Brain arteriolosclerosis.

Brain arteriolosclerosis (B-ASC), characterized by pathologic arteriolar wall thickening, is a common finding at autopsy in aged persons and is associated with cognitive impairment. Hypertension and diabetes are widely recognized as risk factors for B-ASC. Recent research indicates other and more complex risk factors and pathogenetic mechanisms. Here, we describe aspects of the unique architecture of brain arterioles, histomorphologic features of B-ASC, relevant neuroimaging findings, epidemiology and association with aging, established genetic risk factors, and the co-occurrence of B-ASC with other neuropathologic conditions such as Alzheimer's disease and limbic-predominant age-related TDP-43 encephalopathy (LATE). There may also be complex physiologic interactions between metabolic syndrome (e.g., hypertension and inflammation) and brain arteriolar pathology. Although there is no universally applied diagnostic methodology, several classification schemes and neuroimaging techniques are used to diagnose and categorize cerebral small vessel disease pathologies that include B-ASC, microinfarcts, microbleeds, lacunar infarcts, and cerebral amyloid angiopathy (CAA). In clinical-pathologic studies that factored in comorbid diseases, B-ASC was independently associated with impairments of global cognition, episodic memory, working memory, and perceptual speed, and has been linked to autonomic dysfunction and motor symptoms including parkinsonism. We conclude by discussing critical knowledge gaps related to B-ASC and suggest that there are probably subcategories of B-ASC that differ in pathogenesis. Observed in over 80% of autopsied individuals beyond 80 years of age, B-ASC is a complex and under-studied contributor to neurologic disability.

Associations Between Plasma Ceramides and Cerebral Microbleeds or Lacunes.

OBJECTIVE: High plasma ceramide levels and ratios are associated with poor outcomes in individuals with cardiovascular disease; less is known about their relation to cerebral small vessel disease. We examined whether high plasma ceramide levels or ratios were associated with cerebral microbleeds (CMBs) and lacunes and whether associations differ by sex. Approach and Results: We included 548 participants enrolled in the MCSA (Mayo Clinic Study of Aging) with concurrent plasma ceramide assays and magnetic resonance imaging. CMBs were quantified on T2* magnetic resonance imaging and lacunes on T2 fluid-attenuated inversion recovery magnetic resonance imaging. Fasting plasma ceramides were assayed using liquid chromatography-electrospray ionization tandem mass spectrometry. We used logistic regression models adjusting for age, sex, hypertension, and diabetes mellitus to examine the relationship between ceramides and presence of a lacune; hurdle models were used for presence and number of CMBs. Each SD increase in the log ceramide C16:0/24:0 ratio was associated with greater odds of a CMB (odds ratio, 1.28 [95% CI, 1.01-1.64]). There was an interaction between sex and the ceramide C16:0/24:0 ratio (P=0.049). The association between this ratio and presence of a CMB was stronger for women (odds ratio, 1.87 [95% CI, 1.20-3.00]) than men (odds ratio, 1.09 [95% CI, 0.80-1.46]). Several ceramides and all ceramide ratios were associated with number of CMBs. We did not find associations between plasma ceramides and lacunes. CONCLUSIONS: In a population-based sample, the plasma ceramide C16:0/24:0 ratio was associated with CMBs and was stronger for women. Plasma ceramides are differentially associated with cerebral small vessel pathologies.

Perspectives of African American Older Adults on Brain Health: "Brains Get Tired Too".

BACKGROUND: Statistics suggest that African Americans have a disproportionately high prevalence of Alzheimer disease (AD), yet are less likely to enroll in AD clinical trials than white individuals. Although research has previously identified various barriers to participation, relatively little is known about how to overcome these barriers and engage African American individuals in AD research. The purpose of this study is to better understand how African Americans conceptualize brain health and their ability to influence healthy brain aging. METHODS: Three African American community advocates each facilitated a small group of African American participants over 8 to 10 sessions of a photovoice process involving discussion and sharing of images focused on brain health. Sessions were audiotaped and transcribed verbatim and photographs were uploaded. FINDINGS: Participants recognized a diversity of what brain health can mean and indicated an interconnectedness between brain health and its influences. Key factors that were identified by group members as key to brain health included lifestyle factors, activity, and engagement and nature, resiliency, and positivity. DISCUSSION: These emic insights into perceptions of brain health may represent important foci for targeted messaging strategies to promote brain health and research engagement within the African American population.

Outcomes after diagnosis of mild cognitive impairment in a large autopsy series.

OBJECTIVE: To determine clinical and neuropathological outcomes following a clinical diagnosis of mild cognitive impairment (MCI). METHODS: Data were drawn from a large autopsy series (N = 1,337) of individuals followed longitudinally from normal or MCI status to death, derived from 4 Alzheimer Disease (AD) Centers in the United States. RESULTS: Mean follow-up was 7.9 years. Of the 874 individuals ever diagnosed with MCI, final clinical diagnoses were varied: 39.2% died with an MCI diagnosis, 46.8% with a dementia diagnosis, and 13.9% with a diagnosis of intact cognition. The latter group had pathological features resembling those with a final clinical diagnosis of MCI. In terms of non-AD pathologies, both primary age-related tauopathy (p < 0.05) and brain arteriolosclerosis pathology (p < 0.001) were more severe in MCI than cognitively intact controls. Among the group that remained MCI until death, mixed AD neuropathologic changes (ADNC; ≥1 comorbid pathology) were more frequent than "pure" ADNC pathology (55% vs 22%); suspected non-Alzheimer pathology comprised the remaining 22% of cases. A majority (74%) of subjects who died with MCI were without "high"-level ADNC, Lewy body disease, or hippocampal sclerosis pathologies; this group was enriched in cerebrovascular pathologies. Subjects who died with dementia and were without severe neurodegenerative pathologies tended to have cerebrovascular pathology and carry the MCI diagnosis for a longer interval. INTERPRETATION: MCI diagnosis usually was associated with comorbid neuropathologies; less than one-quarter of MCI cases showed "pure" AD at autopsy. Ann Neurol 2017;81:549-559.

Novel human ABCC9/SUR2 brain-expressed transcripts and an eQTL relevant to hippocampal sclerosis of aging.

ABCC9 genetic polymorphisms are associated with increased risk for various human diseases including hippocampal sclerosis of aging. The main goals of this study were 1 > to detect the ABCC9 variants and define the specific 3' untranslated region (3'UTR) for each variant in human brain, and 2 > to determine whether a polymorphism (rs704180) associated with risk for hippocampal sclerosis of aging pathology is also associated with variation in ABCC9 transcript expression and/or splicing. Rapid amplification of ABCC9 cDNA ends (3'RACE) provided evidence of novel 3' UTR portions of ABCC9 in human brain. In silico and experimental studies were performed focusing on the single nucleotide polymorphism, rs704180. Analyses from multiple databases, focusing on rs704180 only, indicated that this risk allele is a local expression quantitative trait locus (eQTL). Analyses of RNA from human brains showed increased ABCC9 transcript levels in individuals with the risk genotype, corresponding with enrichment for a shorter 3' UTR which may be more stable than variants with the longer 3' UTR. MicroRNA transfection experiments yielded results compatible with the hypothesis that miR-30c causes down-regulation of SUR2 transcripts with the longer 3' UTR. Thus we report evidence of complex ABCC9 genetic regulation in brain, which may be of direct relevance to human disease. ABCC9 gene variants are associated with increased risk for hippocampal sclerosis of aging (HS-Aging--a prevalent brain disease with symptoms that mimic Alzheimer's disease). We describe novel ABCC9 variants in human brain, corresponding to altered 3'UTR length, which could lead to targeting by miR-30c. We also determined that the HS-Aging risk mutation is associated with variation in ABCC9 transcript expression.

Oligomerization and higher-order assembly contribute to sub-cellular localization of a bacterial scaffold.

In Caulobacter crescentus, the PopZ polar scaffold protein supports asymmetric cell division by recruiting distinct sets of binding partners to opposite cell poles. To understand how polar organizing centres are established by PopZ, we investigated a set of mutated PopZ proteins for defects in sub-cellular localization and recruitment activity. We identified a domain within the C-terminal 76 amino acids that is necessary and sufficient for accumulation as a single subcellular focus, a domain within the N-terminal 23 amino acids that is necessary for bipolar targeting, and a linker domain between these localization determinants that tolerates large variation. Mutations that inhibited dynamic PopZ localization inhibited the recruitment of other factors to cell poles. Mutations in the C-terminal domain also blocked discrete steps in the assembly of higher-order structures. Biophysical analysis of purified wild type and assembly defective mutant proteins indicates that PopZ self-associates into an elongated trimer, which readily forms a dimer of trimers through lateral contact. The final six amino acids of PopZ are necessary for connecting the hexamers into filaments, and these structures are important for sub-cellular localization. Thus, PopZ undergoes multiple orders of self-assembly, and the formation of an interconnected superstructure is a key feature of polar organization in Caulobacter.

ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology.

Hippocampal sclerosis of aging (HS-Aging) is a high-morbidity brain disease in the elderly but risk factors are largely unknown. We report the first genome-wide association study (GWAS) with HS-Aging pathology as an endophenotype. In collaboration with the Alzheimer's Disease Genetics Consortium, data were analyzed from large autopsy cohorts: (#1) National Alzheimer's Coordinating Center (NACC); (#2) Rush University Religious Orders Study and Memory and Aging Project; (#3) Group Health Research Institute Adult Changes in Thought study; (#4) University of California at Irvine 90+ Study; and (#5) University of Kentucky Alzheimer's Disease Center. Altogether, 363 HS-Aging cases and 2,303 controls, all pathologically confirmed, provided statistical power to test for risk alleles with large effect size. A two-tier study design included GWAS from cohorts #1-3 (Stage I) to identify promising SNP candidates, followed by focused evaluation of particular SNPs in cohorts #4-5 (Stage II). Polymorphism in the ATP-binding cassette, sub-family C member 9 (ABCC9) gene, also known as sulfonylurea receptor 2, was associated with HS-Aging pathology. In the meta-analyzed Stage I GWAS, ABCC9 polymorphisms yielded the lowest p values, and factoring in the Stage II results, the meta-analyzed risk SNP (rs704178:G) attained genome-wide statistical significance (p = 1.4 × 10(-9)), with odds ratio (OR) of 2.13 (recessive mode of inheritance). For SNPs previously linked to hippocampal sclerosis, meta-analyses of Stage I results show OR = 1.16 for rs5848 (GRN) and OR = 1.22 rs1990622 (TMEM106B), with the risk alleles as previously described. Sulfonylureas, a widely prescribed drug class used to treat diabetes, also modify human ABCC9 protein function. A subsample of patients from the NACC database (n = 624) were identified who were older than age 85 at death with known drug history. Controlling for important confounders such as diabetes itself, exposure to a sulfonylurea drug was associated with risk for HS-Aging pathology (p = 0.03). Thus, we describe a novel and targetable dementia risk factor.

Creating an Undergraduate Research Program in Otolaryngology-Head and Neck Surgery (Oto-HNS) for Students Underrepresented in Medicine.

Objectives: To report implementation and outcomes associated with a novel paid Summer Undergraduate Research Education Program (SREP) over the first 2 years in an academic otolaryngology program recruiting students underrepresented in medicine (URiM). Methods: A 10-week program including a research bootcamp, curriculum, mentoring, and clinical shadowing was created. Grant funding to provide salary and support for transportation, conference attendance, and graduate school preparation or applications was procured. Primary objectives included (1) development of successful mentorship relationships; (2) increasing student-reported outcomes using pre- and post-program surveys to assess confidence, career planning, and overall satisfaction; (3) increasing exposure to medicine; (4) completion of an oral presentation; and (5) submission of a manuscript. Secondary objectives included abstract submission and completion of a graduate exam course or graduate school applications. Tertiary objectives included conference attendance and graduate school matriculation. Results: One hundred thirty-five total applications were reviewed (89 from year 1 and 46 from year 2). Twelve students were interviewed for 3 spots in year 1, while 11 students were interviewed for 6 spots in year 2 (median application score, 9.25 (range, 1-14); median interview score, 8.7 (range, 5.4-10); acceptance rate, 6.7% (9/135)). Students met all primary objectives. Mean program survey scores increased from 3.8 to 4.77 (p < 0.0001). Eight of nine students submitted an abstract to a national conference, with five of eight students accepted for a presentation. Two students were accepted into graduate school, while five others are on track for graduate school application. Conclusion: Identifying mentors, curriculum, and opportunities to meaningfully strengthen graduate school applications for URiM students through a clinically rigorous, financially supported, and research-focused summer program in an academic otolaryngology program is feasible and may be an effective means of increasing diversity in medicine and otolaryngology. Supplementary Information: The online version contains supplementary material available at 10.1007/s40670-024-02021-z.

Racial and Ethnic Bias in the Diagnosis of Alcohol Use Disorder in Veterans.

OBJECTIVE: Studies show that racially and ethnically minoritized veterans have a higher prevalence of alcohol use disorder (AUD) than White veterans. The investigators examined whether the relationship between self-reported race and ethnicity and AUD diagnosis remains after adjusting for alcohol consumption, and if so, whether it varies by self-reported alcohol consumption. METHODS: The sample included 700,012 Black, White, and Hispanic veterans enrolled in the Million Veteran Program. Alcohol consumption was defined as an individual's maximum score on the consumption subscale of the Alcohol Use Disorders Identification Test (AUDIT-C), a screen for unhealthy alcohol use. A diagnosis of AUD, the primary outcome, was defined by the presence of relevant ICD-9 or ICD-10 codes in electronic health records. Logistic regression with interactions was used to assess the association between race and ethnicity and AUD as a function of maximum AUDIT-C score. RESULTS: Black and Hispanic veterans were more likely than White veterans to have an AUD diagnosis despite similar levels of alcohol consumption. The difference was greatest between Black and White men; at all but the lowest and highest levels of alcohol consumption, Black men had 23%-109% greater odds of an AUD diagnosis. The findings were unchanged after adjustment for alcohol consumption, alcohol-related disorders, and other potential confounders. CONCLUSIONS: The large discrepancy in the prevalence of AUD across groups despite a similar distribution of alcohol consumption levels suggests that there is racial and ethnic bias, with Black and Hispanic veterans more likely than White veterans to receive an AUD diagnosis. Efforts are needed to reduce bias in the diagnostic process to address racialized differences in AUD diagnosis.

A neuropathologic feature of brain aging: multi-lumen vascular profiles.

Cerebrovascular pathologies other than frank infarctions are commonly seen in aged brains. Here, we focus on multi-lumen vascular profiles (MVPs), which are characterized by multiple vessel lumens enclosed in a single vascular channel. Little information exists on the prevalence, risk factors, and co-pathologies of MVPs. Therefore, we used samples and data from the University of Kentucky Alzheimer's Disease Research Center (n = 91), the University of Kentucky Pathology Department (n = 31), and the University of Pittsburgh Pathology Department (n = 4) to study MVPs. Age at death was correlated with MVP density in the frontal neocortex, Brodmann Area 9 (r = 0.51; p < 0.0001). Exploratory analyses were performed to evaluate the association between conventional vascular risk factors (e.g., hypertension, diabetes), cardiovascular diseases (e.g., heart attack, arrhythmia), and cerebrovascular disease (e.g., stroke); the only nominal association with MVP density was a self-reported history of brain trauma (Prevalence Ratio = 2.1; 95 CI 1.1-3.9, before correcting for multiple comparisons). No specific associations were detected between neuropathological (e.g., brain arteriolosclerosis) or genetic (e.g., APOE) variables and MVP density. Using a tissue clearing method called SeeDB, we provide 3-dimensional images of MVPs in brain tissue. We conclude that MVPs are an age-related brain pathology and more work is required to identify their clinical-pathological correlation and associated risk factors.

Pearls & Oy-sters: Postpipeline Headache Phenomenon: Nummular Headache Presenting After Intracranial Aneurysm Stenting.

We report on a 31-year-old right-handed woman with a medical history of presyncopal episodes and migraine headaches who presented to the outpatient clinic with a nummular headache after intracerebral stenting, which was different than her previous migraines. This represents postpipeline embolization headache phenomenon, which is a relatively new term to describe a new or different headache in individuals who recently underwent intracranial vascular stenting as a treatment for cerebral aneurysms.

Management of Chronic Subdural Hematoma in Patients Requiring Therapeutic Anticoagulation.

INTRODUCTION: A common risk factor of chronic, nontraumatic subdural hematoma (SDH) is anticoagulation therapy. Anticoagulation is generally held in patients who develop SDH, but this can lead to thromboembolic events. While prior studies have reported the clinical outcomes of patients with anticoagulation-related SDH, there remains little evidence regarding ongoing anticoagulation treatment. CASE REPORT: We report the management of 2 patients who developed anticoagulation-related SDH and underwent middle meningeal artery (MMA) embolization and successful reinitiation of anticoagulation therapy. In both patients, we conservatively managed anticoagulation with heparin and/or enoxaparin as a bridge to warfarin after MMA embolization. Follow-up computed tomography head revealed interval decrease of SDH and stable neurological status. CONCLUSIONS: These cases provide anecdotal evidence of a challenging clinical scenario where there is a necessary indication for therapeutic anticoagulation (ie, venous sinus thrombosis or atrial appendage thrombus) and comorbid SDH. Endovascular MMA embolization may be an effective adjunct therapy for clinical scenarios in patients with SDH and an urgent indication for anticoagulation. Longer follow-up, prospective series, and future randomized clinical trials are needed to objectively assess outcomes in this clinically challenging patient population.

Underreporting and Underrepresentation of Race and Ethnicity in Head and Neck Cancer Trials, 2010-2020: A Systematic Review.

Importance: There is substantial evidence demonstrating racial disparities in the survival outcomes of patients with head and neck cancer. The reporting and representation of race and ethnicity in cancer trials is crucial for generalizability of trial results to patient care and reduction of racial health disparities in head and neck cancers. Racial disparities in oncologic outcomes across various therapeutic interventions may only manifest when diverse races are appropriately represented in trials. Objective: To characterize the reporting and representation of race and ethnicity in head and neck cancer clinical trials. Evidence Review: A systematic search of published trials and those available on ClinicalTrials.gov was conducted to identify 3973 studies from 2010 to 2020. Title, abstract, and full-text review yielded 155 trials for data extraction of patient demographics. Year of publication, type of intervention, publication source, and funding source were also collected. Race and ethnicity data were compared with Surveillance, Epidemiology, and End Results (SEER) Program cancer registry data. Findings: Of the 155 included studies, only 89 (57%) reported race or ethnicity. Only 81 (52%) of the studies reported detailed classification of race or ethnicity per the US Census Bureau classification scheme. Race and ethnicity reporting varied considerably with year of publication, type of intervention, data source, and funding source. Studies in the latter half of the decade were more likely to report race or ethnicity (odds ratio, 2.78; 95% CI, 1.33-5.80), with the highest number in 2019 (24 of 30 [80%] trials), followed by 2020 (20 of 29 [69%] trials). Among the possible interventions, trials on therapeutic chemoradiation most frequently reported race or ethnicity (11 of 12 [92%]), followed by supportive drug trials (22 of 31 [71%]), and then therapeutic chemotherapy trials (28 of 48 [58%]). When compared with SEER data, race and ethnicity distribution in clinical trials showed fewer Black patients (10% vs 8%) and Asian or Pacific Islander patients (6% vs 2%). Conclusions and Relevance: In this systematic review, nearly half of head and neck cancer trials in the past decade did not report the race or ethnicity of participants. Participation of Black and Asian or Pacific Islander patients does not adequately reflect the US population's head and neck cancer demographics, limiting the generalizability of trial results and adding to racial health disparities in patients with head and neck cancers.

Insights From African American Older Adults on Brain Health Research Engagement: "Need to See the Need".

African Americans (AAs) have an elevated risk of developing dementia, yet are underrepresented in clinical research. This project uses a community-engaged photovoice approach to add to existing understanding of barriers and facilitators to AA participation in Alzheimer's disease research and identify strategies to enhance engagement. Three AA research advocates served as community facilitators to identify and guide groups of AA adults through an eight to nine session photovoice project. Group sessions involved discussions and sharing of images pertaining to various prompts in the area of brain health and research participation. Sessions were audiotaped and transcribed verbatim. Participants identified three categories of barriers to AA research participation: (a) Mistrust, (b) avoidance and fear of acknowledging problems, and (c) seeing the risks of research but not the need. Participants shared suggestions and approaches for ameliorating each of these barriers. This process revealed unique insights into barriers and opportunities for increasing AA engagement in aging and dementia research.

Dystrophic microglia are associated with neurodegenerative disease and not healthy aging in the human brain.

Loss of physiological microglial function may increase the propagation of neurodegenerative diseases. Cellular senescence is a hallmark of aging; thus, we hypothesized age could be a cause of dystrophic microglia. Stereological counts were performed for total microglia, 2 microglia morphologies (hypertrophic and dystrophic) across the human lifespan. An age-associated increase in the number of dystrophic microglia was found in the hippocampus and frontal cortex. However, the increase in dystrophic microglia was proportional to the age-related increase in the total number of microglia. Thus, aging alone does not explain the presence of dystrophic microglia. We next tested if dystrophic microglia could be a disease-associated microglia morphology. Compared with controls, the number of dystrophic microglia was greater in cases with either Alzheimer's disease, dementia with Lewy bodies, or limbic-predominant age-related TDP-43 encephalopathy. These results demonstrate that microglia dystrophy, and not hypertrophic microglia, are the disease-associated microglia morphology. Finally, we found strong evidence for iron homeostasis changes in dystrophic microglia, providing a possible molecular mechanism driving the degeneration of microglia in neurodegenerative disease.

Overlapping but distinct TDP-43 and tau pathologic patterns in aged hippocampi.

Intracellular proteinaceous aggregates (inclusion bodies) are almost always detectable at autopsy in brains of elderly individuals. Inclusion bodies composed of TDP-43 and tau proteins often coexist in the same brain, and each of these pathologic biomarkers is associated independently with cognitive impairment. However, uncertainties remain about how the presence and neuroanatomical distribution of inclusion bodies correlate with underlying diseases including Alzheimer's disease (AD). To address this knowledge gap, we analyzed data from the University of Kentucky AD Center autopsy series (n = 247); none of the brains had frontotemporal lobar degeneration. A specific question for this study was whether neurofibrillary tangle (NFT) pathology outside of the Braak NFT staging scheme is characteristic of brains with TDP-43 pathology but lacking AD, that is those with cerebral age-related TDP-43 with sclerosis (CARTS). We also tested whether TDP-43 pathology is associated with comorbid AD pathology, and whether argyrophilic grains are relatively likely to be present in cases with, vs. without, TDP-43 pathology. Consistent with prior studies, hippocampal TDP-43 pathology was associated with advanced AD - Braak NFT stages V/VI. However, argyrophilic grain pathology was not more common in cases with TDP-43 pathology in this data set. In brains with CARTS (TDP-43[+]/AD[-] cases), there were more NFTs in dentate granule neurons than were seen in TDP-43[-]/AD[-] cases. These dentate granule cell NFTs could provide a proxy indicator of CARTS pathology in cases lacking substantial AD pathology. Immunofluorescent experiments in a subsample of cases found that, in both advanced AD and CARTS, approximately 1% of dentate granule neurons were PHF-1 immunopositive, whereas ∼25% of TDP-43 positive cells showed colocalized PHF-1 immunoreactivity. We conclude that NFTs in hippocampal dentate granule neurons are often present in CARTS, and TDP-43 pathology may be secondary to or occurring in parallel with tauopathy.