History of obstructive sleep apnea associated with incident cognitive impairment in white but not black individuals in a US national cohort study.

BACKGROUND: We sought to determine if risk for obstructive sleep apnea (OSA), a history of OSA, and/or treatment of OSA has a different association with incident cognitive impairment or cognitive decline in Black individuals and White individuals. METHODS: To determine whether the risk for OSA, a history of OSA, and/or treatment of OSA has a different association with incident cognitive impairment or cognitive decline in Black individuals and White individuals; data from the REasons for Geographic and Racial Differences in Stroke (REGARDS) was used. Participants that completed the sleep questionnaire module, had baseline cognitive assessment, and at least one cognitive assessment during follow-up were included. Risk of OSA was determined based on Berlin Sleep Questionnaire. History of sleep apnea was determined based on structured interview questions. Optimally treated OSA was defined as treated sleep apnea as at least 4 h of continuous positive airway pressure use per night for ≥5 nights per week. RESULTS: In 19,017 participants stratified by race, White participants with history of OSA were 1.62 times more likely to have incident cognitive impairment compared to White participants without history of OSA after adjusting for demographic characteristics, history, and lifestyle factors (OR = 1.62, 95% CI = 1.05-2.50, p-value = 0.03). This relationship was not seen in Black participants (OR = 0.92, 95% CI = 0.60-1.43, p-value = 0.72). DISCUSSION: A previous diagnosis of OSA is associated with incident cognitive impairment in White Americans but not Black Americans. Further investigations are required to determine the mechanism for this difference.

Development and Validation of the Lewy Body Disease Caregiver Activities Scale.

Background and Purpose: Caring for someone with Lewy body disease (LBD) is difficult. This study describes the development and validity testing of the LBD Caregiver Activities Scale (LBD-CAS). Methods: Caregiver interviews informed the development of the LBD-CAS. Experts estimated the content validity of items (I-CVI) and provided feedback about the scale. Family caregivers evaluated items for face validity. Results: Expert I-CVI ratings yielded 49 items with scores of 0.83 or higher. Four items with I-CVI scores <.83 were retained due to conceptual significance. The overall scale CVI was 0.86. Items evaluated by caregivers for face validity showed excellent variability in responses, with no major ceiling or floor effects. Conclusions: LBD-CAS showed evidence of content and face validity for the assessment of activities performed by LBD caregivers. Further psychometric testing is recommended.

MicroRNA expression within neuronal-derived small extracellular vesicles in frontotemporal degeneration.

MicroRNAs (miRNAs) are small non-coding RNA that are powerful regulators of gene expression and can affect the expression of hundreds of genes. miRNAs can be packed in small extracellular vesicles (SEV) and released into the extracellular space by neurons and microglia to act locally as well as pass through the blood-brain barrier and act systemically. We sought to understand the differences in neuronal SEV miRNA expression between frontotemporal dementia (FTD), Alzheimer's disease (AD), and healthy aging. Plasma was obtained from FTD, AD, and healthy aging participants that were matched based on age, sex, and race/ethnicity. Additionally, a subset of participants also provided paired cerebrospinal fluid samples to compare neuronal SEV miRNAs in plasma and cerebrospinal fluid. Neuronal SEV were isolated using differential ultracentrifugation and antibody conjugated Dynabeads® for the neuronal surface marker, L1CAM. RNA sequencing was performed. 12 FTD, 11 with AD, and 10 healthy aging participants were enrolled in the study. In FTD, SEV miRNA-181c was downregulated compared to healthy controls. In AD, miRNA-122 and miRNA-3591 were downregulated compared to those in healthy controls and FTD. Using an FDR <0.2, only miRNA-21-5p was found to have increased expression in the cerebrospinal fluid compared to plasma in a group of AD and FTD participants. SEV miRNA-181c is significantly downregulated in FTD compared to healthy controls and may mediate its effects through microglial-directed neuroinflammation and interaction with TAR DNA-binding protein 43 (TDP-43) based on pathway analysis. Additionally, the FOXO and Hippo pathways may be important mediators of FTD, based on pathway analysis. Lastly, because only one SEV miRNA was differentially expressed between the plasma and cerebrospinal fluid in paired samples, plasma represents an appropriate biofluid for studying neuronal SEV miRNA.

Preliminary Outcomes of Combined Treadmill and Overground High-Intensity Interval Training in Ambulatory Chronic Stroke.

PURPOSE: Locomotor high-intensity interval training (HIIT) is a promising intervention for stroke rehabilitation. However, overground translation of treadmill speed gains has been somewhat limited, some important outcomes have not been tested and baseline response predictors are poorly understood. This pilot study aimed to guide future research by assessing preliminary outcomes of combined overground and treadmill HIIT. MATERIALS AND METHODS: Ten participants >6 months post-stroke were assessed before and after a 4-week no-intervention control phase and a 4-week treatment phase involving 12 sessions of overground and treadmill HIIT. RESULTS: Overground and treadmill gait function both improved during the treatment phase relative to the control phase, with overground speed changes averaging 61% of treadmill speed changes (95% CI: 33-89%). Moderate or larger effect sizes were observed for measures of gait performance, balance, fitness, cognition, fatigue, perceived change and brain volume. Participants with baseline comfortable gait speed <0.4 m/s had less absolute improvement in walking capacity but similar proportional and perceived changes. CONCLUSIONS: These findings reinforce the potential of locomotor HIIT research for stroke rehabilitation and provide guidance for more definitive studies. Based on the current results, future locomotor HIIT studies should consider including: (1) both overground and treadmill training; (2) measures of cognition, fatigue and brain volume, to complement typical motor and fitness assessment; and (3) baseline gait speed as a covariate.

Differences in peripheral immune system gene expression in frontotemporal degeneration.

ABSTRACT: The peripheral immune system has a key pathophysiologic role in Frontotemporal degeneration (FTD). We sought a comprehensive transcriptome-wide evaluation of gene expression alterations unique to the peripheral immune system in FTD compared to healthy controls and amyotrophic lateral sclerosis.Nineteen subjects with FTD with 19 matched healthy controls and 9 subjects with amyotrophic lateral sclerosis underwent isolation of peripheral blood mononuclear cells (PBMCs) which then underwent bulk ribonucleic acid sequencing.There was increased expression in genes associated with CD19+ B-cells, CD4+ T-cells, and CD8+ T-cells in FTD participants compared to healthy controls. In contrast, there was decreased expression in CD33+ myeloid cells, CD14+ monocytes, BDCA4+ dendritic cells, and CD56+ natural killer cells in FTD and healthy controls. Additionally, there was decreased expression is seen in associated with 2 molecular processes: autophagy with phagosomes and lysosomes, and protein processing/export. Significantly downregulated in PBMCs of FTD subjects were genes involved in antigen processing and presentation as well as lysosomal lumen formation compared to healthy control PBMCs.Our findings that the immune signature based on gene expression in PBMCs of FTD participants favors adaptive immune cells compared to innate immune cells. And decreased expression in genes associated with phagosomes and lysosomes in PBMCs of FTD participants compared to healthy controls.

Needs and Concerns of Lewy Body Disease Family Caregivers: A Qualitative Study.

Lewy body disease (LBD) is a devastating condition with cognitive and physical deficits that pose a challenge to family caregivers. The purpose of this study was to identify the needs and concerns of family caregivers of persons with LBD. A convenience sample of LBD caregivers were interviewed regarding their caregiving needs, concerns, strategies, and advice. A content analysis approach was used to organize data into themes from an existing needs and concerns framework. Findings included the need for more information about the disease, strategies for managing LBD-related emotions and behaviors, support and assistance with physical and instrumental care, and strategies for managing one's own personal responses to caregiving. Findings highlight the need for a Lewy body specific caregiver assessment tool and future caregiver interventions.

Interdisciplinary Approaches to Survivorship with a Focus on the Low-grade and Benign Brain Tumor Populations.

PURPOSE OF REVIEW: "Brain tumor is a bump in the road." Sheryl Crow a famous singer was quoted talking about her meningioma, a benign brain tumor that caused her to forget her lyrics. In this review, we focus on low-grade gliomas in adults and benign brain tumors, such as meningiomas, vestibular schwannomas, and pituitary tumors, since these individuals survive a long time and morbidity is a major issue. RECENT FINDINGS: As per the NCI dictionary definition, cancer survivorship focuses on the health and well-being of a person with cancer from the time of diagnosis until the end of life. This includes the physical, mental, emotional, social, and financial effects of cancer that begin at diagnosis and continue through treatment and beyond. The survivorship experience also includes issues related to follow-up care (including regular health and wellness checkups), late effects of treatment, cancer recurrence, second cancers, and quality of life. Family members, friends, and caregivers are also considered part of the survivorship experience (NCI Dictionary: https://www.cancer.gov/publications/dictionaries/cancer-terms ).

Prevalence of Alternative Diagnoses and Implications for Management in Idiopathic Normal Pressure Hydrocephalus Patients.

BACKGROUND: Following Bayes theorem, ventriculomegaly and ataxia confer only a 30% chance of idiopathic Normal Pressure Hydrocephalus (NPH). When coupled with positive responses to best diagnostic testing (extended lumbar drainage), 70% of patients recommended for shunting will not actually have NPH. This is inadequate clinical care. OBJECTIVE: To determine the proportion of alternative and treatable diagnoses in patients referred to a multidisciplinary NPH clinic. METHODS: Patients without previously diagnosed NPH were queried from prospectively collected data. At least 1 neurosurgeon, cognitive neurologist, and neuropsychologist jointly formulated best treatment plans. RESULTS: Of 328 total patients, 45% had an alternative diagnosis; 11% of all patients improved with treatment of an alternative diagnosis. Of 87 patients with treatable conditions, the highest frequency of pathologies included sleep disorders, and cervical stenosis, followed by Parkinson disease. Anti-cholinergic burden was a contributor for multiple patients. Of 142 patients undergoing lumbar puncture, 71% had positive responses and referred to surgery. Compared to NPH patients, mimickers were statistically significantly older with lower Montreal Cognitive Assessment (MoCA) score and worse gait parameters. Overall, 26% of the original patients underwent shunting. Pre-post testing revealed a statistically significant improved MoCA score and gait parameters in those patients who underwent surgery with follow-up. CONCLUSION: Because the Multidisciplinary NPH Clinic selected only 26% for surgery (corroborating 30% in Bayes theorem), an overwhelming majority of patients with suspected NPH will harbor alternative diagnoses. Identification of contributing/confounding conditions will support the meticulous work-up necessary to appropriately manage patients without NPH while optimizing clinical responses to shunting in correctly diagnosed patients.

Diagnosing the frontal variant of Alzheimer's disease: a clinician's yellow brick road.

BACKGROUND: Disruption of the frontal lobes and its associated networks are a common consequence of neurodegenerative disorders. Given the wide range of cognitive, behavioral and motor processes in which the frontal lobes are involved, there can be a great variety of manifestations depending on the pathology distribution. The most common are the behavioral variant of frontotemporal dementia (bvFTD) and the frontal variant of Alzheimer's disease (fvAD), which are particularly challenging to disentangle. Recognizing fvAD from bvFTD-related pathologies is a diagnostic challenge and a critical need in the management and counseling of these patients. CASE PRESENTATION: Here we present three pathology-proven cases of Alzheimer's disease initially misdiagnosed as bvFTD and discuss the distinctive or less overlapping historical, examination, and laboratory findings of fvAD and bvFTD, deriving analogies for mnemonic endurance from the Wizard of Oz worldview. CONCLUSION: The Yellow Brick Road to diagnosing these disorders may be served by the metaphor of fvAD as the irritable, paranoid, and tremulous Scarecrow and bvFTD the heartless, ritualistic, and rigid Tin Man. An Oz-inspired creative license may help the clinician recognize the differential disease progression, caregiver burden, and treatment response of fvAD compared with bvFTD.

Treatment and Management of Dementia Due to Alzheimer's Disease.

OPINION STATEMENT: Alzheimer's disease (AD) is a progressive neurological disorder typically associated with episodic memory loss as the initial symptom, but individuals <65 years old may present with executive dysfunction, word finding difficulties, or visual processing deficits. In those with AD, curative treatments are not available, but there are interventions which may modify disease course, symptom appearance and severity, enhance quality of life for patient and caregivers, and maintain safety. Both pharmacological and non-pharmacological interventions are important.

A comprehensive genetic association study of Alzheimer disease in African Americans.

OBJECTIVES: To evaluate the association of genetic variation with late-onset Alzheimer disease (AD) in African Americans, including genes implicated in recent genome-wide association studies of whites. DESIGN: We analyzed a genome-wide set of 2.5 million imputed markers to evaluate the genetic basis of AD in an African American population. SUBJECTS: Five hundred thirteen well-characterized African American AD cases and 496 cognitively normal African American control subjects. SETTING: Data were collected from multiple sites as part of the Multi-Institutional Research on Alzheimer Genetic Epidemiology (MIRAGE) Study and the Henry Ford Health System as part of the Genetic and Environmental Risk Factors for Alzheimer Disease Among African Americans (GenerAAtions) Study. RESULTS: Several significant single-nucleotide polymorphisms (SNPs) were observed in the region of the apolipoprotein E gene (APOE). After adjusting for the confounding effects of APOE genotype, one of these SNPs, rs6859 in PVRL2, remained significantly associated with AD (P = .0087). Association was also observed with SNPs in CLU, PICALM, BIN1, EPHA1, MS4A, ABCA7, and CD33, although the effect direction for some SNPs and the most significant SNPs differed from findings in data sets consisting of whites. Finally, using the African American genome-wide association study data set as a discovery sample, we obtained suggestive evidence of association with SNPs for several novel candidate genes. CONCLUSIONS: Some genes contribute to AD pathogenesis in both white and African American cohorts, although it is unclear whether the causal variants are the same. A larger African American sample will be needed to confirm novel gene associations, which may be population specific.