a dynamic equilibrium, whereas MG accumulates in cells in the case of aging or pathological states. Studies have shown that increasing glyoxalase activity and reducing the MG level can inhibit the generation of oxidative stress and AGEs, thereby alleviating the symptoms and signs of AD to some extent. This paper focuses on the relevant mechanisms of action of the glyoxalase system and MG in the pathogenesis of AD, as well as the potential of inhibiting the production of advanced glycation end products in the treatment of AD.

This paper proposes a novel fully automatic computer-aided diagnosis (CAD) system for the early detection of Alzheimer's disease (AD) based on supervised machine learning methods. The novelty of the approach, which is based on histogram analysis, is twofold: 1) a feature extraction process that aims to detect differences in brain regions of interest (ROIs) relevant for the recognition of subjects with AD and 2) an original greedy algorithm that predicts the severity of the effects of AD on these regions. This algorithm takes account of the progressive nature of AD that affects the brain structure with different levels of severity, i.e., the loss of gray matter in AD is found first in memory-related areas of the brain such as the hippocampus. Moreover, the proposed feature extraction process generates a reduced set of attributes which allows the use of general-purpose classification machine learning algorithms. In particular, the proposed feature extraction approach assesses the ROI image separability between classes in order to identify the ones with greater discriminant power. These regions will have the highest influence in the classification decision at the final stage. Several experiments were carried out on segmented magnetic resonance images from the Alzheimer's Disease Neuroimaging Initiative (ADNI) in order to show the benefits of the overall method. The proposed CAD system achieved competitive classification results in a highly efficient and straightforward way.

Three articles have very recently appeared that are of especial relevance to the causes ofdementia and its potential treatment. The first two (Tsai et al., published in PLoS One inNovember 2017, and (Chen et al., published in the January/February 2018 issue of Journal ofClinical Psychiatry) demonstrate an increased risk of subsequent senile dementia (SD)development in patients with acute varicella zoster (herpes zoster) infection. These articlespresent data highly relevant to the third, and most important, paper – by Tzeng et al., publishedonline in the journal Neurotherapeutics at the end of February 2018. These authors report thatinfection with a different herpes virus, herpes simplex virus type 1 (HSV1), leads to a similarlyincreased risk of later developing SD. Further, when the authors looked at patients treatedaggressively with antiherpetic medications at the time, the relative risk of SD was reduced by afactor of 10. It should be stressed that no investigations were made on subjects already sufferingfrom SD, and that those treated were the few rare cases severely affected by HSV. Nonetheless,antiherpetic medication prevented later SD development in 90% of their study group. Thesearticles provide the first population evidence for a causal link between herpes virus infection andsenile dementia.

T1-weighted MRI has been extensively used to extract imaging biomarkers and build classification models for differentiating AD from healthy controls, but only recently have brain connectome networks derived from diffusion-weighted MRI been used to model AD progression and various stages of disease such as mild cognitive impairment. Mild cognitive impairment, as a possible prodromal stage of AD, has gained intense interest recently, since it may be used to assess risk factors for AD. Little work has been done to combine information from both white matter and gray matter, and it is unknown how much classification power the diffusion-weighted MRI-derived structural connectome could provide beyond information available from T1-weighted MRI. In this paper, we focused on investigating whether diffusion-weighted MRI-derived structural connectome can improve differentiating healthy controls subjects from those with mild cognitive impairment. Specifically, we proposed a novel feature-ranking method to build classification models using the most highly ranked feature variables to classify mild cognitive impairment with healthy controls. We verified our method on two independent cohorts including the second stage of Alzheimer's Disease Neuroimaging Initiative (ADNI2) database and the National Alzheimer's Coordinating Center (NACC) database. Our results indicated that 1) diffusion-weighted MRI-derived structural connectome can complement T1-weighted MRI in the classification task; 2) the feature-rank method is effective because of the identified consistent T1-weighted MRI and network feature variables on ADNI2 and NACC. Furthermore, by comparing the top-ranked feature variables from ADNI2, NACC and combined dataset, we concluded that cross-validation using independent cohorts is necessary and highly recommended.

According to the projections of the statistical office of the European Union, Eurostat, nearly one third of EU citizens will be at least 65 in 2060. The U.S. population age 65 and older continues to increase and is projected to nearly double from 48 million to 88 million by 2050. Elderly people are especially exposed to neurodegenerative diseases (NDs). The most common ND is Alzheimer's disease (AD), a chronic and progressive disorder with a variety of pathological changes within neuronal tissue, which begin even 10-15 years before the onset of cognitive impairment symptoms. AD is perceived as a disease continuum and considered to include three basic phases: preclinical (asymptomatic) stage, mild cognitive impairment (MCI), and dementia due to AD. A very important issue, from medical and legal perspectives, is the NDs patient's consent to medical procedures, including diagnostic procedures, such as lumber puncture. NDs patients are not always able to express their consent and do not always understand the information provided by a physician. This applies to a group of patients in the final stages of NDs. This paper presents legal regulations of selected European countries and signalizes the U.S. legal solutions on the issue of NDs patients' informed consent to medical procedures.

A growing body of evidence supports a clear association between Alzheimer's disease and diabetes and several mechanistic links have been revealed. This paper is mainly devoted to the discussion of the role of diabetes-associated mitochondrial defects in the pathogenesis of Alzheimer's disease. The research experience and views of the author on this subject will be highlighted.

In the last decades, progress in neuroimaging techniques and cerebrospinal fluid assays has enabled the characterization of several Alzheimer’s disease (AD) biomarkers. This knowledge has shifted the conceptualization of AD from a clinical-pathological construct, where its diagnosis required the presence of dementia with distinct pathologic features, toward a clinical-biological one that recognizes AD as a pathological continuum with a clinical picture that ranges from normal cognition to a dementia stage. Specifically, AD is now divided into three stages: preclinical (abnormal biomarkers and no or only subtle cognitive impairment), mild cognitive impairment or prodromal AD (abnormal pathophysiological biomarkers and episodic memory impairment), and dementia (abnormal biomarkers and clear cognitive and functional impairment). The possibility of assessing AD pathophysiologyin vivobefore the onset of clinical symptoms in the preclinical stage provides the unprecedented opportunity to intervene at earlier stages of the continuum in secondary prevention trials. Currently, large cohort studies of cognitively healthy participants are undergoing with the main aim of disentangling the natural history of AD to identify individuals with an increased risk of developing AD in the near future to be recruited in these clinical trials. In this paper, we review how the concept of AD has changed over the years as well as discuss the implications of this conceptual change.