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WRKY transcription factor (TF) family is well known to govern essential physiological functioning as well as regulate plant response to biotic and abiotic stress. In this study, we have identified 108 OsWRKY genes in the genome of Oryza sativa subsp. japonica, using the updated genomic data from the Rice Annotation Project Database and Oryzabase, which were further used to conduct the phylogenetic study, motif analysis, gene structure analysis, chromosomal mapping, and prediction of sub‐cellular localization. The multiple sequence alignment OsWRKY proteins revealed the presence of nine different types of alterations in the conserved heptapeptide sequence WRKYGQK associated with 19 OsWRKY genes. Physiochemical analysis discloses the hydrophobic amino acid‐rich, thermally stable, and polar nature of OsWRKY proteins. These genes were noted as highly conserved between the two cultivated sub‐species of Oryza sativa, that is Indica and japonica type. Additionally, from motif analysis, we have found a new motif, which was categorized as hAT family C‐terminal dimerization region associated with four members of group IIc. We have identified 21 stress‐responsive OsWRKY genes, and their significance to the different biotic and abiotic stress‐mediated cascades was further evaluated by analysing 1500 kb upstream sequences and this disclosed the presence of important phytohormone‐responsive cis‐elements in the OsWRKY gene, suggesting its direct involvement in defence against a wide range of external stressors and these 21 OsWRKY genes are tentatively listed as possible candidates for more study. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a devastating, age‐associated neurodegenerative disorder and the most common cause of dementia. The clinical continuum of AD spans from preclinical disease to subjective cognitive decline, mild cognitive impairment, and dementia stages (mild, moderate, and severe). Neuropathologically, AD is defined by the accumulation of amyloid β (Aβ) into extracellular plaques in the brain parenchyma and in the cerebral vasculature, and by abnormally phosphorylated tau that accumulates intraneuronally forming neurofibrillary tangles (NFTs). Development of treatment approaches that prevent or even reduce the cognitive decline because of AD has been slow compared to other major causes of death. Recently, the United States Food and Drug Administration gave full approval to 2 different Aβ‐targeting monoclonal antibodies. However, this breakthrough disease modifying approach only applies to a limited subset of patients in the AD continuum and there are stringent eligibility criteria. Furthermore, these approaches do not prevent progression of disease, because other AD‐related pathologies, such as NFTs, are not directly targeted. A non‐mutually exclusive alternative is to address lifestyle interventions that can help reduce the risk of AD and AD‐related dementias (ADRD). It is estimated that addressing such modifiable risk factors could potentially delay up to 40% of AD/ADRD cases. In this review, we discuss some of the many modifiable risk factors that may be associated with prevention of AD/ADRD and/or increasing brain resilience, as well as other factors that may interact with these modifiable risk factors to influence AD/ADRD progression. [Color figure can be viewed at www.annalsofneurology.org] ANN NEUROL 2024;96:633–649 [ABSTRACT FROM AUTHOR]

Background: The choroid plexus (ChP), a densely vascularized structure, has drawn increasing attention for its involvement in brain homeostasis and waste clearance. While the volumetric changes have been explored in many imaging studies, few studies have investigated the vascular degeneration associated with aging in the ChP. Purpose: To investigate the sub‐structural characteristics of the ChP, particularly the vascular compartment using high‐resolution 7T imaging enhanced with Ferumoxytol, an ultrasmall super‐paramagnetic iron oxide, which greatly increase the susceptibility contrast for vessels. Study Type: Prospective. Subjects: Forty‐nine subjects without neurological disorders (age: 21–80 years; 42 ± 17 years; 20 females). Field Strength/Sequence: 7‐T with 2D and 3D T2* GRE, 3D MPRAGE T1, 2D TSE T2, and 2D FLAIR. Assessment: The vascular and stromal compartments of the ChP were segmented using K‐means clustering on post‐contrast 2D GRE images. Visual and qualitative assessment of ChP vascular characteristics were conducted independently by three observers. Vascular density (Volvessel/VolChP ratio) and susceptibility change (Δχ) induced by Ferumoxytol were analyzed on 3D GRE‐derived susceptibility‐weighted imaging and quantitative susceptibility mapping, respectively. Statistical Tests: Independent t‐test, Mann–Whitney U test, and Chi‐square test were utilized for group comparisons. The relationship between age and ChP's vascular alterations was examined using Pearson's correlation. Intra‐class coefficient was calculated for inter‐observer agreement. A P value <0.05 was considered statistically significant. Results: 2D GRE images demonstrated superior contrast and accurate delineation of ChP substructures (ICC = 0.86). Older subjects exhibited a significantly smaller vascular density (16.5 ± 4.34%) and lower Δχ (22.10 ± 12.82 ppb) compared to younger subjects (24.85 ± 6.84% and 34.64 ± 12.69 ppb). Vascular density and mean Δχ within the ChP negatively correlated with age (r = −0.48, and r = −0.45). Data Conclusion: Ferumoxytol‐enhanced 7T images can demonstrate ChP alterations in elderly with decreased vascular density and expansion of nonvascular compartment. Evidence Level: 1 Technical Efficacy: Stage 2 [ABSTRACT FROM AUTHOR]

Background and Purpose: The purpose of this study is to evaluate the feasibility of using 3‐dimensional (3D) ultra‐short echo time (UTE) radial imaging method for measurement of the permeability of the blood‐brain barrier (BBB) to gadolinium‐based contrast agent. In this study, we propose to use the golden‐angle radial sparse parallel (GRASP) method with 3D center‐out trajectories for UTE, hence named as 3D UTE‐GRASP. We first examined the feasibility of using 3D UTE‐GRASP dynamic contrast‐enhanced (DCE)‐magnetic resonance imaging (MRI) for differentiating subtle BBB disruptions induced by focused ultrasound (FUS). Then, we examined the BBB permeability changes in Alzheimer's disease (AD) pathology using Alzheimer's disease transgenic mice (5xFAD) at different ages. Methods: For FUS experiments, we used four Sprague Dawley rats at similar ages where we compared BBB permeability of each rat receiving the FUS sonication with different acoustic power (0.4‐1.0 MPa). For AD transgenic mice experiments, we included three 5xFAD mice (6, 12, and 16 months old) and three wild‐type mice (4, 8, and 12 months old). Results: The result from FUS experiments showed a progressive increase in BBB permeability with increase of acoustic power (p <.05), demonstrating the sensitivity of DCE‐MRI method for detecting subtle changes in BBB disruption. Our AD transgenic mice experiments suggest an early BBB disruption in 5xFAD mice, which is further impaired with aging. Conclusion: The results in this study substantiate the feasibility of using the proposed 3D UTE‐GRASP method for detecting subtle BBB permeability changes expected in neurodegenerative diseases, such as AD. [ABSTRACT FROM AUTHOR]

Background: Diffusion tensor imaging (DTI) can separate subjective cognitive decline (SCD) participants who progress to mild cognitive impairment and those who do not 1. We explored the effect age and memory performance has on DTI measures in SCD and controls in the hippocampal cingulum bundle, which is typically affected early in the course of Alzheimer's disease2. Method: 325 participants Cam‐CAN 3 (127 SCD) older than 55 were included in the analysis. Diffusion imaging data was collected on a 3T Siemens TIM Trio scanner with a 32‐channel head coil for 0, 1000 and 2000 s/mm2 b‐values and 30 gradient directions. Preprocessing and calculation of the DTI metrics fractional anisotropy (FA, mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AxD) were completed using MRTrix3, FSL and MATLAB. The hippocampal cingulum bundle regions of interest (ROIs) were extracted from the ICBM‐DTI‐81 atlas. Memory was assessed using the delayed story recall (DSR) task from WMS‐III. Linear regression models were completed in R. Gender was included as a nuisance variable. Result: There were no differences in gender or age distribution between cohorts, however participants with SCD had a 14% lower DSR score (Table 1). There was a significant interaction effect between age and cohort in MD, AxD, and RD (Figure 1), as well as between memory and age in AxD (Figure 2). In post‐hoc analyses, compared to controls, the SCD group showed a stronger correlation with age in MD, AxD, and RD (Figure 1) while participants with worse memory showed a stronger correlation with age in MD (Figure 2), indicating an accelerated aging effect. Conclusion: Participants with SCD and worse memory present with an accelerated aging effect, showing steeper variations in diffusion microstructure with age. Since SCD is likely to be a preclinical stage of Alzheimer's disease, future work will analyze this effect with more advanced diffusion microstructure models to further elucidate the underlying pathophysiology. 1. Selnes P, Aarsland D, Bjornerud A, et al. J Alzheimers Dis. 2013;33(3):723‐36. 2. Jack Jr CR, Knopman DS, Jagust WJ, et al. The Lancet Neurology. 2013;12(2):207‐16. 3. Shafto MA, Tyler LK, Dixon M, et al. BMC neurology. 2014;14(1):1‐25. [ABSTRACT FROM AUTHOR]

Background: Rates of hospitalization are 3 times higher for community‐dwelling Alzheimer's disease (AD) persons than non‐affected, age‐matched persons (Rudolph et al., J Am Geriatr Soc. 2010). These investigators reported that hospital outcomes were significantly worse for AD patients regarding delirium, prolonged length of stay, institutionalization and death. They concluded, "Given the frequency of hospitalization in ...[AD]... patients, an intervention to prevent or shorten hospitalization would potentially save Medicare billions of dollars per year." We conducted 28‐week, controlled, clinician‐blind, parallel group and 24‐week extension studies in which advanced AD persons were randomized to receive a comprehensive, individualized, person‐centered management program (CI‐PCM) developed by Sunnie Kenowsky and memantine or usual community care (UCC) and memantine (Reisberg...Kenowsky, Dement Geriatr Cogn Disord., 2017). Herein, we investigate the occurrence of hospitalization and emergency department visits (EDV) in the two groups at 52‐weeks. Methods: Each occurrence of death, hospitalization and EDV was documented. Investigators blind to group assignment analyzed occurrences. Any fraction of a hospital stay or EDV occurring on or between the baseline and week 52 visit days was recorded as one incident. Relative Risk Reduction (RRR) was calculated for the incidence of hospitalization and EDV. Results: 40% of UCC subjects experienced EDV, 40% were hospitalized and 10% died. Comparatively, only 10% of CI‐PCM subjects experienced EDV and 10% were hospitalized. UCC subjects were hospitalized for C. difficile infection, a fall and subsequent pelvic fracture, syncope and gastrointestinal disease. One CI‐PCM subject was hospitalized for a fall and hip fracture secondary to osteoporosis. UCC subject falls were attributed to neuropsychiatric symptoms of dementia. A CI‐PCM subject had C. difficile successfully treated by their physician. The RRR for utilization of the CI‐PCM program was 0.75 for EDV and 0.75 for hospitalizations (Tables 1&2). Conclusions: CI‐PCM subjects had a 75% decreased risk of EDV and a 75% decreased risk of hospitalization. Given the 5.8 million USA AD persons and the current high cost of hospitalization, the CI‐PCM program could potentially, significantly decrease the costs of care for AD persons, Medicare, and Medicaid while greatly increasing the AD person's quality of life and alleviating their caregiver's burden. [ABSTRACT FROM AUTHOR]

Background: A common criticism of considering Subjective Cognitive Decline (SCD) as a preclinical stage of Alzheimer's Disease is that it may be explained by depression or anxiety1. We used NODDI, a diffusion microstructural model2, to explore the pathophysiology of depression and anxiety in SCD versus controls. Method: 325 participants in the Cam‐CAN study 3 (127 SCD) older than 55 were included in the analysis. Diffusion imaging data was collected on a 3T Siemens TIM Trio scanner with a 32‐channel head coil for 0, 1000 and 2000 s/mm2 b‐values and 30 gradient directions. Preprocessing and calculation of the NODDI metric Intracellular Volume Fraction (ICVF) were completed using MRTrix3, AMICO and MATLAB. The hippocampal cingulum bundle and fornix regions of interest (ROIs)4 were extracted from the ICBM‐DTI‐81 atlas. Depression and anxiety were assessed using the Hamilton Anxiety and Depression Scale (HADS). Linear regression models were completed in R. Gender and age were included as nuisance variables. Result: There were no differences in gender or age distribution between cohorts, however participants with SCD were more depressed and anxious on average (Table 1). There was a significant interaction effect between depression and cohort in the fornix (Figure 1), as well as between anxiety and cohort in the hippocampal cingulum (Figure 2). In post‐hoc analyses, only the SCD group showed a correlation between depression and ICVF in the fornix (Figure 1) while only controls showed a correlation between anxiety and ICVF in the hippocampal cingulum (Figure 2), indicating different pathophysiology underlying psychiatric symptoms in the two groups. Conclusion: Anxiety and depression appear to be associated with different microstructural features in SCD versus controls, suggesting anxiety and depression in SCD is a phenomenon distinct from anxiety and depression in healthy aging. Future work will explore the relationship between anxiety and depression and risk of conversion to mild cognitive impairment. 1. Mitchell AJ, Beaumont H, Ferguson D, et al. Acta Psychiatrica Scandinavica. 2014;130(6):439‐51. 2. Daducci A, Canales‐Rodriguez EJ, Zhang H, et al. Neuroimage. 2015;105:32‐44. 3. Shafto MA, Tyler LK, Dixon M, et al. BMC neurology. 2014;14(1):1‐25. 4. Kantarci K. Frontiers in Aging Neuroscience. 2014;6. [ABSTRACT FROM AUTHOR]

Objectives: Subjective cognitive decline (SCD) is a preclinical stage of AD. White matter hyperintensities (WMH), an MRI marker of cerebral small vessel disease, associate with AD biomarkers and progression. The impact of WMH on SCD phenotype is unclear. Methods/Design: A retrospective, cross‐sectional analysis was conducted on a diverse cohort with SCD evaluated at the NYU Alzheimer's Disease Research Center between January 2017 and November 2021 (n = 234). The cohort was dichotomized into none‐to‐mild (n = 202) and moderate‐to‐severe (n = 32) WMH. Differences in SCD and neurocognitive assessments were evaluated via Wilcoxon or Fisher exact tests, with p‐values adjusted for demographics using multivariable logistic regression. Results: Moderate‐to‐severe WMH participants reported more difficulty with decision making on the Cognitive Change Index (1.5 SD 0.7 vs. 1.2 SD 0.5, p = 0.0187) and worse short‐term memory (2.2 SD 0.4 vs. 1.9 SD 0.3, p = 0.0049) and higher SCD burden (9.5 SD 1.6 vs. 8.7 SD 1.7, p = 0.0411) on the Brief Cognitive Rating Scale. Moderate‐to‐severe WMH participants scored lower on the Mini‐Mental State Examination (28.0 SD 1.6 vs. 28.5 SD 1.9, p = 0.0491), and on delayed paragraph (7.2 SD 2.0 vs. 8.8 SD 2.9, p = 0.0222) and designs recall (4.5 SD 2.3 vs. 6.1 SD 2.5, p = 0.0373) of the Guild Memory Test. Conclusions: In SCD, WMH impact overall symptom severity, specifically in executive and memory domains, as well as objective performance on global and domain‐specific tests in verbal memory and visual working/associative memory. Key points: White matter hyperintensities impact subjective cognitive decline in executive and memory domainsWhite matter hyperintensities also affect objective measures of cognition in verbal memory and visual working/associative memory [ABSTRACT FROM AUTHOR]

Introduction: Mild to moderate exercise may decrease Alzheimer's disease (AD) risk, but the effects of vigorous, regular physical exercise remain unclear. Methods: Two patients with initial diagnoses of amnestic mild cognitive impairment (MCI) demonstrated positive AD biomarkers throughout 16 and 8 years of follow‐up, with final diagnoses of mild AD and amnestic MCI, respectively. Results: Patient 1 was diagnosed with amnestic MCI at age 64. Neuropsychological testing, magnetic resonance imaging (MRI), fluorodeoxyglucose–positron emission tomography (FDG‐PET), amyloid imaging PET, and cerebrospinal fluid (CSF) biomarkers during follow‐ups remained consistent with AD. By age 80, progression was minimal with Montreal Cognitive Assessment (MoCA) 26 of 30. Patient 2 was diagnosed with amnestic MCI at age 72. Neuropsychological testing, MRI, FDG‐PET, and amyloid imaging PET during follow‐ups remained consistent with AD. At age 80, MoCA was 27 of 30 with no clinical progression. Both patients regularly performed vigorous, regular exercise that increased after retirement/work reduction. Discussion: Vigorous, regular exercise may slow disease progression in biomarker‐positive amnestic MCI and mild AD. [ABSTRACT FROM AUTHOR]

Objectives: This non‐interventional observational study described the current standard‐of‐care for transplant‐eligible newly diagnosed multiple myeloma (TE‐NDMM) patients in France, Germany, Spain, and Italy, and recorded the evolution in regimen adoption in distinct elements of frontline treatment during 2017–2020/2021. Methods: Clinical information on ongoing (I) or previous (II) TE‐NDMM patients was extracted from the Cancerology database. Proportions of patients receiving regimens in each element and the evolution in regimen adoption were determined for the entire population and each country. Results: Most common induction regimens among I patients were VRd in France (75.3%) and Spain (44.1%), VTd in Italy (65.2%), and regimens other than VRd/VTd/VCd in Germany. Maintenance was ongoing/planned for 78.3%, 62.3%, 65.2%, and 61.4% patients in France, Germany, Spain, and Italy, respectively. Among II patients, VRd induction increased from 27.0% in 2017 to 65.7% in 2019 in France, remained relatively low in Spain and Germany, and not present in Italy. In Italy and Spain, VTd induction declined from 72.4% and 58.3% in 2017 to 52.8% and 17.3% in 2019, respectively. VCd induction in Germany declined from 85.2% in 2017 to 64.1% in 2019. Conclusion: The use of bortezomib triplets in induction varied markedly over time and between selected countries. [ABSTRACT FROM AUTHOR]

Introduction: Neurological complications among hospitalized COVID‐19 patients may be associated with elevated neurodegenerative biomarkers. Methods: Among hospitalized COVID‐19 patients without a history of dementia (N = 251), we compared serum total tau (t‐tau), phosphorylated tau‐181 (p‐tau181), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), ubiquitin carboxy‐terminal hydrolase L1 (UCHL1), and amyloid beta (Aβ40,42) between patients with or without encephalopathy, in‐hospital death versus survival, and discharge home versus other dispositions. COVID‐19 patient biomarker levels were also compared to non‐COVID cognitively normal, mild cognitive impairment (MCI), and Alzheimer's disease (AD) dementia controls (N = 161). Results: Admission t‐tau, p‐tau181, GFAP, and NfL were significantly elevated in patients with encephalopathy and in those who died in‐hospital, while t‐tau, GFAP, and NfL were significantly lower in those discharged home. These markers correlated with severity of COVID illness. NfL, GFAP, and UCHL1 were higher in COVID patients than in non‐COVID controls with MCI or AD. Discussion: Neurodegenerative biomarkers were elevated to levels observed in AD dementia and associated with encephalopathy and worse outcomes among hospitalized COVID‐19 patients. [ABSTRACT FROM AUTHOR]

BACKGROUND: Although cholinesterase inhibitors (ChEIs) are the primary treatment for dementia, they are associated with overactive bladder (OAB), necessitating antimuscarinic use. Limited data exist regarding the risk of OAB across individual ChEIs in dementia. This study evaluated the risk of OAB associated with individual ChEIs in older adults with dementia. METHODS: This was a new user retrospective cohort study using Medicare claims data involving Parts A, B, and D claims dataset from 2013 to 2015. The study included older adults (aged 65 and older) with a diagnosis of dementia using donepezil, galantamine, or rivastigmine. New ChEI claims were identified with a 6‐month baseline washout period. Patients with OAB diagnosis or any antimuscarinic or mirabegron use in the baseline period were excluded. The primary outcome of interest was OAB diagnosis or prescription of antimuscarinics or mirabegron within 6 months of ChEI initiation. Multivariable cox proportional hazards regression with propensity scores (PS) as covariates and inverse probability of treatment weighting generated using generalized boosted models was used to assess the risk of OAB among donepezil, galantamine, and rivastigmine users. RESULTS: The study included 524,975 older adults with dementia who were incident users of ChEIs (donepezil 80.72%, rivastigmine 16.41%, galantamine 2.87%). Overall, OAB diagnosis/antimuscarinic/mirabegron prescription was observed in 5.07% of the cohort within 6 months of ChEIs prescription. The Cox regression model with PS as covariate approach found that donepezil use increased the risk of OAB compared to rivastigmine (aHR, 1.13; 95% CI, 1.08–1.28; p < 0.0001). However, there was no differential risk of OAB between galantamine and rivastigmine. The findings were consistent with the generalized boosted models. CONCLUSIONS: The study found that the risk of OAB varies across individual ChEIs with an increased risk of OAB with donepezil compared to rivastigmine. The study findings suggest the need to understand and manage medication‐related morbidity in older adults with dementia. [ABSTRACT FROM AUTHOR]

Background: White matter hyperintensities (WMHs) are observed frequently on MRI in elderly and associated with cognitive dysfunction. Many studies focused on intracranial small vessel disease (SVD), however, few studies linked WMHs with changes of extracranial large feeding arteries. We aimed to investigate the effects of internal carotid artery (ICA) tortuosity changes through quantitative MR Angiography. Method: Fifty‐seven patients (age: 72.98±5.62; 32 females/25 males) with WMHs were included. WMHs lesions were semi‐automatically segmented on FLAIR images. ICAs were segmented on the TOF images to generate tortuosity quantitative metrics, including tortuosity index (TI), inflection count metric (ICM), and ICA angle (Figure 1). According to the Fazekas scores, patients were categorized into mild, moderate and severe groups as summarized in Table 1. One‐way ANOVA analyses were applied to reveal the difference of averaged bilateral ICAs' tortuosity measurements. Pearson's correlation coefficients were calculated to quantitatively investigate the relationship between tortuosity and volumes of lesions that are apart from the ventricle in subcortical white matter, i.e., deep white matter lesions (DWMLs), as well as the lesions attached with the ventricular system, i.e., periventricular white matter lesions (PVWMLs). Result: Patients with higher Fazekas scores have higher TI and ICM, indicating higher tortuosity (Figure 2). The correlation results showed that TI and ICM were positively correlated with DWMLs volumes (r = 0.33, P< 0.05; r = 0.4, P< 0.01), however, they did not show associations with PVWMLs. While there's no correlation between averaged bilateral ICA angles and DWMLs or PVWMLs, we found significant correlations between left ICA angles and DWML volumes on left brain (r =0.56, P < 0.005) as well as between right ICA angles and DWML volumes on right brain (r = 0.49, P < 0.05) (Figure 3). Conclusion: Tortuosity measurements derived from TOF images showed that subjects with higher degree of ICA tortuosity had higher lesion volumes of DWMLs not PVWMLs, indicating DWMLs may have different etiologies such as ischemic origin. The findings also highlight the importance of ICA angle as a risk factor for WMHs development which might be associated with the local hemodynamic shear stress at the bulb, where the ICA plaques are often developed. [ABSTRACT FROM AUTHOR]

False smut, caused by Ustilaginoidea virens, is one of the emerging diseases of rice in the world. The fungi show a high degree of morphological and cultural variability and produce diverse symptoms. India is a vast country with 44‐million‐ha rice production area and has only one report on genetic diversity and population analysis of U. virens from the eastern and north‐eastern region. Ten polymorphic RAPD and 21 SSR markers were used to analyse the genetic diversity and population structure of 81 isolates of U. virens from northern India, the second largest rice‐growing region. In this study, higher Polymorphic Information Content (PIC) and Quality Nature of Data (QND) data in simple‐sequence repeats (SSR) markers over random amplified polymorphic DNA (RAPD) revealed its higher efficacy; thus, SSR markers are highly informative and can help to dissect the genetic structures of U. virens. All markers yielded a total of 180 alleles with 1.0 effective alleles per loci. Genetic diversity ranged from 0.1 to 0.39. The principal coordinate analysis (PCoA), and structure analysis identified two genetic clusters of U. virens isolates with some degree of distinctness according to locations. But clusters, PCoA and structure analysis did not group the isolates according to their geographical origin and this may be due to high gene flow (Nm = 1.14). [ABSTRACT FROM AUTHOR]

Background: In this proof‐of‐concept study, we examined whether NREM slow wave activity (SWA) is associated with regional in‐vivo tau deposition; and whether race‐specific differences exist in this association, in clinically normal older adults with normal sleep, in the context of Aβ. Method: This was a cross‐sectional analysis of baseline data from 21 community‐dwelling cognitively normal older‐adults with normal sleep. Participants were matched on age, sex, BMI, and APOE4 carrier status in a 1:3 ratio, blacks: whites. Normal sleep was defined as 6‐9 h of total sleep time and absence of AHI4%>15 and AHI4%>5 with sleepiness. SWA was defined as power between 0.5‐4.0 Hz during NREM with NREM cycles characterized as stages NREM 2‐3 of ≥15 min. terminated by rapid eye movement (REM) or wakefulness of ≥5 min. Tau burden was assessed using 18F‐PI2620. Linear mixed‐effects models with random intercept and slope were used to assess associations between NREM SWA, and regional in‐vivo tau PET deposition, respectively, controlling for Aβ, age, BMI, sex, APOE4‐status, education and other sleep variables. Result: Of the 21 participants, 7 (33.3%) were black, 12 (57.1%) were women and 5 (24%) were APOE4 carriers. The mean (SD) age, and education were 69.1 (5.5), and 17.2 (3.8) years respectively. NREM SWA was associated with tau deposition in the entorhinal cortex, inferior and middle temporal ROIs, including gray matter neocortical ROIs i.e., anterior ventral striatum, orbitofrontal, precuneus, superior frontal, lateral temporal and posterior cingulate gyrus cortices (p <.01 for all). Racial differences existed in the entorhinal cortex, and inferior and middle temporal ROIs, including the lateral temporal, parietal, precuneus and posterior cingulate gyrus cortices (p <.02 for all), with black participants having lower tau levels relative to white participants. Divergent NREM SWA and tau associations were observed in the entorhinal cortex, precuneus, and inferior and middle temporal ROIs with NREM SWA negatively correlated with tau‐PET levels in whites and positively correlated in blacks. Conclusion: Racial differences in physiological sleep features, uniquely associated with tau levels in the brain, may reflect one mechanism of how sociocultural factors, often through behavioral processes, become physiologically expressed as increased AD‐risk in blacks. [ABSTRACT FROM AUTHOR]

ABSTRACT High‐dimensional multinomial regression models are very useful in practice but have received less research attention than logistic regression models, especially from the perspective of statistical inference. In this work, we analyze the estimation and prediction error of the contrast‐based ℓ1$$ {\ell}_1 $$‐penalized multinomial regression model and extend the debiasing method to the multinomial case, providing a valid confidence interval for each coefficient and p$$ p $$ value of the individual hypothesis test. We also examine cases of model misspecification and non‐identically distributed data to demonstrate the robustness of our method when some assumptions are violated. We apply the debiasing method to identify important predictors in the progression into dementia of different subtypes. Results from extensive simulations show the superiority of the debiasing method compared to other inference methods. [ABSTRACT FROM AUTHOR]

Genetic diversity assessment and population structure analysis are essential for characterization of pathogens and their isolates. Markers are essential tools for exploring genetic variation among the isolates. False smut of rice caused by Ustilaginoidea virens, formerly Villosiclava virens, is a major emerging disease of rice in India. A high level of variability is observed at the field level, but no information is available from India on genetic diversity and population structure. This is the first report of genetic diversity and population structure of U. virens from India that included 63 isolates distributed across the vast geographical area of eastern and north‐eastern India (18.9 to 26.7°N and 82.6 to 94.2°E). Seventeen RAPDs and 14 SSRs were identified as polymorphic and a total of 140 alleles were detected across the populations. The average number of alleles per locus for each primer was 4.5. All the isolates were grouped into two major clusters, with partial geographical segregation that was supported by principal coordinate analysis. Mantel test suggested genetic distance within the isolates increased with increasing geographical distance. Analysis of molecular variation showed more genetic variation within populations and less among populations. This outcome will help in understanding genetic diversity of U. virens from eastern and north‐eastern India and in planning effective management strategies. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) and Lewy body disease (LBD) are most common dementias, and can occur concurrently (AD+LBD). Due to overlapping biomarkers and symptoms, clinical differentiation could be difficult. Yet it is unclear how the magnitude of diagnostic uncertainty varies across dementia spectrums and demographic variables. We aimed to compare clinical diagnosis and post‐mortem autopsy‐confirmed pathological results to assess the clinical subtype diagnosis quality across these factors. Method: Participants were selected from the National Alzheimer's Coordinating Center dataset, with autopsy‐confirmed AD and/or LBD results, and initial visits with Clinical Dementia Rating (CDR) of 0, 0.5, or 1.0. We analyzed the clinical AD and/or LBD diagnosis in first visits at each CDR stage. This analysis included precision (PPV), sensitivity and specificity of the clinical diagnosis, and disparities in these metrics by sex, race/ethnicity, age and education. If autopsy‐confirmed AD, LBD, or AD+LBD was missed in the clinic, the alternative clinical diagnosis was analyzed. Result: 1887 qualified participants (Table 1) from September 1, 2005 to August 20, 2019 were included. Clinical AD+LBD diagnosis had poor sensitivity from 3% (CDR 0.5) to 6% (CDR 2.0). Over 60% of participants with autopsy‐confirmed AD+LBD were diagnosed clinically as AD (Table 2). Clinical AD diagnosis had low sensitivities at early dementia stage (57%) and low specificities at all stages (Table 3). Among participants clinically diagnosed as AD, over 33% had autopsy‐confirmed concurrent LBD neuropathology. Clinical LBD diagnosis had poor PPVs from mild cognitive impairment (22%) to severe dementia (20%). Within participants clinically diagnosed as LBD, 32% to 54% revealed autopsy‐confirmed AD+LBD pathology. When clinicians missed these three subtypes, "No cognitive impairment", "Undecided" and "Primary progressive aphasia or behavioral variant frontotemporal dementia" were the leading alternative clinical diagnosis. With increasing dementia stages, the difference in clinical diagnosis accuracy significantly increased between White and Black/African‐American participants, and diagnosis quality significantly improved for males but not for females. Conclusion: Our findings demonstrates that the clinical diagnosis of AD, LBD and AD+LBD are inaccurate and harbor significant disparities based on race and sex at all dementia stages. [ABSTRACT FROM AUTHOR]

Background: The complications of intraperitoneal onlay mesh repair for ventral hernia has favored sublay mesh placement like open Rives–Stoppa repair (ORS). There was a need for low-cost laparoscopic trans-abdominal repair using a polypropylene mesh (PPM) with sublay, midline closure and addition of posterior component separation (PCS) by transversus abdominis release (TAR). Methods: The techniques used three or six operating ports with triangulation. After adhesiolysis, a transverse incision was made on the peritoneum (P) and posterior rectus sheath (PRS). The retromuscular space was developed by raising a P-PRS flap. Midline closure was performed with No. 1 polydioxanone, and a PPM was placed in sublay, followed by closure of defect and P-PRS incision. For large hernias with divarication; myo-fascial medialization using PCS-TAR aided low-tension midline closure. Results: Eighty-nine patients were operated from 2010 to 2019, 26 primary ventral; 63 incisional; and 22 recurrent hernias. Of the primary, 21 were umbilical, one Spigelian and four epigastric hernias. The incisional group had 57 patients with lower midline scars (C-section 25, open tubal ligation 15, abdominal hysterectomy 17), five lateral (appendicectomy), one post-laparotomy. The mean age, male/female sex ratio and BMI were 41.23 years, 1:10.1 and 29.2 kg/m2, respectively. Mean defect and mesh area were 110 cm2 and 392 cm2. Mean operating time was 192 min. Conversion to open, mesh infection and recurrence rates were 3.4%, 1.1% and 5.62%. Conclusion: Laparoscopic TARM with PPM in sublay avoids mesh–bowel contact. It provides midline closure and PCS-TAR within the same port geometry with results comparable with ORS. [ABSTRACT FROM AUTHOR]

Background: Hispanics are at higher risk for Alzheimer disease (AD) than non‐Hispanic Whites (NHW), motivating further study of differences and risk factors at the preclinical level. Subjective cognitive decline (SCD) is considered a preclinical AD stage, but its features and outcomes in Hispanics are less studied. We investigated the differences in longitudinal change in SCD phenotype, cognition, and function among Hispanics compared to NHW. Method: Longitudinal analyses were performed on consecutive participants with SCD who were evaluated at the NYU Alzheimer's Disease Research Center. Inclusion criteria were self‐identification as Hispanic (n = 23) or NWH (n = 165) and a 2‐year follow‐up visit. Demographics, conversion rate to mild cognitive impairment (MCI), SCD characteristics, and psychometric performance were analyzed by t‐test, multiple linear regression models, or Cox models as appropriate. Models were adjusted for age, sex, education, depression, and baseline values. Result: Hispanics were at higher risk for conversion to MCI (HR: 6.57, 95% CI 1.25‐34.47, p = 0.02596). Hispanic ethnicity was associated with increased SCD severity in time as measured via the total Brief Cognitive Rating Scale (BCRS) score (OR: 4.28, 95% CI 1.42‐12.83, p = 0.0094), and in specific BCRS domains: mood and behavior (OR: 0.18, 95% CI 0.03‐0.89, p = 0.0355) and calculation (OR: 29.68, 95% CI 4.02‐219.18, p = 0.0009). Global cognitive function by Mini‐Mental State Examination had a higher risk of declining in time in Hispanics (HR: 2.83, CI 1.09‐7.35, p = 0.0320). Likelihood of decline in domain‐specific tests associated with Hispanic ethnicity for Trails A (HR: 4.05, 95% CI 1.93‐8.47, p = 0.0002), Trails B (HR: 3.16, 95% CI 1.62‐6.14, p = 0.0007), and delayed paragraph recall (HR: 2.08, 95% CI 1.01‐4.24, p = 0.0444). Conclusion: Hispanics present a higher risk of conversion from SCD to MCI than NHW. Apart from stage conversion, subjective and objective measure of cognition worsen more in Hispanics, but in a domain‐specific manner. These findings suggests that Hispanics not only decline at a faster rate, but that this decline is expressed with a different phenotype. This should be considered when studying this population in preclinical investigations. [ABSTRACT FROM AUTHOR]

Background: Depression is increasingly recognized as a modulator of dementia risk and course, and is associated with multiple etiologies of cognitive decline. While it has been studied in clinically diagnosed cohorts, which may suffer from diagnostic error, there is less information in neuropathologically‐defined subjects. We sought to define the depression prevalence and sex difference at mild cognitive impairment (MCI) and mild dementia in an autopsy‐confirmed cohort of Alzheimer's disease (AD) and vascular neuropathology. Method: Retrospective data was gathered from the National Alzheimer's Coordinating Center database on autopsy‐confirmed cases of primary Alzheimer's disease (AD) and vascular neuropathology. Prevalence of depression was measured by the Geriatric Depression Scale score > = 5 during any visits at MCI (n = 364 AD cases, n = 51 vascular cases) and mild dementia (n = 557 AD cases, n = 24 vascular cases). We excluded those without pathology report, sex data or GDS results. Groups were compared via the chi‐squared test. Result: Depression prevalence was equal in MCI from AD and vascular neuropathology (27% in each, p = 0.9974). At mild dementia, depression was significantly more prevalent in vascular neuropathology compared to AD (37% versus 20%, p = 0.0363). In AD, at MCI there was no sex difference in depression prevalence (male 28% versus female 27%, p = 0.7560) but at mild dementia there was a female predominance (male 16% versus female 25%, p = 0.0075). In contrast, with vascular neuropathology, at MCI there was a trend for female predominance (male 21% versus female 33%, p = 0.3181) and no sex difference at mild dementia (male 38% versus female 36%, p = 0.9158). Conclusion: These results demonstrate that the prevalence of depression in cognitive disorders is driven by etiology, stage, and sex, which promotes further mechanistic studies on the interaction of these factors. Moreover, this illustrates the importance of depression screening in dementia, especially in females and those with suspected vascular etiology. [ABSTRACT FROM AUTHOR]

Background: We examined self‐ and informant‐based report of memory loss in mild cognitive impairment due to Alzheimer's disease (AD‐MCI) and vascular disease (Va‐MCI). We hypothesized that drivers of underreport would differ based on etiology and participant characteristics. Method: This retrospective cross‐sectional study included participants with AD‐MCI (n = 2874) and Va‐MCI (n = 376) in the National Alzheimer's Coordinating center dataset (NACC). Report of memory loss by the participant and informant was recorded as a binary (yes/no) value. We examined the role of demographic variables (age, sex, education, race, ethnicity) and neuropsychological variables (anxiety, depression on NPI‐Q) in driving underreporting of memory loss using Fisher's exact test. Result: Compared to AD‐MCI, Va‐MCI was associated with significantly more underreport of memory loss by participants (24.5% vs 19.7%, p = 0.031) and informants (31.4% vs 21.6%, p<0.0001). Black/African American participants displayed higher rates of underreport in both AD‐MCI (27.1% vs. 18.4%, p<0.0001) and Va‐MCI (37.8% vs. 20.8%, p = 0.0022). Informant underreport was increased in both AD‐MCI and Va‐MCI for participants who were female (AD: 24.3% vs 18.6%, p = 0.0002; Va:38.1% vs 22.2%, p = 0.0011) and Black/African American (AD: 35.1% vs 19.3%, p<0.0001; Va: 48.8% vs. 26.5%, p = 0.0002), and in AD‐MCI for participants who had less than 16 years of education (AD: 23.9% vs 20.3%, p = 0.0262). In both AD‐MCI and Va‐MCI, anxiety associated with less underreport in both participants (AD: 13.1% vs 22.0%, p<0.0001; Va: 15.91% vs. 31.2%, p = 0.0071) and informants (AD: 10.8% vs. 25.5%, p<0.0001; Va: 15.9% vs. 37.4%, p = 0.0002). Underreport was similarly lowered with depression in participants (AD: 14.7% vs 21.4%, p<0.0001; Va: 15.1% vs 28.3%, p = 0.0146) and informants (AD: 11.5% vs 25.2%, p<0.0001; Va: 17.4% vs. 36.8%, p = 0.0008). Conclusion: Persons with MCI and who have likely vascular presentations, or who are female, Black/African American, or have lower education are at increased risk for self‐ and/or informant‐based underreport of memory loss. Affective symptoms appear to increase the likelihood of correctly reporting memory loss. These factors may be particularly important in influencing interview‐based MCI detection and would suggest extra vigilance in persons at‐risk for self‐ or informant‐based misreport. [ABSTRACT FROM AUTHOR]

Background: Anxiety is associated with faster progression of Alzheimer's disease (AD) and related imaging biomarkers. However, the association of anxiety with plasma biomarkers of AD is unclear. We investigated the relationship between various plasma AD biomarkers and anxiety at different AD stages. Method: The study included 192 older adults evaluated at the NYU Alzheimer's Disease Research Center with a consensus diagnosis of cognitively normal (CN, n = 99), mild cognitive impairment (MCI, n = 52), and mild AD dementia (AD, n = 41). Anxiety and depression were measured by study partner report via the Neuropsychiatric Inventory Questionnaire (NPI‐Q). Plasma levels of Aβ40, Aβ42, neurofilament light (NfL) and total tau were measured using ultra‐sensitive, single‐molecule array (SIMOA) technology. Secondarily‐calculated measures included Aβ42/Aβ40 and tau/Aβ42 ratios. Result: Anxiety had a prevalence of 14%, 48%, and 24% at CN, MCI, and AD, respectively. Comparing plasma biomarkers from participants with and without anxiety within each stage, anxiety associated with a significantly higher plasma tau/Aβ42 ratio in AD (p = 0.0127). In contrast, while depression had a higher prevalence of 37% at the AD stage, it was not associated with a significant difference in tau/Aβ42 ratio (p = 0.6459). Comparing stages, plasma tau/Aβ42 was significantly elevated in AD versus CN only among participants with anxiety (p = 0.034). In contrast, plasma NfL was significantly elevated in AD versus CN among participants with (p = 0.0475) and without (p < 0.0001) anxiety. Conclusion: The presence of anxiety uniquely modulates the levels of specific plasma biomarkers depending on stage, as well as the ability of specific biomarkers to distinguish AD stages. These results highlight a complex relationship between neuropsychiatric symptoms and plasma biomarkers that warrants further study. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is the most common cause of dementia, and a challenging disease for the development of plasma biomarkers. Blood samples are the most easily collectable samples for medical diagnosis. This study evaluates the potential of plasma biomarkers in identifying early stages of AD. Method: 189 participants were recruited at the NYU Alzheimer Disease Research Center. This cohort includes n = 75 with normal cognition (NL), n = 77 with subjective cognitive decline (SCD), n = 37 with mild cognitive impairment (MCI). Comprehensive neuropsychological and magnetic resonance imaging evaluations were conducted for all patients. Plasma biomarkers assays (total tau [t‐tau], neurofilament light [NfL], glial fibrillary acid protein [GFAP], ubiquitin carboxyl‐terminal hydrolase L1 [UCH‐L1], Aβ1‐42, Aβ1‐40 and pTau181) were measured using the SIMOA SR‐X, a novel technology that employs highly sensitive immunoassays with a limit of detection (LOD) under 100 fg/ml. Result: The levels of NfL, t‐Tau, GFAP and UCH‐L1 were measured using the Neurology 4‐plex A. NfL levels showed a significant difference between NL and SCD (one tailed t‐ test p = 0.0459). GFAP showed statistically significant differences between NL and MCI, (one tailed t‐test p = 0.0369). Aβ1‐42 showed a significant difference between SCD and MCI (one tailed t‐test p = 0.0493). pTau181 levels showed a significant difference between NL, SCD and NL, MCI (p = 0.0447 and p = 0.0439, respectively). The ratio of pTau181/Aβ1‐42 shows a significant difference between NL and MCI (one tailed t‐test p = 0.0187). Correlation of these biomarkers with brain imaging and cognitive measures is underway. Conclusion: Biomarker levels of NfL, GFAP, Aβ1‐42, pTau181 and Ratio pTau181/Aβ1‐42 in plasma samples showed several significant differences between the three groups of subjects. Plasma biomarkers can be useful for the diagnosis of AD related pathology at early stages. [ABSTRACT FROM AUTHOR]

Background: Subjective cognitive decline (SCD) is considered a preclinical stage of Alzheimer's disease, but drivers and nature of progression remain unclear. We evaluated risk factor differences between SCD decliners and non‐decliners related to demographics, genetics, and presence of comorbidities. We also investigated cognitive domain markers associated with progression over time. Method: A longitudinal analysis was performed on subjects with SCD at baseline from the NYU Alzheimer's Disease Research Center. We included subjects classified as non‐decliners (n = 27), who remained stable for six annual visits, and decliners (n = 24), who progressed to mild cognitive impairment or worse between the second to sixth follow‐up visits. Generalized linear models examined group differences in demographic and genetic (presence of APOE4 or APOE2 allele) risk factors. Linear and logistic mixed‐effects models with random intercept and slope examined associations of psychometric test performance and comorbidities with longitudinal decline, comparing decliners to non‐decliners. Models included age, sex, education, Hispanic ethnicity, baseline psychometric data, APOE status, and their interactions with time. Time was operationalized as years from baseline for each participant. Result: Mean (SD) age was 68.5 (11.3) vs. 66.3 (7.1) years (p = 0.41), and follow‐up time was 3.7 (1.97) vs. 6.3 (1.60) years, (p <0.001) for decliners vs. non‐decliners. Subjects with lower years of education (14.9 (3.2) vs. 17.3 (2.1)) and those of Hispanic ethnicity (52.2% vs. 47.8%) were more likely to be decliners (p ≤ 0.004 for both). There were no differences in APOE2 or APOE4 status between decliners vs. non‐decliners. Decliners were approximately 7 times more likely (aOR: 6.67; 95% CI: 1.30 – 33.33, p = 0.002) to have hypercholesterolemia compared to non‐decliners. SCD decliners were at increased risk for psychometric changes in memory, executive, and language domains (p < 0.001 for all). Conclusion: In this cohort, lower education, Hispanic ethnicity, and hypercholesterolemia are risk factors for progression in SCD, whereas APOE status is not. Although SCD has been primarily defined with regard to concern about memory, SCD decliners are at increased risk for both amnestic and non‐amnestic cognitive decline. This supports further work to relate risk factors to SCD outcomes. [ABSTRACT FROM AUTHOR]

Background: Anxiety is increasingly recognized as an early neuropsychiatric symptom in Alzheimer's disease (AD) that portends faster progression. The etiology of anxiety in AD and the mechanism of this faster progression are unclear. Vascular risk factors independently associate with anxiety and dementia, and thus may play an important role in AD‐related anxiety. We aimed to study the prevalence of vascular risk factors in memory clinic patients with and without anxiety at the mild cognitive impairment (MCI) and AD dementia stages. Method: The cohort included patients aged ≥ 65 years who were evaluated at the NYU Langone Barlow Center for Memory Evaluation and Treatment between January 1, 2015 and June 24, 2019. Analysis was limited to patients who received a diagnosis of mild cognitive impairment (MCI) or Alzheimer's dementia (AD). At each stage, the cohort was divided into those with and without a coded diagnosis related to anxiety. Outcomes and clinical variables were based on electronic health records. Definitions for AD, MCI, anxiety, and vascular risk factors are shown in Tables 1‐2. Result: 2046 and 1594 patients were included in the MCI and AD cohorts, with anxiety prevalence of 26% and 20% in each cohort respectively. Characteristics of MCI and AD patients with and without anxiety are reported in Table 3. The rates of key cardio‐ and cerebrovascular risk factors were of increased frequency in anxious vs. non‐anxious patients in both MCI and AD cohorts: hypertension, hyperlipidemia, myocardial infarction, atrial fibrillation, ischemic heart disease, heart failure, and diabetes mellitus. Moreover, these differences were amplified in the dementia stage compared to the MCI stage. Peripheral vascular disease, stroke, and sleep apnea differences were unique to the dementia stage. Conclusion: These results suggest that vascular risk factors could play a critical role in the relationship between anxiety and AD. This relationship strengthens as AD progresses from prodromal to dementia stage, and also involves additional factors. Further characterization of these relationships and their mechanisms may uncover novel pathways to manage AD‐related neuropsychiatric symptoms and modify AD progression. [ABSTRACT FROM AUTHOR]

Objective To examine the association between odor identification deficits and future mortality in a multiethnic community cohort of older adults. Methods Participants were evaluated with the 40-item University of Pennsylvania Smell Identification Test (UPSIT). Follow-up occurred at 2-year intervals with information on death obtained from informant interviews and the National Death Index. Results During follow-up (mean = 4.1 years, standard deviation = 2.6), 349 of 1,169 (29.9%) participants died. Participants who died were more likely to be older ( p < 0.001), be male ( p < 0.001), have lower UPSIT scores ( p < 0.001), and have a diagnosis of dementia ( p < 0.001). In a Cox model, the association between lower UPSIT score and mortality (hazard ratio [HR] = 1.07 per point interval, 95% confidence interval [CI] = 1.05-1.08, p < 0.001) persisted after controlling for age, gender, education, ethnicity, language, modified Charlson medical comorbidity index, dementia, depression, alcohol abuse, head injury, smoking, body mass index, and vision and hearing impairment (HR = 1.05, 95% CI = 1.03-1.07, p < 0.001). Compared to the fourth quartile with the highest UPSIT scores, HRs for mortality for the first, second, and third quartiles of UPSIT scores were 3.81 (95% CI = 2.71-5.34), 1.75 (95% CI = 1.23-2.50), and 1.58 (95% CI = 1.09-2.30), respectively. Participant mortality rate was 45% in the lowest quartile of UPSIT scores (anosmia) and 18% in the highest quartile of UPSIT scores. Interpretation Impaired odor identification, particularly in the anosmic range, is associated with increased mortality in older adults even after controlling for dementia and medical comorbidity. Ann Neurol 2015;78:401-411 [ABSTRACT FROM AUTHOR]

ABSTRACT BACKGROUND Cerebral autoregulation (CA) enables the brain to maintain stable cerebral blood flow (CBF). CA can be assessed noninvasively by determining correlations between CBF velocity (CBFV) and spontaneous changes in blood pressure. Postrecording signal analysis methods have included both frequency- and time-domain methods. However, the test-retest reliability, cross-validation, and determination of normal values have not been adequately established. METHODS In 53 healthy volunteers, a transfer function analysis was applied to calculate phase shift (PS) and gain in the low frequency range (.06-.12 Hz) where CA is most apparent. Correlation analysis was used to derive mean velocity index (Mx). Intraclass correlation and bivariate correlation coefficients were applied to assess asymmetry, cross-validity, and test-retest results: The bihemispheric average PS, gain, and Mx means were 45.99+/−14.24°, .62+/−.38 cm/second/mmHg, and .41+/−.13, respectively. Gain exhibited a difference by age ( P = .03). PS, gain, and Mx values showed excellent interhemispheric correlation ( r > .8; P < .001). PS and gain showed good reliability ( R ICC = .632, L ICC = .576; P < .001). PS and Mx showed fair correlation ( r = −.37; P < .001). CONCLUSIONS CA parameters obtained by time- and frequency-domain methods correlate well, and show good interhemispheric and test-retest reliability. Group means from healthy controls may provide adequate norms for determining abnormal CA in cerebrovascular patients. [ABSTRACT FROM AUTHOR]

The synchronization of neuronal activity is thought to enhance information processing. There is much evidence supporting rhythmically bursting external tufted cells (ETCs) of the rodent olfactory bulb glomeruli coordinating the activation of glomerular interneurons and mitral cells via dendrodendritic excitation. However, as bursting has variable significance at axodendritic cortical synapses, it is not clear if ETC bursting imparts a specific functional advantage over the preliminary spike in dendrodendritic synaptic networks. To answer this question, we investigated the influence of single ETC bursts and spikes with the in vitro rat olfactory bulb preparation at different levels of processing, via calcium imaging of presynaptic ETC dendrites, dual electrical recording of ETC -interneuron synaptic pairs, and multicellular calcium imaging of ETC-induced population activity. Our findings supported single ETC bursts, versus single spikes, driving robust presynaptic calcium signaling, which in turn was associated with profound extension of the initial monosynaptic spike-driven dendrodendritic excitatory postsynaptic potential. This extension could be driven by either the spike-dependent or spike-independent components of the burst. At the population level, burst-induced excitation was more widespread and reliable compared with single spikes. This further supports the ETC network, in part due to a functional advantage of bursting at excitatory dendrodendritic synapses, coordinating synchronous activity at behaviorally relevant frequencies related to odor processing in vivo. [ABSTRACT FROM AUTHOR]

Background: There is increasing emphasis on research recruitment of persons of color to understand the influence of race/ethnicity on Alzheimer's disease (AD) and AD‐related dementia (ADRD) risk. Normal persons with subjective cognitive decline (SCD) are considered at risk for future decline as SCD is thought to be a preclinical stage of AD/ADRD. Yet the validity of SCD across racial and ethnic groups is unclear. Race/ethnicity‐related conditions such as socio‐economic disadvantage, neighborhood segregation, and poor housing quality (neighborhood deprivation) are important factors in stress, discrimination and other social determinants of health and may provide more in‐depth explanations for SCD than race/ethnicity alone. Method: We examined the role of neighborhood deprivation and compared this to the role of race/ethnicity in SCD using a validated instrument, the Brief Cognitive Rating Scale (BCRS). Using the Area Deprivation Index (ADI), we cross‐sectionally examined the relationship between neighborhood characteristics and SCD in a racially and ethnically diverse group of community‐residing older adults in New York City. For those having available addresses, we used data from participants with normal cognition in the NYU Alzheimer's Disease Research Center (n=313) and conducted multivariable logistic regressions, comparing two models with the BCRS as our outcome: using the ADI without race/ethnicity and then with race/ethnicity, both adjusting for age, sex, education (years). Result: Participant mean age was 72.8.0 ± 7.4 years; mean education was 16.3± 3.1 years. Seventy‐six percent of the cohort was female (n=232); 12.1% (n= 38) reported as Hispanic, 73.5% (n=230) non‐Hispanic (NH) White; 13.4% reported as NH Black or African‐American (n=42); and 3 were other. In multivariable logistic regressions of BCRS domain‐specific analysis, ADI was a significant predictor of BCRS‐measured SCD even when race/ethnicity was included as a covariate (p<0.05), suggesting independent influence of neighborhood deprivation. Conclusion: Neighborhood characteristics may play an influential role in SCD regardless of race/ethnicity and thus are likely important risk factors for AD/ADRD. If larger and more diverse studies generate similar findings, neighborhood investment and recruitment goals for AD/ADRD studies will require more focus on neighborhoods with greater deprivation. [ABSTRACT FROM AUTHOR]

Background: It is estimated that up to 40% of Alzheimer's Disease and Related Dementias cases can be prevented or delayed by addressing modifiable factors including those that influence vascular risk (hypertension, obesity, smoking, physical activity, diabetes). Prevention may be particularly important in the vascular dementia subtypes. Despite the supporting evidence, the rates of medical therapy to reduce vascular risk are not well described. Method: We assessed the utilization of statins, aspirin, and blood pressure (BP) medications in adults age ≥65 years cared for at NYU Langone Health, as recorded in the electronic health record. We included two cohorts: cohort 1 included patients who were diagnosed with vascular dementia (VaD) at NYU Langone Barlow Center for Memory Evaluation between January 1, 2015 and June 24, 2019. Cohort 2 extended the inclusion to seniors with VD diagnosis by any NYU Langone physician. Definitions for vascular dementia, the covariates assessed, and medications that we included in each category are shown in Tables 1‐3. Result: We included 419 and 3745 patients in cohort 1 and cohort 2, respectively. Table 4 shows the characteristics and medication adherence in cohorts 1 and 2. In cohort 1, the prescription rates for statins, aspirin, and BP medications were 66%, 66%, 70%. In cohort 2, the rates for statin, aspirin, and BP medications were 56%, 46%, and 65%, respectively. The differences between prescription rates in cohort 1 and 2 for the three medication groups were statistically significant (p<0.05). Conclusion: Our analysis of the utilization of cardiovascular medications among patients with vascular dementia illuminates potential gaps both among patients who receive care at specialty clinics, as well as the overall population with vascular dementia. The rates of medication utilization are higher for patients under the care of cognitive neurologists. Electronic health records can help identify large cohorts of patients who may benefit from improved access to preventative measures including cardiovascular medications. [ABSTRACT FROM AUTHOR]

Background: Most hippocampal physiologic studies in Alzheimer disease (AD) have focused on memory circuit dysfunction in dorsal CA1. Ventral CA1 (vCA1) has received little attention, despite evidence supporting its increased susceptibility and its role in mood and affective symptoms, which play a prominent role in AD. We aimed to study the effect of amyloid pathology on circuit dysfunction in vCA1 using 5xFAD mice. We evaluated intrinsic excitability of vCA1 pyramidal neurons (PNs) as well as the impact of two distinct inputs onto their apical dendrite: entorhinal cortex (EC) input onto the distal compartment and CA3 inputs onto the proximal compartment. Method: Acute ventral hippocampal slices were prepared from 12‐14 month old 5xFAD and age‐matched wild type (WT) mice. Whole cell patch clamp recordings were performed on vCA1 PNs. EC and CA3 input responses were elicited with extracellular stimulation of stratum lacunosum moleculare and stratum radiatum. We also addressed presynaptic function (paired pulse ratio), dendritic excitability (decay time constant of synaptic response), and intrinsic excitability (resting membrane potential, input resistance, sag ratio, firing rate). Result: The EC stimulus‐response curve reduced in 5xFAD vs. WT mice (n=6‐10 PNs; p=0.0096) with a peak reduction of ∼33% (1.5mV vs. 1.0mV). In these same cells, the CA3 stimulus‐response curve was also reduced (p<0.0001) but to a much larger extent of ∼67% at the peak (4.3mV vs. 1.4mV). The paired pulse ratio and response decay time constant were not affected with either input. Lastly, there were no statistically significant changes in intrinsic excitability measures. Conclusion: In 5xFAD mice, vCA1 PN circuit dysfunction is dominated by synaptic not intrinsic excitability changes. These changes are not in presynaptic function or postsynaptic ion currents, suggesting glutamate receptor changes or spine loss as alternative mechanisms. Moreover, these alterations are much more evident in CA3 versus EC input responses, perhaps driven by the inherent differences of the proximal and distal dendritic compartment. As such, with amyloidosis, vCA1 PN output shifts from being heavily dependent on CA3 input to being nearly equivalently dependent on EC input. These changes are important for understanding the circuit basis of mood and affect dysfunction in AD. [ABSTRACT FROM AUTHOR]

Background: Subjective cognitive decline (SCD) is thought to be a prodromal stage of Alzheimer's disease (AD), yet has been primarily studied in non‐Hispanic whites. This study aimed to understand the differences in SCD presentation between Hispanics (of any race) and non‐Hispanic whites. Method: A cross‐sectional analysis was performed on participants seen at the NYU Alzheimer's Disease Center with subjective cognitive decline and who identified as Hispanic (of any race, n=52) and non‐Hispanic white (n=265). Demographics, SCD characteristics, mood/behavioral symptoms, and performance on psychometrics tests were analyzed, with statistical analysis by t‐test, ANOVA, or Fisher's exact test where appropriate. Result: Hispanic participants with SCD were younger (64.3 vs. 68.2, p=0.0008) and had less education (14.3 vs. 17.6, p<0.0001). The Cognitive Change Index (CCI), a measure of SCD, did not distinguish the two groups (total CCI score nor amnestic and non‐amnestic subgroups). In contrast, on the Brief Cognitive Rating Scale (BCRS), another SCD metric, Hispanic participants showed increased severity in concentration (2.62 vs. 1.93), praxis (2.60 vs. 2.13) and calculation (2.96 vs. 2.10), all p<0.001. Study partner observations on the Neuropsychiatric Inventory‐Questionnaire (NPIQ) revealed an increased prevalence of depression (27% vs. 14%, p<0.001) and appetite changes (10% vs. 0%, p<0.0001) in Hispanic SCD participants. When self‐rated via the Geriatric Depression Scale, there were also notable differences in the quality of depression, with increased prevalence in Hispanics of dropping activities (33% vs. 6%), emptiness (19% vs. 3%), boredom (19% vs. 3%), fear (27% vs. 6%), preference to stay home (31% vs. 8%), and helplessness (15% vs. 4%), all p<0.01. On psychometric testing there were no differences in MoCA or MMSE scores. However, Hispanic participants showed lower performance on the Digit Symbol Substitution Test (DSST) (39.2 vs. 56.1, p<0.0001), which can be influenced by mood and has previously shown to be a marker of decline in SCD. Conclusion: These findings support that the characteristics, neuropsychiatric comorbidities, and psychometric features of SCD are notably different between Hispanics and non‐Hispanic whites. In particular, depression in Hispanics warrants further study as a particularly significant variable in determining SCD conversion to AD. [ABSTRACT FROM AUTHOR]

Background: Area CA1 of hippocampus is highly vulnerable to Alzheimer's disease (AD), with denser pathology towards the subiculum versus the CA2 border. Spatial and non‐spatial memory processing in CA1 is also segregated along this transverse axis. Towards CA2, deep and superficial CA1 pyramidal neurons (PNs) uniquely process spatial information from medial entorhinal cortex (MEC) and CA3. Towards subiculum, deep and superficial CA1 PNs differentially integrate non‐spatial information from lateral entorhinal cortex (LEC) and CA3. It is unclear how AD affects these distinct processing architectures, and if it is reflective of the known gradient of AD pathology within CA1. Method: MEC or LEC of 3xTg‐AD (12‐24 month old) and age‐matched wild type (WT) mice were injected with an AAV expressing channelrhodopsin (ChrR2). Acute hippocampal slices were prepared two weeks later. Whole cell patch clamp recordings were performed on deep and superficial CA1 PNs, with MEC or LEC axons optogenetically activated by blue light and CA3 axons activated by extracellular stimulation in stratum radiatum. In separate mice, immunohistochemistry (IHC) was performed for AD pathology. Result: IHC confirmed increased AD pathology in 3xTg‐AD mice towards subiculum versus CA2. Near CA2, 3xTg‐AD mice (compared to WT) showed reduced MEC input responses in both deep (0.7mV vs. 1.8mV, n=7 each, p<0.05) and superficial PNs (0.8mV vs. 2.0mV, n=8 each, p<0.05). In contrast, CA3 input responses were unchanged in deep PNs but was surprisingly increased in superficial PNs (10.4mV vs. 6.6mV, n=8 each, p<0.05). Near subiculum, 3xTg‐AD mice (compared to WT) showed a reduction in LEC input response only in superficial PNs (0.9mV, n=8, vs. 1.7mV, n=7, p<0.05). Response to CA3 input was also selectively reduced in superficial PNs (3.0mV, n=8, vs. 8.2mV, n=7, p<0.01). Conclusion: Spatial and non‐spatial memory circuits in CA1 are differentially affected in 3xTg‐AD mice, in a synapse‐ and cell type‐specific manner. Furthermore, they are not merely a direct reflection of AD pathology gradient in CA1, and may be also reflective of indirect or compensatory mechanisms related to the disease. These results also have implications on dysfunctional in vivo activity of CA1 PNs related to AD‐induced memory deficits. [ABSTRACT FROM AUTHOR]

Background: Hippocampal CA1 pyramidal neurons (PNs) are highly vulnerable to Alzheimer's disease (AD). There is increasing evidence that superficial and deep CA1 PNs are molecularly and functionally distinct. Yet, it is unknown if these sublayers show differential molecular profiles in human AD. Method: Laser capture microdissection was used to extract superficial and deep CA1 PN sublayers from hippocampal slices derived from formalin‐fixed, paraffin‐embedded (FFPE) Braak VI human AD brains (n = 8). Proteomics was performed using label‐free, quantitative liquid chromatography‐mass spectrometry (LC‐MS). Paired t‐test was used to identify protein hits whose abundance was significantly different (permutation‐based FDR correction, FDR cutoff at 5%) between neuron types. Result: LC‐MS on these samples was high yield, with detection of 3159 unique proteins spanning ∼6 orders of magnitude in abundance, with ∼15% of identifications related to synaptic and ion channel function. Differences between superficial and deep CA1 PN sublayers included those related to AMPAR regulation (SIRT2), synapse function (ARHGAP23, SEPTIN4), neurodegeneration markers (NEFH), and markers of late versus early vulnerability in AD (INA). Differences that were nearly significant included CNTN2, associated with hippocampal PN Kv1 channels, components of the postsynaptic density dysregulated in AD (DLG4 and variants), and KCTD16, which impacts GABAB currents. Conclusion: Proteomics combining LCM and LC‐MS from FFPE samples can be readily applied to address differences between PN sublayers. As such, these data support novel molecular differences between these layers in advanced AD, as related to physiologic dysfunction and disease‐related changes. [ABSTRACT FROM AUTHOR]

Background: Subjective cognitive decline (SCD) is thought to be a preclinical stage of Alzheimer's disease (AD) and is based largely on subjective report data in the context of normal neuropsychological functioning. There is, however, an unclear relationship between SCD and potential plasma markers along the AD spectrum. Method: 213 older adults (53 cognitively normal, [NL], 52 SCD, 54 mild cognitive impairment [MCI] and 54 AD), mean age 74.9±9.6, completed the UDS 3.0 battery, the Global Deterioration Scale (GDS) and a blood draw. Plasma levels of Aβ40, Aβ42, neurofilament light (NfL) and tau were measured using ultra‐sensitive, single‐molecule array (SIMOA) technology. Result: Plasma NfL levels were high in MCI patients and higher still in those with AD over cognitively unimpaired people (NL and SCD) (F(2,198)=22, p<.001) before and after correction for age, sex and apoE4 status. Both plasma tau and Aβ42 levels were higher in SCD over NL subjects (F(1,95)=7.8 and F(1,96)=6.5; both p<0.05). Importantly, plasma tau but not Aβ42, Aβ42/ Aβ40 ratio or NfL was correlated with self‐reported Cognitive Change Index (CCI) scores both in the overall sample (r154=2.4, p<0.01) and in the NL and SCD only (r89=2.15, p<0.5). Conclusion: Plasma NfL is a potential biomarker of cognitive decline to MCI and AD, while plasma tau may have higher discriminatory value in the preclinical stages of the disease and is associated with SCD. [ABSTRACT FROM AUTHOR]