More Similar than Different: Memory, Executive Functions, Cortical Thickness, and Glucose Metabolism in Biomarker-Positive Alzheimer's Disease and Behavioral Variant Frontotemporal Dementia.

Background: Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) are typically associated with very different clinical and neuroanatomical presentations; however, there is increasing recognition of similarities. Objective: To examine memory and executive functions, as well as cortical thickness, and glucose metabolism in AD and bvFTD signature brain regions. Methods: We compared differences in a group of biomarker-defined participants with Alzheimer's disease and a group of clinically diagnosed participants with bvFTD. These groups were also contrasted with healthy controls (HC). Results: As expected, memory functions were generally more impaired in AD, followed by bvFTD, and both clinical groups performed more poorly than the HC group. Executive function measures were similar in AD compared to bvFTD for motor sequencing and go/no-go, but bvFTD had more difficulty with a set shifting task. Participants with AD showed thinner cortex and lower glucose metabolism in the angular gyrus compared to bvFTD. Participants with bvFTD had thinner cortex in the insula and temporal pole relative to AD and healthy controls, but otherwise the two clinical groups were similar for other frontal and temporal signature regions. Conclusions: Overall, the results of this study highlight more similarities than differences between AD and bvFTD in terms of cognitive functions, cortical thickness, and glucose metabolism. Further research is needed to better understand the mechanisms mediating this overlap and how these relationships evolve longitudinally.

Surface-based correlates of cognition along the Alzheimer's continuum in a memory clinic population.

Composite cognitive measures in large-scale studies with biomarker data for amyloid and tau have been widely used to characterize Alzheimer's disease (AD). However, little is known about how the findings from these studies translate to memory clinic populations without biomarker data, using single measures of cognition. Additionally, most studies have utilized voxel-based morphometry or limited surface-based morphometry such as cortical thickness, to measure the neurodegeneration associated with cognitive deficits. In this study, we aimed to replicate and extend the biomarker, composite study relationships using expanded surface-based morphometry and single measures of cognition in a memory clinic population. We examined 271 clinically diagnosed symptomatic individuals with mild cognitive impairment (N = 93) and Alzheimer's disease dementia (N = 178), as well as healthy controls (N = 29). Surface-based morphometry measures included cortical thickness, sulcal depth, and gyrification index within the "signature areas" of Alzheimer's disease. The cognitive variables pertained to hallmark features of Alzheimer's disease including verbal learning, verbal memory retention, and language, as well as executive function. The results demonstrated that verbal learning, language, and executive function correlated with the cortical thickness of the temporal, frontal, and parietal areas. Verbal memory retention was correlated to the thickness of temporal regions and gyrification of the inferior temporal gyrus. Language was related to the temporal regions and the supramarginal gyrus' sulcal depth and gyrification index. Executive function was correlated with the medial temporal gyrus and supramarginal gyrus sulcal depth, and the gyrification index of temporal regions and supramarginal gyrus, but not with the frontal areas. Predictions of each of these cognitive measures were dependent on a combination of structures and each of the morphometry measurements, and often included medial temporal gyrus thickness and sulcal depth. Overall, the results demonstrated that the relationships between cortical thinning and cognition are widespread and can be observed using single measures of cognition in a clinically diagnosed AD population. The utility of sulcal depth and gyrification index measures may be more focal to certain brain areas and cognitive measures. The relative importance of temporal, frontal, and parietal regions in verbal learning, language, and executive function, but not verbal memory retention, was replicated in this clinic cohort.

Procedural learning and retention relative to explicit learning and retention in mild cognitive impairment and Alzheimer's disease using a modification of the trail making test.

Amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD) dementia are characterized by pathological changes to the medial temporal lobes, resulting in explicit learning and retention reductions. Studies demonstrate that implicit/procedural memory processes are relatively intact in these populations, supporting different anatomical substrates for differing memory systems. This study examined differences between explicit and procedural learning and retention in individuals with aMCI and AD dementia relative to matched healthy controls. We also examined anatomical substrates using volumetric MRI. Results revealed expected difficulties with explicit learning and retention in individuals with aMCI and AD with relatively preserved procedural memory. Explicit verbal retention was associated with medial temporal cortex volumes. However, procedural retention was not related to medial temporal or basal ganglia volumes. Overall, this study confirms the dissociation between explicit relative to procedural learning and retention in aMCI and AD dementia and supports differing anatomical substrates.

Frontal and temporal lobe correlates of verbal learning and memory in aMCI and suspected Alzheimer's disease dementia.

Alzheimer's disease is primarily known for deficits in learning and retaining new information. This has long been associated with pathological changes in the mesial temporal lobes. The role of the frontal lobes in memory in Alzheimer's disease is less well understood. In this study, we examined the role of the frontal lobes in learning, recognition, and retention of new verbal information, as well as the presence of specific errors (i.e., intrusions and false-positive errors). Participants included one hundred sixty-seven patients clinically diagnosed with amnestic mild cognitive impairment or suspected Alzheimer's disease dementia who were administered the California Verbal Learning Test and completed high-resolution MRI. We confirmed the role of the mesial temporal lobes in learning and retention, including the volumes of the hippocampus, entorhinal cortex, and parahippocampal gyrus. In addition, false-positive errors were associated with all volumes of the mesial temporal lobes and widespread areas within the frontal lobes. Errors of intrusion were related to the supplementary motor cortex and hippocampus. Most importantly, the mesial temporal lobes interacted with the frontal lobes for learning, recognition, and memory errors. Lower volumes in both regions explained more performance variance than any single structure. This study supports the interaction of the frontal lobes with the temporal lobes in many aspects of memory in Alzheimer's disease.

Epidemiology and Pathophysiology of Multiple Sclerosis.

PURPOSE OF REVIEW: This article provides an overview of genetic, environmental, and lifestyle risk factors affecting the disease course of multiple sclerosis (MS) and reviews the pathophysiologic characteristics of both relapsing and progressive MS. RECENT FINDINGS: The prevalence of MS has increased in recent decades, and costs of care for patients with MS have risen dramatically. Black, Asian, and Hispanic individuals may be at risk for more severe MS-related disability. Multiple genetic MS risk factors have been identified. Factors such as low vitamin D levels and a history of Epstein-Barr virus, smoking, and obesity, especially during childhood, also influence MS risk. Traditionally thought to be a T-cell-mediated disease, recent research has highlighted the additional roles of B cells and microglia in both relapsing and progressive MS. SUMMARY: Complex interactions between genetic, environmental, and lifestyle factors affect the risk for MS as well as the disease course. People of color have historically been underrepresented in both MS clinical trials and literature, but current research is attempting to better clarify unique considerations in these groups. MS pathology consists of the focal inflammatory lesions that have been well characterized in relapsing MS, as well as a more widespread neurodegenerative component that is posited to drive progressive disease. Recent advances in characterization of both the inflammatory and neurodegenerative aspects of MS pathophysiology have yielded potential targets for future therapeutic options.

A multi-site service evaluation of the tinnitus care decision aid.

OBJECTIVE: Shared decision-making is a principle of health care delivery across the world. The first international standard decision aid for tinnitus care was developed in 2018. This decision aid is in use across the UK. It is free to use and access from the British Tinnitus Association website. Our objective was to compare routine care with the care that also included the decision aid as part of care for their patients. DESIGN: A multi-site service evaluation included pre-post comparison of decisional conflict in sequential new patients seeking help with tinnitus. Informal interviews with staff and service managers explored how practical and feasible the decision aid was in routine practice. STUDY SAMPLE: We present data from four contrasting clinical services, including services in England and Wales, acute and community services and those operated by Hearing Therapists and Audiologists. RESULTS: Across these contrasting services, the inclusion of the decision aid was associated with a reduction in decisional conflict in patients. The decision aid was feasible to administer, acceptable to patients and clinicians without creating a burden in appointments. CONCLUSIONS: These evaluations suggest that the decision aid is feasible to administer and reduces patient decisional conflict. It appears to benefit clinical services in practice.

COVID-19 Vaccine intent in appalachian patients with multiple sclerosis.

BACKGROUND: Rural people with Multiple Sclerosis (PwMS) face distinctive challenges in the COVID-19 pandemic. The purpose of this study was to determine the COVID-19 vaccine intent and factors associated with vaccine hesitancy among Appalachian adults with MS. METHOD: We conducted a cross sectional phone and in-person survey of PwMS in a large academic center in West Virginia (WV) from February to May 2021. The study sample consists of 306 adult participants. RESULTS: Among the 306 participants, 104 (33.99%) indicated vaccine hesitancy. Statistically significant factors (p<0.05) associated with vaccine hesitancy compared to those who received or intend to get vaccinated included concerns about vaccine safety, vaccine causing MS relapse, vaccine making MS medication ineffective, vaccine causing other diseases, getting the COVID-19 infection, vaccine fast approval, vaccine ingredients, how well the vaccine works, and its side-effects. Additional factors included prior bad experiences with other vaccines, history of not getting the flu vaccine, and lack of consultation about COVID-19 vaccine with healthcare providers. CONCLUSIONS: Vaccine hesitancy among Appalachian adult PwMS is higher compared to PwMS in the larger United States. Vaccine hesitancy is especially higher among those who are female, younger than 50 years old, and residing in rural areas. Concerns about vaccine safety, perception of infection risks, past vaccine behaviors and consultation with healthcare providers are important factors associated with vaccine intent. Factors influencing vaccine hesitancy in Appalachian PwMS are largely consistent with the general public, however, concerns for interaction between the vaccine and MS are specific to this population and thus could be the focus of further vaccine effort.

Enhancing research informatics core user satisfaction through agile practices.

OBJECTIVE: The Huntsman Cancer Institute Research Informatics Shared Resource (RISR), a software and database development core facility, sought to address a lack of published operational best practices for research informatics cores. It aimed to use those insights to enhance effectiveness after an increase in team size from 20 to 31 full-time equivalents coincided with a reduction in user satisfaction. MATERIALS AND METHODS: RISR migrated from a water-scrum-fall model of software development to agile software development practices, which emphasize iteration and collaboration. RISR's agile implementation emphasizes the product owner role, which is responsible for user engagement and may be particularly valuable in software development that requires close engagement with users like in science. RESULTS: All RISR's software development teams implemented agile practices in early 2020. All project teams are led by a product owner who serves as the voice of the user on the development team. Annual user survey scores for service quality and turnaround time recorded 9 months after implementation increased by 17% and 11%, respectively. DISCUSSION: RISR is illustrative of the increasing size of research informatics cores and the need to identify best practices for maintaining high effectiveness. Agile practices may address concerns about the fit of software engineering practices in science. The study had one time point after implementing agile practices and one site, limiting its generalizability. CONCLUSIONS: Agile software development may substantially increase a research informatics core facility's effectiveness and should be studied further as a potential best practice for how such cores are operated.

Histone-mutant glioma presenting as diffuse leptomeningeal disease.

Glioblastoma multiforme is the most common malignant primary brain tumor in adults. Histone H3 mutations have been identified in pediatric and adult gliomas, with H3K27M mutations typically associated with a posterior fossa midline tumor location and poor prognosis. Leptomeningeal disease is a known complication of histone-mutant glioma, but uncommon at the time of initial diagnosis. We describe a case of glioblastoma with H3K27M mutation that initially presented with progressive vision loss due to diffuse leptomeningeal disease in the absence of a mass lesion other than a small cerebellar area of enhancement and with cerebrospinal fluid cytology negative for malignant cells on two occasions, highlighting the importance of including primary CNS malignancies in the differential of diffuse radiographic leptomeningeal enhancement.

Lay abstract Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. Histones are molecules around which DNA winds. GBM and other gliomas sometimes have genetic alterations called mutations in histone genes. Of these, a specific alteration in histone 3 called H3K27M has been described in a variety of primary brain tumors. In adult gliomas, the H3K27M mutation is typically associated with tumors located within the brainstem or other structures in the midline of the central nervous system and a poor prognosis. Although previously reported, involvement of the leptomeninges (the thin membranes covering the brain and spinal cord) is uncommon at the time of initial diagnosis of gliomas harboring H3K27M mutations. We describe a case of GBM that initially presented with vision loss due to diffuse leptomeningeal involvement. Imaging and laboratory studies, including two cerebrospinal fluid analyses by lumbar puncture, did not establish a diagnosis. Brain biopsy confirmed the presence of a tumor, and genetic testing performed on the tumor tissue identified the histone mutation. This case highlights the importance of including primary central nervous system malignancies as a possible diagnosis when there is diffuse radiographic leptomeningeal enhancement.

Independent and joint contributions of economic, social and physical environmental characteristics to mortality in the Detroit Metropolitan Area: A study of cumulative effects and pathways.

OBJECTIVE: Previous studies have demonstrated associations between race-based residential segregation, neighborhood socioeconomic and physical environmental characteristics, and mortality. Relatively few studies have examined independent and joint effects of these multiple neighborhood characteristics and mortality, including potential mediating pathways. In this study we examine the extent to which associations between race-based residential segregation and all-cause mortality may be explained by multiple socioeconomic indicators and exposure to air pollutants. METHODS: Drawing on data from multiple sources, we assessed bivariate associations between race-based residential segregation (operationalized as percent non-Hispanic Black), education (percent with graduate equivalency degree), poverty (percent below poverty), income inequality (GINI coefficient) and air pollution (ambient PM2.5) and age adjusted all-cause, all race mortality (henceforth all cause mortality) at the census tract level in the Detroit Metropolitan Area. We used inequality curves to assess the (in)equitable distribution of economic and environmental characteristics by census tract racial composition. Finally, we used generalized estimating equations (GEE) to examine independent and joint associations among percent NHB, education, income inequality, and air pollution to all-cause mortality, and test for mediating effects. RESULTS: Bivariate associations between racial composition, education, poverty, income inequality, PM2.5 and all-cause mortality were statistically significant. Census tracts with higher concentrations of NHB residents had significantly lower educational attainment, higher poverty, and greater exposure to PM2.5. In multivariate models, education, income inequality and PM2.5 fully attenuated associations between racial composition and all-cause mortality. CONCLUSIONS: Results are consistent with the hypothesis that race-based residential segregation is associated with heightened all-cause mortality, and that those effects are mediated by education, income inequality, and exposure to air pollution at the census tract level. Public health and cross-sector interventions to eliminate race-based residential segregation or to eliminate the maldistribution of educational and economic resources, and environmental exposures, across census tracts could substantially reduce regional inequities in all-cause mortality.

A conceptual framework for evaluating health equity promotion within community-based participatory research partnerships.

Community-based participatory research (CBPR) approaches present strong opportunities to promote health equity by improving health within low-income communities and communities of color. CBPR principles and evaluation frameworks highlight an emphasis on equitable group dynamics (e.g., shared leadership and power, participatory decision-making, two-way open communication) that promote both equitable processes within partnerships and health equity in the communities with whom they engage. The development of an evaluation framework that describes the manner in which equitable group dynamics promote intermediate and long-term equity outcomes can aid partners in assessing their ability to work together effectively and improve health equity in the broader community. CBPR principles align with health equity evaluation guidelines recently developed for Health Impact Assessments (HIAs), which emphasize meaningful engagement of communities in decision-making processes that influence their health. In this paper, we propose a synergistic framework integrating contributions from CBPR and HIA evaluation frameworks in order to guide efforts to evaluate partnership effectiveness in addressing health inequities. We suggest specific indicators that might be used to assess partnership effectiveness in addressing health equity and discuss implications for evaluation of partnership approaches to address health equity.

Independent and Joint Contributions of Fine Particulate Matter Exposure and Population Vulnerability to Mortality in the Detroit Metropolitan Area.

Fine particulate matter is associated with adverse health outcomes. Exposure to fine particulate matter may disproportionately affect urban communities with larger numbers of vulnerable residents. We used multilevel logistic regression models to estimate the joint effects of fine particulate matter (PM2.5) and population vulnerabilities on cardiopulmonary mortality (CPM). We estimated the health benefits of reductions in PM2.5 across census tracts in the Detroit metropolitan area with varying levels of population vulnerability, using cluster-specific odds ratios scaled to reflect PM2.5-attributable cardiopulmonary risk. PM2.5 and population vulnerability were independently associated with odds of CPM. Odds of CPM and the number of deaths attributable to PM2.5 were greatest in census tracts with both high PM2.5 exposures and population vulnerability. Reducing PM2.5 in census tracts with high PM2.5 would lead to an estimated 18% annual reduction in PM2.5-attributable CPM. Between 78⁻79% of those reductions in CPM would occur within census tracts with high population vulnerabilities. These health benefits of reductions in PM2.5 occurred at levels below current U.S. reference concentrations. Focusing efforts to reduce PM2.5 in the Detroit metropolitan area in census tracts with currently high levels would also lead to greater benefits for residents of census tracts with high population vulnerabilities.

The development of a decision aid for tinnitus.

OBJECTIVE: To develop a decision aid for tinnitus care that would meet international consensus for decision aid quality. DESIGN: A mixed methods design that included qualitative in-depth interviews, literature review, focus groups, user testing and readability checking. STUDY SAMPLE: Patients and clinicians who have clinical experience of tinnitus. RESULTS: A decision aid for tinnitus care was developed. This incorporates key evidence of efficacy for the most frequently used tinnitus care options, together with information derived from patient priorities when deciding which choice to make. CONCLUSION: The decision aid has potential to enable shared decision making between clinicians and patients in audiology. The decision aid meets consensus standards.

Identification and validation of clinically meaningful benchmarks in the 12-item Multiple Sclerosis Walking Scale.

BACKGROUND: The 12-item Multiple Sclerosis Walking Scale (12-MSWS) is a validated questionnaire which assessed walking function; it has been widely adopted in multiple sclerosis (MS) clinical research. OBJECTIVE: Identify and validate clinically meaningful 12-MSWS benchmarks in MS. METHODS: Cross-sectional study of 159 MS patients permitted identification of clinically meaningful 12-MSWS benchmarks based on their relationship to real-life anchors. Identified 12-MSWS benchmarks were then validated in a second population of 96 subjects using measures of ambulation, cognition, and patient-reported outcomes. RESULTS: 12-MSWS score of 0-24.99 was associated with working outside the home and assistance-free mobility; 25-49.99 was associated with gait disability and difficulty doing housework; 50-74.99 was associated with unemployment, government healthcare, cane use, and difficulty performing instrumental activities of daily living (IADLs); and 75-100 was associated with change in occupation due to walking, mobility impairment requiring bilateral assistance, and inability to perform IADLs. During the validation step, strong linear associations were identified between 12-MSWS benchmarks and other MS-related disability outcome measures, including ambulatory and non-ambulatory measures. CONCLUSION: We have identified clinically meaningful 12-MSWS benchmarks which define four groups differentiated by increasing levels of mobility impairment and associated loss of functional independence. These data provide insight into how 12-MSWS translate to meaningful functional limitations in MS.

Cryptococcal meningitis after fingolimod discontinuation in a patient with multiple sclerosis.

Fingolimod (Gilenya, Novartis) is an oral sphingosine-1-phosphate analogue used in the treatment of relapsing multiple sclerosis (MS). Fingolimod treatment is associated with relative lymphopenia and was associated with an increased risk of herpes infection in clinical trials. In the post-marketing setting, fingolimod has been associated with several cases of cryptococcal meningitis, recently prompting an update to its prescribing information. To date, all cases have been associated with active treatment with fingolimod. In this report, we describe the first case of cryptococcal meningitis diagnosed after fingolimod discontinuation.

LINC00507 Is Specifically Expressed in the Primate Cortex and Has Age-Dependent Expression Patterns.

Over the past decade, there has been an increase in the appreciation of the role of non-coding RNA in the development of organism phenotype. It is possible to divide the non-coding elements of the transcriptome into three categories: short non-coding RNAs, circular RNAs and long non-coding RNAs. Long non-coding RNAs are those transcripts that are greater than 200 nts in length and lack any significant open reading frames that produce proteins greater then 100 amino acids. Long intervening non-coding RNAs (lincRNAs) are a subclass of long non-coding RNAs. In contrast to protein coding RNAs, lincRNAs are expressed in a more tissue- and species-specific manner. In particular, many lincRNAs are only conserved amongst higher primates. This coupled with the propensity of many lincRNAs to be expressed in the brain, suggests that they are in fact one of the major drivers of organism complexity. We analysed 39 lincRNAs that are expressed in the frontal cortex and identified LINC00507 as being expressed in a cortex-specific manner in non-human primates and humans. The expression patterns of LINC00507 appear to be age-dependent, suggesting it may be involved in brain development of higher primates. Moreover, the analysis of LINC00507 potential to bind ribosomes revealed that this previously identified non-coding transcript may harbour a micropeptide.

RACE AND THE DISTRIBUTION OF SOCIAL AND PHYSICAL ENVIRONMENTAL RISK: A Case Example from the Detroit Metropolitan Area.

Since W. E. B. Du Bois documented the physical and social environments of Philadelphia's predominantly African American Seventh Ward over a century ago, there has been continued interest in understanding the distribution of social and physical environments by racial make-up of communities. Characterization of these environments allows for documentation of inequities, identifies communities which encounter heightened risk, and can inform action to promote health equity. In this paper, we apply and extend Du Bois's approach to examine the contemporary distribution of physical environmental exposures, health risks, and social vulnerabilities in the Detroit metropolitan area, one of the most racially-segregated areas in the United States. We begin by mapping the proximity of sensitive populations to hazardous land uses, their exposure to air pollutants and associated health risks, and social vulnerabilities, as well as cumulative risk (combined proximity, exposure, and vulnerability), across Census tracts. Next, we assess, quantitatively, the extent to which communities of color experience excess burdens of environmental exposures and associated health risks, economic and age-related vulnerabilities, and cumulative risk. The results, depicted in maps presented in the paper, suggest that Census tracts with greater proportions of people of color disproportionately encounter physical environmental exposures, socioeconomic vulnerabilities, and combined risk. Quantitative tests of inequality confirm these distributions, with statistically greater exposures, vulnerabilities, and cumulative risk in Census tracts with larger proportions of people of color. Together, these findings identify communities that experience disproportionate cumulative risk in the Detroit metropolitan area and quantify the inequitable distribution of risk by Census tract relative to the proportion of people of color. They identify clear opportunities for prioritizing communities for legislative, regulatory, policy, and local actions to promote environmental justice and health equity.

Conservation and tissue-specific transcription patterns of long noncoding RNAs.

Over the past decade, the focus of molecular biology has shifted from being predominately DNA and protein-centric to having a greater appreciation of RNA. It is now accepted that the genome is pervasively transcribed in tissue- and cell-specific manner, to produce not only protein-coding RNAs, but also an array of noncoding RNAs (ncRNAs). Many of these ncRNAs have been found to interact with DNA, protein and other RNA molecules where they exert regulatory functions. Long ncRNAs (lncRNAs) are a subclass of ncRNAs that are particularly interesting due to their cell-specific and species-specific expression patterns and unique conservation patterns. Currently, individual lncRNAs have been classified functionally; however, for the vast majority the functional relevance is unknown. To better categorize lncRNAs, an understanding of their specific expression patterns and evolutionary constraints are needed.

Overview and safety of fingolimod hydrochloride use in patients with multiple sclerosis.

INTRODUCTION: Fingolimod (Gilenya®, FTY720) is an oral sphingosine-1-phosphate analogue that was approved by the FDA in 2010 for the treatment of relapsing forms of multiple sclerosis (MS). Fingolimod's mechanism of action is primarily related to lymphocyte sequestration in primary and secondary lymphoid tissues. Phase III trials demonstrated a reduction in annualized relapse rate and MRI progression in fingolimod-treated subjects compared with both placebo and IFN-ß-treated subjects. Frequent adverse effects include fatigue, gastrointestinal disturbance, headache and upper respiratory tract infection. More serious, but rare, adverse events associated with fingolimod include atrioventricular block, symptomatic bradycardia, herpetic viral infections and macular edema. AREAS COVERED: We discuss the mechanism of action, pharmacokinetics, clinical efficacy and safety profile of fingolimod in patients with relapsing MS. EXPERT OPINION: Fingolimod is an effective treatment for relapsing MS and its oral route of administration may be preferred by some. Fingolimod is generally well tolerated but requires diligence in patient selection and monitoring. Additional information is needed regarding risk of infection, malignancy and rebound disease with long-term use of fingolimod.