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The brain changes of Alzheimer’s disease and other degenerative dementias begin long before cognitive dysfunction develops, and in people with subtle cognitive complaints, clinicians often struggle to predict who will develop dementia. The public increasingly sees benefits to accessing dementia risk evidence (DRE) such as biomarkers, predictive algorithms, and genetic information, particularly as this information moves from research to demonstrated usefulness in guiding diagnosis and clinical management. For example, the knowledge that one has high levels of amyloid in the brain may lead one to seek amyloid reducing medications, plan for disability, or engage in health promoting behaviors to fight cognitive decline. Researchers often hesitate to share DRE data, either because they are insufficiently validated or reliable for use in individuals, or there are concerns about assuring responsible use and ensuring adequate understanding of potential problems when one’s biomarker status is known. Concerns include warning people receiving DRE about situations in which they might be compelled to disclose their risk status potentially leading to discrimination or stigma. The Advisory Group on Risk Evidence Education for Dementia (AGREEDementia) welcomes all concerned with how best to share and use DRE. Supporting understanding in clinicians, stakeholders, and people with or at risk for dementia and clearly delineating risks, benefits, and gaps in knowledge is vital. This brief overview describes elements that made this group effective as a model for other health conditions where there is interest in unfettered collaboration to discuss diagnostic uncertainty and the appropriate use and communication of health-related risk information.

Background: A valid, reliable, accessible, engaging, and affordable digital cognitive screen instrument for clinical use is in urgent demand. Objective: To assess the clinical utility of the MemTrax memory test for early detection of cognitive impairment in a Chinese cohort. Methods: The 2.5-minute MemTrax and the Montreal Cognitive Assessment (MoCA) were performed by 50 clinically diagnosed cognitively normal (CON), 50 mild cognitive impairment due to AD (MCI-AD), and 50 Alzheimer’s disease (AD) volunteer participants. The percentage of correct responses (MTx-% C), the mean response time (MTx-RT), and the composite scores (MTx-Cp) of MemTrax and the MoCA scores were comparatively analyzed and receiver operating characteristic (ROC) curves generated. Results: Multivariate linear regression analyses indicated MTx-% C, MTx-Cp, and the MoCA score were significantly lower in MCI-AD versus CON and in AD versus MCI-AD groups (all with p≤0.001). For the differentiation of MCI-AD from CON, an optimized MTx-% C cutoff of 81% had 72% sensitivity and 84% specificity with an area under the curve (AUC) of 0.839, whereas the MoCA score of 23 had 54% sensitivity and 86% specificity with an AUC of 0.740. For the differentiation of AD from MCI-AD, MTx-Cp of 43.0 had 70% sensitivity and 82% specificity with an AUC of 0.799, whereas the MoCA score of 20 had 84% sensitivity and 62% specificity with an AUC of 0.767. Conclusion: MemTrax can effectively detect both clinically diagnosed MCI and AD with better accuracy as compared to the MoCA based on AUCs in a Chinese cohort.

Background: The widespread incidence and prevalence of Alzheimer’s disease and mild cognitive impairment (MCI) has prompted an urgent call for research to validate early detection cognitive screening and assessment. Objective: Our primary research aim was to determine if selected MemTrax performance metrics and relevant demographics and health profile characteristics can be effectively utilized in predictive models developed with machine learning to classify cognitive health (normal versus MCI), as would be indicated by the Montreal Cognitive Assessment (MoCA). Methods: We conducted a cross-sectional study on 259 neurology, memory clinic, and internal medicine adult patients recruited from two hospitals in China. Each patient was given the Chinese-language MoCA and self-administered the continuous recognition MemTrax online episodic memory test on the same day. Predictive classification models were built using machine learning with 10-fold cross validation, and model performance was measured using Area Under the Receiver Operating Characteristic Curve (AUC). Models were built using two MemTrax performance metrics (percent correct, response time), along with the eight common demographic and personal history features. Results: Comparing the learners across selected combinations of MoCA scores and thresholds, Naïve Bayes was generally the top-performing learner with an overall classification performance of 0.9093. Further, among the top three learners, MemTrax-based classification performance overall was superior using just the top-ranked four features (0.9119) compared to using all 10 common features (0.8999). Conclusion: MemTrax performance can be effectively utilized in a machine learning classification predictive model screening application for detecting early stage cognitive impairment.

In a 1990 JAMA cover story Frank Meshberger reported that Michelangelo's central composition on the Sistine Chapel ceiling (1508-1512), The Creation of Adam, portrays God in the form of a brain. The present report suggests that Michelangelo's images on the chapel ceiling depicting Creation describe the course of vertebrate brain development. Further, on the front wall of the Sistine Chapel, within the work titled The Last Judgment (1525-1541), the central ellipse, where Jesus is making judgments about good and evil, represents a mid-coronal cross-section of a human brain, implying that the brain is man's instrument for making decisions.

Wang et al. analyze Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment accuracy as screening tests for detecting dementia associated with Alzheimer’s disease (AD). Such tests are at the center of controversy regarding recognition and treatment of AD. The continued widespread use of tools such as MMSE (1975) underscores the failure of advancing cognitive screening and assessment, which has hampered the development and evaluation of AD treatments. It is time to employ readily available, efficient computerized measures for population/mass screening, clinical assessment of dementia progression, and accurate determination of approaches for prevention and treatment of AD and related conditions.

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.

Introduction Cortical thickness and diffusion properties can be served as an indicator of aging and other brain changes such as those related to brain injury. It can additionally provide another platform by which we can characterize the injury and its associated symptoms, especially in the chronic condition. Methods We examined the changes in cortical thickness and diffusion properties in white matter tracts in 51 patients with and without traumatic brain injury (TBI) and/or self-report chronic symptoms. Results Significant cortical thinning was observed in the frontal lobe and temporal lobe for TBI patients with chronic symptoms, but not for TBI patients without chronic symptoms, compared with control group. Significant reduction in fractional anisotropy occurred on average across left and right major fiber tracts for TBI patients with chronic symptoms. No mean diffusivity changes were found in any individual white matter tract for TBI patients with or without chronic symptoms. Conclusions Traumatic brain injury patients with chronic symptoms have more significant cortical thinning or degeneration of diffusion properties than the mild to severe TBI patients without chronic symptoms. This finding suggests that symptom reporting should be assessed in line with objective measures in clinical practice.

Background Memory dysfunction is characteristic of aging and often attributed to Alzheimer's disease (AD). An easily administered tool for preliminary assessment of memory function and early AD detection would be integral in improving patient management. Objective Our primary aim was to utilize machine learning in determining initial viable models to serve as complementary instruments in demonstrating efficacy of the MemTrax online Continuous Recognition Tasks (M-CRT) test for episodic-memory screening and assessing cognitive impairment. Methods We used an existing dataset subset (n = 18,395) of demographic information, general health screening questions (addressing memory, sleep quality, medications, and medical conditions affecting thinking), and test results from a convenience sample of adults who took the M-CRT test. M-CRT performance and participant features were used as independent attributes: true positive/negative, percent responses/correct, response time, age, sex, and recent alcohol consumption. For predictive modeling, we used demographic information and test scores to predict binary classification of the health-related questions (yes/no) and general health status (healthy/unhealthy), based on the screening questions. Results ANOVA revealed significant differences among HealthQScore groups for response time true positive (p = 0.000) and true positive (p = 0.020), but none for true negative (p = 0.0551). Both % responses and % correct had significant differences (p = 0.026 and p = 0.037, respectively). Logistic regression was generally the top-performing learner with moderately robust prediction performance (AUC) for HealthQScore (0.648-0.680) and selected general health questions (0.713-0.769). Conclusion Our novel application of supervised machine learning and predictive modeling helps to demonstrate and validate cross-sectional utility of MemTrax in assessing early-stage cognitive impairment and general screening for AD.

Based on clinical observations of severe episodic memory (EM) impairment in dementia of Alzheimer's disease (AD), a brief, computerized EM test was developed for AD patient evaluation. A continuous recognition task (CRT) was chosen because of its extensive use in EM research. Initial experience with this computerized CRT (CCRT) showed patients were very engaged in the test, but AD patients had marked failure in recognizing repeated images. Subsequently, the test was administered to audiences, and then a two-minute online version was implemented (http://www.memtrax.com). The online CCRT shows 50 images, 25 unique and 25 repeats, which subjects respectively either try to remember or indicate recognition as quickly as possible. The pictures contain 5 sets of 5 images of scenes or objects (e.g., mountains, clothing, vehicles, etc.). A French company (HAPPYneuron, SAS) provided the test for 2 years, with these results. Of 18,477 individuals, who indicated sex and age 21-99 years and took the test for the first time, 18,007 individuals performed better than chance. In this group, age explained 1.5% of the variance in incorrect responses and 3.5% of recognition time variance, indicating considerable population variability. However, when averaging for specific year of age, age explained 58% of percent incorrect variance and 78% of recognition time variance, showing substantial population variability but a major age effect. There were no apparent sex effects. Further studies are indicated to determine the value of this CCRT as an AD screening test and validity as a measure of EM impairment in other clinical conditions.

The study of cognition in Parkinson's disease (PD) traditionally requires exhaustive recruitment strategies. The current study examines data collected by the Brain Health Registry (BHR) to determine whether ongoing efforts to improve the recruitment base for therapeutic trials in Alzheimer's disease may be similarly effective for PD research, and whether online cognitive measurements can discriminate between participants who do and do not report a PD diagnosis. Participants enrolled in the BHR (age ≥50) with self-reported PD data and online cognitive testing available were included (n = 11,813). Associations between baseline cognitive variables and diagnostic group were analyzed using logistic regression. Linear mixed effects models were used to analyze longitudinal data. A total of 634 participants reported PD diagnosis at baseline with no self-reported cognitive impairment and completed cognitive testing. Measures of visual learning and memory, processing speed, attention, and working memory discriminated between self-reported PD and non-PD participants after correcting for multiple comparisons (p values < 0.006). Scores on all cognitive tests improved over time in PD and controls with the exception of processing speed, which remained stable in participants with PD while improving in those without. We demonstrate that a novel online approach to recruitment and longitudinal follow-up of study participants is effective for those with self-reported PD, and that significant differences exist between those with and without a reported diagnosis of PD on computerized cognitive measures. These results have important implications for recruitment of participants with PD into targeted therapeutic trials or large-scale genetic and cognitive studies.

Inheritance of a single copy of the apolipoprotein E (APOE) ɛ4 allele increases risk of Alzheimer's disease (AD) by 3-4-fold, with homozygosity associated with a 12-16-fold increase in risk, relative to ɛ3 allele homozygosity. There is a decreased risk associated with the APOE ɛ2 allele. The pathological consequence of APOE genotype has led to intense efforts to understand the mechanistic basis of the interplay between APOE status and loss of synapses. Numerous ɛ4 allele-related associations have been reported with the potential relevance of these associations to the pathogenesis of AD unknown at this time. In primarily young subjects, we have reviewed a representative body of literature on ɛ4 allele-associations related to the following: cardiovascular responses; impacts on reproduction and fetal development; co-morbidities; resistance to infectious disease; responses to head injury; biochemical differences possibly related to neural stress; and brain structure-function differences. In addition, the literature on the association between the ɛ4 allele and cognitive performance has been reviewed comprehensively. The weight-of-the-evidence supports the hypothesis that possession of the ancestral ɛ4 allele in youth is associated with improved fitness during fetal development, infancy, and youth relative to the more recently appearing ɛ3 allele, at the expense of decreased fitness in old age, which is substantially improved by the ɛ3 allele. However, possession of the ɛ4 allele is also associated with higher levels of synaptic macromolecular turnover, which likely stresses basic cellular neuroplasticity mechanisms. Clinical trials of potential AD therapeutics should consider APOE status as an enrollment criterion.

Michelangelo Buonarroti (1475–1564) presented some of the most spectacular artworks of all times in frescos on the ceiling and behind the altar of the Sistine Chapel. While Michelangelo’s presentations depict events described in the Bible, there is broad consensus that Michelangelo was conveying his knowledge and theoretical ideas gleaned from his experiences with anatomic dissection. Michelangelo appears to have communicated several ideas about the brain in the images of the Days of Creation and the Last Judgment. Taking the Days of Creation and the Last Judgment together, Michelangelo appears to be symbolizing that God is in the brain, specifically the brainstem, and the brain performs mental functions. The five images on the ceiling of the chapel showing Days of Creation may be interpreted as reflecting the course of vertebrate brain evolution. There are further suggestions about brain function, including perceiving light and complex images and giving spirit to Adam. Furthermore, on the front wall of the Sistine Chapel behind the altar, within the work titled the Last Judgment, the central ellipse, in which Jesus is sitting, appears to represent a midcoronal cross section of a human brain, suggesting that it is the brain that renders judgments about good and evil.

Aims There is an inadequate portfolio of treatments for Gulf War Illness (GWI), a complex disease involving multiple organ systems, and early-phase clinical trials are hampered by many logistical problems. To address these challenges, the Gulf War Illness Clinical Trials and Interventions Consortium (GWICTIC) was formed with the aims of (i) creating a collaborative consortium of clinical and scientific researchers that will rapidly implement rigorous and innovative phase I and II clinical trials for GWI, (ii) perform at least four phase I or II clinical trials, (iii) provide a foundation of scalable infrastructure and management in support of the efficient and successful operation of the GWICTIC, and (iv) partner with the Boston Biorepository, Recruitment & Integrated Network for GWI and other GWI investigators to develop a common data element platform for core assessments and outcomes. Main methods The GWICTIC brings together a multidisciplinary team of researchers at several institutions to provide scientific innovation, statistical and computational rigor, and logistical efficiency in the development and implementation of early-phase low-risk clinical trials for GWI. The GWICTIC core trials adhere to a Veteran-centered philosophy and focus on interventions with multiple mechanistic targets to maximize the likelihood of efficacy. To support rapid and efficient study startup and implementation across the GWI research community, the GWICTIC will share infrastructure with investigator-initiated research studies funded under separate mechanisms. Significance The GWICTIC will leverage the efficiencies of centralized research support and innovative trial designs to address several longstanding needs in the GWI interventions research community.

Aims Gulf War Illness (GWI) is manifested as multiple chronic symptoms, including chronic pain, chronic fatigue, sleep problems, neuropsychiatric disorders, respiratory, gastrointestinal, and skin problems. No single target tissue or unifying pathogenic process has been identified that accounts for this variety of symptoms. The brainstem has been suspected to contribute to this multiple symptomatology. The aim of this study was to assess the role of the brainstem in chronic sleep problems and pain in GWI veterans. Materials and methods We enrolled 90 veterans (Age = 50 ± 5, 87% Male) who were deployed to the 1990–91 Gulf War and presented with GWI symptoms. Sleep quality was evaluated using the global Pittsburgh Sleep Quality Index. Pain intensities were obtained with the Brief Pain Inventory sum score. Volumes in cortical, subcortical, brainstem, and brainstem subregions and diffusion tensor metrics in 10 bilateral brainstem tracts were tested for correlations with symptom measures. Key findings Poorer sleep quality was significantly correlated with atrophy of the whole brainstem and brainstem subregions (including midbrain, pons, medulla). Poorer sleep quality also significantly correlated with lower fractional anisotropy in the nigrostriatal tract, medial forebrain tract, and the dorsal longitudinal fasciculus. There was a significant correlation between increased pain intensity and decreased fractional anisotropy in the dorsal longitudinal fasciculus. These correlations were not altered after controlling for age, sex, total intracranial volumes, or additional factors, e.g., depression and neurological conditions. Significance These findings suggest that the brainstem plays an important role in the aberrant neuromodulation of sleep and pain symptoms in GWI.

Neurological disorders significantly impact the world’s economy due to their often chronic and life-threatening nature afflicting individuals which, in turn, creates a global disease burden. The Group of Twenty (G20) member nations, which represent the largest economies globally, should come together to formulate a plan on how to overcome this burden. The Neuroscience-20 (N20) initiative of the Society for Brain Mapping and Therapeutics (SBMT) is at the vanguard of this global collaboration to comprehensively raise awareness about brain, spine, and mental disorders worldwide. This paper aims to provide a comprehensive review of the various brain initiatives worldwide and highlight the need for cooperation and recommend ways to bring down costs associated with the discovery and treatment of neurological disorders. Our systematic search revealed that the cost of neurological and psychiatric disorders to the world economy by 2030 is roughly $16T. The cost to the economy of the United States is $1.5T annually and growing given the impact of COVID-19. We also discovered there is a shortfall of effective collaboration between nations and a lack of resources in developing countries. Current statistical analyses on the cost of neurological disorders to the world economy strongly suggest that there is a great need for investment in neurotechnology and innovation or fast-tracking therapeutics and diagnostics to curb these costs. During the current COVID-19 pandemic, SBMT, through this paper, intends to showcase the importance of worldwide collaborations to reduce the population’s economic and health burden, specifically regarding neurological/brain, spine, and mental disorders.

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.

In this issue, an article by Tiepolt et al. shows that PET scanning using [11C]PiB can demonstrate both cerebral blood flow (CBF) changes and amyloid-β (Aβ) deposition in patients with mild cognitive dysfunction or mild dementia of Alzheimer's disease (AD). The CBF changes can be determined because the early scan counts (1-9 minutes) reflect the flow of the radiotracer in the blood passing through the brain, while the Aβ levels are measured by later scan counts (40-70 minutes) after the radiotracer has been cleared from regions to which the radiotracer did not bind. Thus, two different diagnostic measures are obtained with a single injection. Unexpectedly, the mild patients with Aβ positivity had scan data with only a weak relationship to memory, while the relationships to executive function and language function were relatively strong. This divergence of findings from studies of severely impaired patients highlights the importance of determining how AD pathology affects the brain. A possibility suggested in this commentary is that Aβ deposits occur early in AD and specifically in critical areas of the neocortex affected only later by the neurofibrillary pathology indicating a different role of the amyloid-β protein precursor (AβPP) in the development of those neocortical regions, and a separate component of AD pathology may selectively impact functions of these neocortical regions. The effects of adverse AβPP metabolism in the medial temporal and brainstem regions occur later possibly because of different developmental issues, and the later, different pathology is clearly more cognitively and socially devastating.

Cognitive impairment is a leading cause of dysfunction in the elderly. When mild cognitive impairment (MCI) occurs in elderly, it is frequently a prodromal condition to dementia. The Montreal Cognitive Assessment (MoCA) is a commonly used tool to screen for MCI. However, this test requires a face-to-face administration and is composed of an assortment of questions whose responses are added together by the rater to provide a score whose precise meaning has been controversial. This study was designed to evaluate the performance of a computerized memory test (MemTrax), which is an adaptation of a continuous recognition task, with respect to the MoCA. Two outcome measures are generated from the MemTrax test: MemTrax speed and MemTrax correct. Subjects were administered the MoCA and the MemTrax test. Based on the results of the MoCA, subjects were divided in two groups of cognitive status: normal cognition (n = 45) and MCI (n = 37). Mean MemTrax scores were significantly lower in the MCI than in the normal cognition group. All MemTrax outcome variables were positively associated with the MoCA. Two methods, computing the average MTX score and linear regression were used to estimate the cutoff values of the MemTrax test to detect MCI. These methods showed that for the outcome MemTrax speed a score below the range of 0.87 - 91 s -1 is an indication of MCI, and for the outcome MemTrax correct a score below the range of 85 - 90% is an indication for MCI.

Aims: Gulf War Illness (GWI) is a chronic, debilitating, multi-symptom condition affecting as many as one-third of the nearly 700,000 U.S. troops deployed to the Middle East during the 1990-1991 Gulf War (GW). The treatment of GWI relies on symptom management. A common challenge in studying the efficacy of interventions for symptom management is participant recruitment related to factors such as the burden of travelling to study sites and the widespread dispersion of Veterans with GWI. The goal of this study is to assess the efficacy of a novel low-risk therapeutic agent, Bacopa monnieri, for cognitive function in Veterans with GWI and to evaluate the utility of a remote patient-centric study design developed to promote recruitment and minimize participant burden. Main Methods: To promote effective participant recruitment, we developed a remote patient-centric study design. Participants will be recruited online through social media and through a web-based research volunteer list of GW Veterans. An online assessment platform will be used, and laboratory blood draws will be performed at clinical laboratory sites that are local to participants. Furthermore, the assigned intervention will be mailed to each participant. Significance: These study design adaptations will open participation to Veterans nearly nationwide and reduce administrative costs while maintaining methodologic rigor and participant safety in a randomized, placebo-controlled phase II clinical trial.

Many Veterans of the 1990-1991 Gulf War report symptoms of Gulf War Illness, a condition involving numerous chronic symptoms including pain, fatigue, and mood/cognition symptoms. Little is known about this condition's etiology and treatment. This study reports outcomes from a randomized controlled single-blind trial comparing yoga to cognitive behavioral therapy for chronic pain and other symptoms of Gulf War Illness. Participants were Veterans with symptoms of GWI: chronic pain, fatigue and cognition-mood symptoms. Seventy-five Veterans were randomized to treatment via selection of envelopes from a bag (39 yoga, 36 cognitive behavioral therapy), which consisted of ten weekly group sessions. The primary outcomes of pain severity and interference (Brief Pain Inventory- Short Form) improved in the yoga condition (Cohen's d = .35, p = 0.002 and d = 0.69, p 0.001, respectively) but not in the CBT condition (d = 0.10, p = 0.59 and d = 0.25 p = 0.23). However, the differences between groups were not statistically significant (d = 0.25, p = 0.25; d = 0.43, p = 0.076), though the difference in an a-priori-defined experimental outcome variable which combines these two variables into a total pain variable (d = 0.47, p = 0.047) was significant. Fatigue, as indicated by a measure of functional exercise capacity (6-min walk test) was reduced significantly more in the yoga group than in the CBT group (between-group d = .27, p = 0.044). Other secondary outcomes of depression, wellbeing, and self-reported autonomic nervous system symptoms did not differ between groups. No adverse events due to treatment were reported. Yoga may be an effective treatment for core Gulf War Illness symptoms of pain and fatigue, making it one of few treatments with empirical support for GWI. Results support further evaluation of yoga for treating veterans with Gulf War Illness. CLINICAL TRIAL REGISTRY: clinicaltrials.gov Registration Number NCT02378025.

The availability and increasing popularity of direct-to-consumer genetic testing for the presence of an APOE4 allelle led the Alzheimer's Foundation of America Medical, Scientific and Memory Screening Advisory Board to identify three critical areas for attention: 1) ensure consumer understanding of test results; 2) address and limit potential negative consequences of acquiring this information; and 3) support linking results with positive health behaviors, including potential clinical trial participation. Improving access to appropriate sources of genetic counseling as part of the testing process is critical and requires action from clinicians and the genetic testing industry. Standardizing information and resources across the industry should start now, with the input of consumers and experts in genetic risk and health information disclosure. Direct-to-consumer testing companies and clinicians should assist consumers by facilitating consultation with genetic counselors and facilitating pursuit of accurate information about testing.

Background Mild Cognitive Impairment (MCI) carries a high risk of progression to Alzheimer’s disease (AD) dementia. Previous clinical trials testing whether cholinesterase inhibitors can slow the rate of progression from MCI to AD dementia have yielded disappointing results. However, recent studies of the effects of repetitive transcranial magnetic stimulation (rTMS) in AD have demonstrated improvements in cognitive function. Because few rTMS trials have been conducted in MCI, we designed a trial to test the short-term efficacy of rTMS in MCI. Yet, in both MCI and AD, we know little about what site of stimulation would be ideal for improving cognitive function. Therefore, two cortical sites will be investigated in this trial: (1) the dorsolateral prefrontal cortex (DLPFC), which has been well studied for treatment of major depressive disorder; and (2) the lateral parietal cortex (LPC), a novel site with connectivity to AD-relevant limbic regions. Methods/design In this single-site trial, we plan to enroll 99 participants with single or multi-domain amnestic MCI. We will randomize participants to one of three groups: (1) Active DLPFC rTMS; (2) Active LPC rTMS; and (3) Sham rTMS (evenly split between DLPFC and LPC locations). After completing 20 bilateral rTMS treatment sessions, participants will be followed for 6 months to test short-term efficacy and track durability of effects. The primary efficacy measure is the California Verbal Learning Test-II (CVLT-II), assessed 1 week after intervention. Secondary analyses will examine effects of rTMS on other cognitive measures, symptoms of depression, and brain function with respect to the site of stimulation. Finally, selected biomarkers will be analyzed to explore predictors of response and mechanisms of action. Discussion The primary aim of this trial is to test the short-term efficacy of rTMS in MCI. Additionally, the project will provide information on the durability of cognitive effects and potentially distinct effects of stimulating DLPFC versus LPC regions. Future efforts would be directed toward better understanding therapeutic mechanisms and optimizing rTMS for treatment of MCI. Ultimately, if rTMS can be utilized to slow the rate of progression to AD dementia, this will be a significant advancement in the field. Trial registration Clinical Trials NCT03331796. Registered 6 November 2017, https://clinicaltrials.gov/ct2/show/NCT03331796. All items from the World Health Organization Trial Registration Data Set are listed in Appendix A. Protocol version This report is based on version 1, approved by the DSMB on 30 November, 2017 and amended on 14 August, 2018 and 19 September, 2019.

Background Gulf War Illness (GWI) is a condition that affects about 30 % of veterans who served in the 1990-91 Persian Gulf War. Given its broad symptomatic manifestation, including chronic pain, fatigue, neurological, gastrointestinal, respiratory, and skin problems, it is of interest to examine whether GWI is associated with changes in the brain. Existing neuroimaging studies, however, have been limited by small sample sizes, inconsistent GWI diagnosis criteria, and potential comorbidity confounds. Objectives Using a large cohort of US veterans with GWI, we assessed regional brain volumes for their associations with GWI, and quantified the relationships between any regional volumetric changes and GWI symptoms. Methods Structural magnetic resonance imaging (MRI) scans from 111 veterans with GWI (Age = 49 ± 6, 88 % Male) and 59 healthy controls (age = 51 ± 9, 78 % male) were collected at the California War Related Illness and Injury Study Center (WRIISC-CA) and from a multicenter study of the Parkinson’s Progression Marker Initiative (PPMI), respectively. Individual MRI volumes were segmented and parcellated using FreeSurfer. Regional volumes of 19 subcortical, 68 cortical, and 3 brainstem structures were evaluated in the GWI cohort relative to healthy controls. The relationships between regional volumes and GWI symptoms were also assessed. Results We found significant subcortical atrophy, but no cortical differences, in the GWI group relative to controls, with the largest effect detected in the brainstem, followed by the ventral diencephalon and the thalamus. In a subsample of 58 veterans with GWI who completed the Chronic Fatigue Scale (CFS) inventory of Centers for Disease Control and Prevention (CDC), smaller brainstem volumes were significantly correlated with increased severities of fatigue and depressive symptoms. Conclusion The findings suggest that brainstem volume may be selectively affected by GWI, and that the resulting atrophy could in turn mediate or moderate GWI-related symptoms such as fatigue and depression. Consequently, the brain stem should be carefully considered in future research focusing on GWI pathology.

At its fundamental basis, Alzheimer's disease (AD) is a pathological process that affects neuroplasticity, leading to a specific disruption of episodic memory. This review will provide a rationale for calls to screen for the early detection of AD, appraise the currently available cognitive instruments for AD detection, and focus on the development of the MemTrax test, which provides a new approach to detect the early manifestations and progression of the dementia associated with AD. MemTrax assesses metrics that reflect the effects of neuroplastic processes on learning, memory, and cognition, which are affected by age and AD, particularly episodic memory functions, which cannot presently be measured with enough precision for meaningful use. Further development of MemTrax would be of great value to the early detection of AD and would provide support for the testing of early interventions.

Standard MRI methods are often inadequate for identifying mild traumatic brain injury (TBI). Advances in diffusion tensor imaging now provide potential biomarkers of TBI among white matter fascicles (tracts). However, it is still unclear which tracts are most pertinent to TBI diagnosis. This study ranked fiber tracts on their ability to discriminate patients with and without TBI. We acquired diffusion tensor imaging data from military veterans admitted to a polytrauma clinic (Overall n = 109; Age: M = 47.2, SD = 11.3; Male: 88%; TBI: 67%). TBI diagnosis was based on self-report and neurological examination. Fiber tractography analysis produced 20 fiber tracts per patient. Each tract yielded four clinically relevant measures (fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity). We applied receiver operating characteristic (ROC) analyses to identify the most diagnostic tract for each measure. The analyses produced an optimal cutpoint for each tract. We then used kappa coefficients to rate the agreement of each cutpoint with the neurologist's diagnosis. The tract with the highest kappa was most diagnostic. As a check on the ROC results, we performed a stepwise logistic regression on each measure using all 20 tracts as predictors. We also bootstrapped the ROC analyses to compute the 95% confidence intervals for sensitivity, specificity, and the highest kappa coefficients. The ROC analyses identified two fiber tracts as most diagnostic of TBI: the left cingulum (LCG) and the left inferior fronto-occipital fasciculus (LIF). Like ROC, logistic regression identified LCG as most predictive for the FA measure but identified the right anterior thalamic tract (RAT) for the MD, RD, and AD measures. These findings are potentially relevant to the development of TBI biomarkers. Our methods also demonstrate how ROC analysis may be used to identify clinically relevant variables in the TBI population., Highlights • We conducted ROC analyses using DTI data from veterans with and without traumatic brain injury. • For each participant, DTI analysis identified measures (FA, MD, RD, AD) from twenty fiber tracts. • ROC analyses determined which fiber tracts best predict TBI status for each measure.

Evaluation of brainstem pathways with diffusion tensor imaging (DTI) and tractography may provide insights into pathophysiologies associated with dysfunction of key brainstem circuits. However, identification of these tracts has been elusive, with relatively few in vivo human studies to date. In this paper we proposed an automated approach for reconstructing nine brainstem fiber trajectories of pathways that might be involved in pain modulation. We first performed native-space manual tractography of these fibers in a small normative cohort of participants and confirmed the anatomical precision of the results using existing anatomical literature. Second, region-of-interest pairs were manually defined at each extracted fiber’s termini and nonlinearly warped to a standard anatomical brain template to create an atlas of the region-of-interest pairs. The resulting atlas was then transformed non-linearly into the native space of 17 veteran patients’ brains for automated brainstem tractography. Lastly, we assessed the relationships between the integrity levels of the obtained fiber bundles and pain severity levels. Fractional anisotropy (FA) measures derived using automated tractography reflected the respective tracts’ FA levels obtained via manual tractography. A significant inverse relationship between FA and pain levels was detected within the automatically derived dorsal and medial longitudinal fasciculi of the brainstem. This study demonstrates the utility of DTI in exploring brainstem circuitries involved in pain processing. In this context, the described automated approach is a viable alternative to the time-consuming manual tractography. The physiological and functional relevance of the measures derived from automated tractography is evidenced by their relationships with individual pain severities.

This chapter updates reviews of methods and techniques related to recognition of cognitive impairment and the progressive steps involved in diagnosing dementia, from screening tests to clinical assessment. Diagnostic criteria for “minor” and “major” neurocognitive disorders are outlined, as well as the typical progressive presentation of dementia over the full course, most typically seen with Alzheimer’s disease. The clinical evaluation of the patient with cognitive impairment is presented in detail, including central parts of the dementia assessment, starting with the physical and neurological examination, including brief cognitive tests, laboratory evaluation, genetic testing, and brain imaging, as well as aspects of the neuropsychological assessment. In the differential diagnosis, numerous pathogenic factors can impair mental processing. The most common problem is the consideration of Alzheimer’s disease, which must be evaluated relative to treatable conditions and distinguished from conditions which can have a similar presentation, such as vascular dementia and diffuse Lewy body dementia. The chapter also considers the broad array of behavioral consequences which may accompany cognitive dysfunction, including the common presentations of dementias more specifically affecting brain memory mechanisms, such as Alzheimer’s disease, and others which predominantly affect inhibitory and executive functions, such as fronto-temporal dementia and chronic traumatic encephalopathy. Two appendices also accompany the chapter – one describing the specific assessment measures used in federally funded Alzheimer’s research centers, and the other describing resources for clinicians available from the Alzheimer’s Association.

In this issue, an article by Waring et al. provides a meta-analysis of the effects of apo-lipo-protein E (APOE) genotype on the beneficial effect of acetyl-cholinesterase inhibitors (AChEIs) in patients with Alzheimer's disease (AD). There was no significant effect found. As of 2015, AChEI medications are the mainstay of AD treatment, and APOE genotype is the most significant factor associated with AD causation. This lack of a significant effect of APOE is analyzed with respect to the "Cholinergic Hypothesis" of AD, dating from 1976, through the recognition that cholinergic neurons are not the sole target of AD, but rather that AD attacks all levels of neuroplasticity in the brain, an idea originated by Ashford and Jarvik in 1985 and which still provides the clearest explanation for AD dementia. The "Amyloid Hypothesis" is dissected back to the alpha/beta pathway switching mechanism affecting the nexin-amyloid pre-protein (NAPP switch). The NAPP switch may be the critical neuroplasticity component of all learning involving synapse remodeling and subserve all learning mechanisms. The gamma-secretase cleavage is discussed, and its normal complementary products, beta-amyloid and the NAPP intracellular domain (NAICD), appear to be involved in natural synapse removal, but the link to AD dementia may involve the NAICD rather than beta-amyloid. Understanding neuroplasticity and the critical pathways to AD dementia are needed to determine therapies and preventive strategies for AD. In particular, the effect of APOE on AD predisposition needs to be established and a means found to adjust its effect to prevent AD.

I read with interest the Null Hypothesis article by Meyer et al.1 In 2001, Weggen et al.2 suggested that flurbiprofen and ibuprofen had an effect on gamma secretase not shared by other cyclooxygenase inhibitors. This finding, along with several other failed studies of anti-inflammatory mechanisms in Alzheimer disease (AD), suggests that the widely replicated epidemiologic findings of nonsteroidal anti-inflammatory drug (NSAID) benefit for decreasing AD risk could be related to the effect on gamma-secretase, not inflammation. A flurbiprofen study failed to show a benefit for patients with AD,3 but a considerable number of studies suggest that the NSAID-related benefit requires years of treatment before dementia develops, which the study by Meyer et al.1 was appropriately targeting. However, the question remains as to whether ibuprofen is the drug to test, not naproxen.

Alzheimer's disease (AD) shortens life-expectancy, but the effects of pharmacological treatments for this disorder on mortality have not been studied. We compared two commonly prescribed medications, donepezil and memantine, with respect to the length of survival of veterans presumed to have AD. The Computerized Medical Records System at the Veterans Affairs Palo Alto Health Care System (VAPAHCS) was used to identify all patients prescribed these medications between 1997 and 2008. The VAPAHCS approved donepezil in 1997 and memantine in 2004. Kaplan-Meier and Cox regression analyses were used to test for chronological and drug-related associations with survival in 2,083 male veterans aged 55 years and older receiving prescriptions for donepezil, memantine, or both. Overall patient mortality decreased in the 2004 to 2008 era, compared with the 1997 to 2003 era, pre-memantine (HR: 0.75; 95% CI: 0.63, 0.89; p = 0.001). In analyses confined to the 2004 to 2008 era, patients prescribed memantine alone survived significantly longer than those prescribed donepezil alone (HR: 2.24; 95% CI: 1.53, 3.28; p < 0.001) or both donepezil and memantine (HR: 1.83; 95% CI: 1.14, 2.94; p = 0.012). While this study has several limitations, these findings suggest that memantine treatment is associated with an increased life-expectancy relative to donepezil treatment. Additional research is needed to replicate these unexpected findings and identify potential mechanisms to explain this apparent association, to establish if the relationship applies to other cholinesterase inhibitors, and to discover whether the findings generalize to women and patient populations with characteristics different from those of the veterans in this study.

The value of screening for cognitive impairment, including dementia and Alzheimer's disease, has been debated for decades. Recent research on causes of and treatments for cognitive impairment has converged to challenge previous thinking about screening for cognitive impairment. Consequently, changes have occurred in health care policies and priorities, including the establishment of the annual wellness visit, which requires detection of any cognitive impairment for Medicare enrollees. In response to these changes, the Alzheimer's Foundation of America and the Alzheimer's Drug Discovery Foundation convened a workgroup to review evidence for screening implementation and to evaluate the implications of routine dementia detection for health care redesign. The primary domains reviewed were consideration of the benefits, harms, and impact of cognitive screening on health care quality. In conference, the workgroup developed 10 recommendations for realizing the national policy goals of early detection as the first step in improving clinical care and ensuring proactive, patient-centered management of dementia.

The described invention relates to compositions and methods for rescuing neurons from Alzheimer's Disease related pathways triggered by lipid burden or metabolic insult.

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by genotypic and phenotypic heterogeneity. Critical components of the two AD pathological pathways, Aβ-amyloidosis and Tauopathy, have been considered as therapeutic targets. Among them, much effort is focused on aberrant Tau phosphorylation and targeting Tau-phosphorylating kinases. Methylene blue (MB), a phenothiazine dye that crosses the blood-brain barrier, has been shown to hit multiple molecular targets involved in AD and have beneficial effects in clinical studies. Here we present evidence that microtubule affinity-regulating kinase (MARK4) is a novel target of MB. MB partially rescued the synaptic toxicity in Drosophila larva overexpressing PAR1 (MARK analog). In 293T culture, MB decreased MARK4-mediated Tau phosphorylation in a dose dependent manner. Further studies revealed a two-fold mechanism by MB including down-regulation of MARK4 protein level through ubiquitin-proteasome pathway and inhibition of MARK4 kinase activity in vitro. This study highlights the importance of MARK4 as a viable target for Tauopathy and provides fresh insight into the complex mechanism used by MB to treat AD.

This supplement to the Journal of Alzheimer's Disease contains more than half of the chapters from The Handbook of Imaging the Alzheimer Brain, which was first presented at the International Conference on Alzheimer's Disease in Paris, in July, 2011. While the Handbook contains 27 chapters that are modified articles from 2009, 2010, and 2011 issues of the Journal of Alzheimer's Disease, this supplement contains the 31 new chapters of that book and an introductory article drawn from the introductions to each section of the book. The Handbook was designed to provide a multilevel overview of the full field of brain imaging related to Alzheimer's disease (AD). The Handbook, as well as this supplement, contains both reviews of the basic concepts of imaging, the latest developments in imaging, and various discussions and perspectives of the problems of the field and promising directions. The Handbook was designed to be useful for students and clinicians interested in AD as well as scientists studying the brain and pathology related to AD.

The data from the initial clinical trials utilizing recombinant human leptin as an obesity therapy were published in 1998. Since then, numerous studies have been described which address dosage, safety and efficacy of leptin replacement for a variety of disorders with diverse patient groups, including pediatric and adult subjects. We review the current clinical trial data, demonstrate that leptin administration is safe for long term use in humans, and summarize reported cognitive benefits. The functions of leptin in neuroprotection and cognition have been largely overlooked. Accumulating data suggest a very significant application of leptin may be a therapy for Alzheimer's disease.

Dementia and its most common cause, Alzheimer’s disease, affect memory and occur predominantly in the elderly. Dementia has become increasingly prevalent in the world as health has improved and life expectancy has increased. However, the fields of clinical care have not responded adequately to develop diagnostic tools and treatments for this rapidly increasing group of conditions. While scientists search for cures for the numerous causes of dementia, improvement of diagnostic measures are needed now and should begin with screening elderly populations for memory difficulties and other cognitive problems. This review examines the history of cognitive screening tests, the numerous excellent tests that are currently available and ready for use, and directions and methods that will lead to progressively better evaluations.

Veterans who have been deployed to combat often have complex medical histories including some combination of traumatic brain injury (TBI); mental health problems; and other chronic, medically unexplained symptoms (i.e., chronic multisymptom illness [CMI] clusters). How these multiple pathologies relate to functional health is unclear. In the current study, 120 Veterans (across multiple combat cohorts) underwent comprehensive clinical evaluations and completed self-report assessments of mental health symptoms (Patient Health Questionnaire-2 [PHQ-2], PTSD Checklist-Civilian Version [PCL-C]) and functional health (Veterans Rand 36-Item Health Survey). Canonical correlation and regression modeling using split-sample permutation tests revealed that the PHQ-2/PCL-C composite variable (among TBI severity and number of problematic CMI clusters) was the primary predictor of multiple functional health domains. Two subscales, Bodily Pain and General Health, were associated with multiple predictors (TBI, PHQ-2/PCL-C, and CMI; and PHQ-2/PCL-C and CMI, respectively), demonstrating the multifaceted nature of how distinct medical problems might uniquely and collectively impair aspects of functional health. Apart from these findings, however, TBI and CMI were not predictors of any other aspects of functional health. Taken together, our findings suggest that mental health problems might exert ubiquitous influence over multiple domains of functional health. Thus, screening of mental health problems and education and promotion of mental health resources can be important to the treatment and care of Veterans.