Growth-suppressor microRNAs mediate synaptic overgrowth and behavioral deficits in Fragile X mental retardation protein deficiency.

Abnormal neuronal and synapse growth is a core pathology resulting from deficiency of the Fragile X mental retardation protein (FMRP), but molecular links underlying the excessive synthesis of key synaptic proteins remain incompletely defined. We find that basal brain levels of the growth suppressor let-7 microRNA (miRNA) family are selectively lowered in FMRP-deficient mice and activity-dependent let-7 downregulation is abrogated. Primary let-7 miRNA transcripts are not altered in FMRP-deficiency and posttranscriptional misregulation occurs downstream of MAPK pathway induction and elevation of Lin28a, a let-7 biogenesis inhibitor. Neonatal restoration of brain let-7 miRNAs corrects hallmarks of FMRP-deficiency, including dendritic spine overgrowth and social and cognitive behavioral deficits, in adult mice. Blockade of MAPK hyperactivation normalizes let-7 miRNA levels in both brain and peripheral blood plasma from Fmr1 KO mice. These results implicate dysregulated let-7 miRNA biogenesis in the pathogenesis of FMRP-deficiency, and highlight let-7 miRNA-based strategies for future biomarker and therapeutic development.

Neurocognitive trajectory and proteomic signature of inherited risk for Alzheimer's disease.

For Alzheimer's disease-a leading cause of dementia and global morbidity-improved identification of presymptomatic high-risk individuals and identification of new circulating biomarkers are key public health needs. Here, we tested the hypothesis that a polygenic predictor of risk for Alzheimer's disease would identify a subset of the population with increased risk of clinically diagnosed dementia, subclinical neurocognitive dysfunction, and a differing circulating proteomic profile. Using summary association statistics from a recent genome-wide association study, we first developed a polygenic predictor of Alzheimer's disease comprised of 7.1 million common DNA variants. We noted a 7.3-fold (95% CI 4.8 to 11.0; p < 0.001) gradient in risk across deciles of the score among 288,289 middle-aged participants of the UK Biobank study. In cross-sectional analyses stratified by age, minimal differences in risk of Alzheimer's disease and performance on a digit recall test were present according to polygenic score decile at age 50 years, but significant gradients emerged by age 65. Similarly, among 30,541 participants of the Mass General Brigham Biobank, we again noted no significant differences in Alzheimer's disease diagnosis at younger ages across deciles of the score, but for those over 65 years we noted an odds ratio of 2.0 (95% CI 1.3 to 3.2; p = 0.002) in the top versus bottom decile of the polygenic score. To understand the proteomic signature of inherited risk, we performed aptamer-based profiling in 636 blood donors (mean age 43 years) with very high or low polygenic scores. In addition to the well-known apolipoprotein E biomarker, this analysis identified 27 additional proteins, several of which have known roles related to disease pathogenesis. Differences in protein concentrations were consistent even among the youngest subset of blood donors (mean age 33 years). Of these 28 proteins, 7 of the 8 proteins with concentrations available were similarly associated with the polygenic score in participants of the Multi-Ethnic Study of Atherosclerosis. These data highlight the potential for a DNA-based score to identify high-risk individuals during the prolonged presymptomatic phase of Alzheimer's disease and to enable biomarker discovery based on profiling of young individuals in the extremes of the score distribution.

Analysis of the Frequency, Characteristics, and Reasons for Termination of Spine-related Clinical Trials.

STUDY DESIGN: Cross-sectional analysis of completed and terminated spine-related clinical trials in the ClinicalTrials.gov registry. OBJECTIVE: The aim was to quantify completed and terminated spine-related clinical trials, assess reasons for termination, and determine predictors of termination by comparing characteristics of completed and terminated trials. SUMMARY OF BACKGROUND DATA: Clinical trials are key to the advancement of products and procedures related to the spine. Unfortunately, trials may be terminated before completion. ClinicalTrials.gov is a registry and results database maintained by the National Library of Medicine that catalogs trial characteristics and tracks overall recruitment status (eg, ongoing, completed, terminated) for each study as well as reasons for termination. Reasons for trial termination have not been specifically evaluated for spine-related clinical trials. METHODS: The ClinicalTrials.gov database was queried on July 20, 2021 for all completed and terminated interventional studies registered to date using all available spine-related search terms. Trial characteristics and reason for termination, were abstracted. Univariate and multivariate analyses were performed determine predictors of trial termination. RESULTS: A total of 969 clinical trials were identified and characterized (833 completed, 136 terminated). Insufficient rate of participant accrual was the most frequently reported reason for trial termination, accounting for 33.8% of terminated trials.Multivariate analysis demonstrated increased odds of trial termination for industry-sponsorship [odds ratio (OR)=1.59] relative to sponsorship from local groups, device studies (OR=2.18) relative to investigations of drug or biological product(s), and phase II (OR=3.07) relative to phase III studies ( P <0.05 for each). CONCLUSIONS: Spine-related clinical trials were found to be terminated 14% of the time, with insufficient accrual being the most common reason for termination. With significant resources put into clinical studies and the need to advance scientific objectives, predictors, and reasons for trial termination should be considered and optimized to increase the completion rate of trials that are initiated.

Tracer-specific reference tissues selection improves detection of 18 F-FDG, 18 F-florbetapir, and 18 F-flortaucipir PET SUVR changes in Alzheimer's disease.

This study sought to identify a reference tissue-based quantification approach for improving the statistical power in detecting changes in brain glucose metabolism, amyloid, and tau deposition in Alzheimer's disease studies. A total of 794, 906, and 903 scans were included for 18 F-FDG, 18 F-florbetapir, and 18 F-flortaucipir, respectively. Positron emission tomography (PET) and T1-weighted images of participants were collected from the Alzheimer's disease Neuroimaging Initiative database, followed by partial volume correction. The standardized uptake value ratios (SUVRs) calculated from the cerebellum gray matter, centrum semiovale, and pons were evaluated at both region of interest (ROI) and voxelwise levels. The statistical power of reference tissues in detecting longitudinal SUVR changes was assessed via paired t-test. In cross-sectional analysis, the impact of reference tissue-based SUVR differences between cognitively normal and cognitively impaired groups was evaluated by effect sizes Cohen's d and two sample t-test adjusted by age, sex, and education levels. The average ROI t values of pons were 86.62 and 38.40% higher than that of centrum semiovale and cerebellum gray matter in detecting glucose metabolism decreases, while the centrum semiovale reference tissue-based SUVR provided higher t values for the detection of amyloid and tau deposition increases. The three reference tissues generated comparable d images for 18 F-FDG, 18 F-florbetapir, and 18 F-flortaucipir and comparable t maps for 18 F-florbetapir and 18 F-flortaucipir, but pons-based t map showed superior performance in 18 F-FDG. In conclusion, the tracer-specific reference tissue improved the detection of 18 F-FDG, 18 F-florbetapir, and 18 F-flortaucipir PET SUVR changes, which helps the early diagnosis, monitoring of disease progression, and therapeutic response in Alzheimer's disease.

Association between long-term donepezil treatment and brain regional amyloid and tau burden among individuals with mild cognitive impairment assessed using 18 F-AV-45 and 18 F-AV-1451 PET.

This study aims to investigate the association between long-term donepezil treatment and brain neuropathological burden and cognitive function in mild cognitive impairment (MCI) patients. Preprocessed 18 F-AV-45 amyloid and 18 F-AV-1451 tau positron emission tomography (PET) images, magnetic resonance imaging images (MRIs), demographic information, and donepezil use status were downloaded from 255 MCI participants enrolled in the Alzheimer's Disease Neuroimaging Initiative database. Partial volume correction was applied to all PET images. Structural MRIs were used for PET spatial normalization. Regions of interest (ROIs) were defined in standard space, and standardized uptake value ratio (SUVR) images relative to the cerebellum were computed. Multiple linear regression with the least absolute shrinkage selector operator was performed to analyze the effect of long-term donepezil treatment on (a) the SUVR of each 18 F-AV-45 or 18 F-AV-1451 brain PET ROI after adjusting for age, sex, education, ApoE ε4 status, and AD-associated disease risk factors; and (b) cognitive performance after adjusting for age, sex education, ApoE ε4 status, AD-associated disease risk factors, and regional amyloid or tau burden. In adjusted models, long-term donepezil treatment was associated with greater amyloid load in the orbital frontal, superior frontal, parietal, posterior precuneus, posterior cingulate, lateral temporal, inferior temporal and fusiform regions, and tau burden in the posterior cingulate, entorhinal and parahippocampal gyrus. Long-term donepezil treatment was also associated with worse performance on the 13-item Alzheimer's Disease Assessment Scale-Cognitive subscale after adjusting for AD-related risk factors and regional brain amyloid or tau load. These results indicate that long-term donepezil treatment is associated with increased regional amyloid and tau burden and worse cognitive performance among individuals with MCI. Our study highlights the importance of using noninvasive and quantitative 18 F-AV-45 and 18 F-AV-1451 PET to elucidate the consequences of drug administration in AD studies.

Selection of 51 predictors from 13,782 candidate multimodal features using machine learning improves coronary artery disease prediction.

Current cardiovascular risk assessment tools use a small number of predictors. Here, we study how machine learning might: (1) enable principled selection from a large multimodal set of candidate variables and (2) improve prediction of incident coronary artery disease (CAD) events. An elastic net-based Cox model (ML4HEN-COX) trained and evaluated in 173,274 UK Biobank participants selected 51 predictors from 13,782 candidates. Beyond most traditional risk factors, ML4HEN-COX selected a polygenic score, waist circumference, socioeconomic deprivation, and several hematologic indices. A more than 30-fold gradient in 10-year risk estimates was noted across ML4HEN-COX quintiles, ranging from 0.25% to 7.8%. ML4HEN-COX improved discrimination of incident CAD (C-statistic = 0.796) compared with the Framingham risk score, pooled cohort equations, and QRISK3 (range 0.754-0.761). This approach to variable selection and model assessment is readily generalizable to a broad range of complex datasets and disease endpoints.

Sex-Specific Cross Tissue Meta-Analysis Identifies Immune Dysregulation in Women With Alzheimer's Disease.

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in the United States. In spite of evidence of females having a greater lifetime risk of developing Alzheimer's Disease (AD) and greater apolipoprotein E4-related (APOE ε4) AD risk compared to males, molecular signatures underlying these differences remain elusive. Methods: We took a meta-analysis approach to study gene expression in the brains of 1,084 AD patients and age-matched controls and whole blood from 645 AD patients and age-matched controls in seven independent datasets. Sex-specific gene expression patterns were investigated through use of gene-based, pathway-based and network-based approaches. The ability of a sex-specific AD gene expression signature to distinguish Alzheimer's disease from healthy controls was assessed using a linear support vector machine model. Cell type deconvolution from whole blood gene expression data was performed to identify differentially regulated cells in males and females with AD. Results: Strikingly gene-expression, network-based analysis and cell type deconvolution approaches revealed a consistent immune signature in the brain and blood of female AD patients that was absent in males. In females, network-based analysis revealed a coordinated program of gene expression involving several zinc finger nuclease genes related to Herpes simplex viral infection whose expression was modulated by the presence of the APOE ε4 allele. Interestingly, this gene expression program was missing in the brains of male AD patients. Cell type deconvolution identified an increase in neutrophils and naïve B cells and a decrease in M2 macrophages, memory B cells, and CD8+ T cells in AD samples compared to controls in females. Interestingly, among males with AD, no significant differences in immune cell proportions compared to controls were observed. Machine learning-based classification of AD using gene expression from whole blood in addition to clinical features produced an improvement in classification accuracy upon stratifying by sex, achieving an AUROC of 0.91 for females and 0.80 for males. Conclusion: These results help identify sex and APOE ε4 genotype-specific transcriptomic signatures of AD and underscore the importance of considering sex in the development of biomarkers and therapeutic strategies for AD.

Sex modifies APOE ε4 dose effect on brain tau deposition in cognitively impaired individuals.

Recent studies in cognitively unimpaired elderly individuals suggest that the APOE ε4 allele exerts a dosage-dependent effect on brain tau deposition. The aim of this study was to investigate sex differences in APOE ε4 gene dosage effects on brain tau deposition in cognitively impaired individuals using quantitative 18F-flortaucipir PET. Preprocessed 18F-flortaucipir tau PET images, T1-weighted structural MRI, demographic information, global cortical amyloid-ß burden measured by 18F-florbetapir PET, CSF total tau and phosphorylated tau measurements were obtained from the Alzheimer's Disease Neuroimaging Initiative database. Two hundred and sixty-eight cognitively impaired individuals with 146 APOE ε4 non-carriers and 122 carriers (85 heterozygotes and 37 homozygotes) were included in the study. An iterative reblurred Van Cittert iteration partial volume correction method was applied to all downloaded PET images. Magnetic resonance images were used for PET spatial normalization. Twelve regional standardized uptake value ratios relative to the cerebellum were computed in standard space. APOE ε4 dosage × sex interaction effect on 18F-flortaucipir standardized uptake value ratios was assessed using generalized linear models and sex-stratified analysis. We observed a significant APOE ε4 dosage × sex interaction effect on tau deposition in the lateral temporal, posterior cingulate, medial temporal, inferior temporal, entorhinal cortex, amygdala, parahippocampal gyrus regions after adjusting for age and education level (P < 0.05). The medial temporal, entorhinal cortex, amygdala and parahippocampal gyrus regions retained a significant APOE ε4 dosage × sex interaction effect on tau deposition after adjusting for global cortical amyloid-ß (P < 0.05). In sex-stratified analysis, there was no significant difference in tau deposition between female homozygotes and heterozygotes (P > 0.05). In contrast, male homozygotes standardized uptake value ratios were significantly greater than heterozygotes or non-carriers throughout all 12 regions of interest (P < 0.05). Female heterozygotes exhibited significantly increased tau deposition compared to male heterozygotes in the orbitofrontal, posterior cingulate, lateral temporal, inferior temporal, entorhinal cortex, amygdala and parahippocampal gyrus (P < 0.05). Results from voxel-wise analysis were similar to the ones obtained from regions of interest analysis. Our findings indicate that an APOE ε4 dosage effect on brain region-specific tau deposition exists in males, but not females. These results have important clinical implications towards developing sex and genotype-guided therapeutics in Alzheimer's disease and uncovers a potential explanation underlying differential APOE ε4-associated Alzheimer's risk in males and females.

Self-reported health without clinically measurable benefits among adult users of multivitamin and multimineral supplements: a cross-sectional study.

OBJECTIVE: Multiple clinical trials fail to identify clinically measurable health benefits of daily multivitamin and multimineral (MVM) consumption in the general adult population. Understanding the determinants of widespread use of MVMs may guide efforts to better educate the public about effective nutritional practices. The objective of this study was to compare self-reported and clinically measurable health outcomes among MVM users and non-users in a large, nationally representative adult civilian non-institutionalised population in the USA surveyed on the use of complementary health practices. DESIGN: Cross-sectional analysis of the effect of MVM consumption on self-reported overall health and clinically measurable health outcomes. PARTICIPANTS: Adult MVM users and non-users from the 2012 National Health Interview Survey (n=21 603). PRIMARY AND SECONDARY OUTCOME MEASURES: Five psychological, physical, and functional health outcomes: (1) self-rated health status, (2) needing help with routine needs, (3) history of 10 chronic diseases, (4) presence of 19 health conditions in the past 12 months, and (5) Kessler 6-Item (K6) Psychological Distress Scale to measure non-specific psychological distress in the past month. RESULTS: Among 4933 adult MVM users and 16 670 adult non-users, MVM users self-reported 30% better overall health than non-users (adjusted OR 1.31; 95% CI 1.17 to 1.46; false discovery rate adjusted p<0.001). There were no differences between MVM users and non-users in history of 10 chronic diseases, number of present health conditions, severity of current psychological distress on the K6 Scale and rates of needing help with daily activities. No effect modification was observed after stratification by sex, education, and race. CONCLUSIONS: MVM users self-reported better overall health despite no apparent differences in clinically measurable health outcomes. These results suggest that widespread use of multivitamins in adults may be a result of individuals' positive expectation that multivitamin use leads to better health outcomes or a self-selection bias in which MVM users intrinsically harbour more positive views regarding their health.

Association of sex and APOE ε4 with brain tau deposition and atrophy in older adults with Alzheimer's disease.

The objective of this study was to assess the association of sex and the apolipoprotein E (APOE) ε4 allele with brain tau deposition and atrophy in older adults with Alzheimer's disease (AD) using quantitative 18F-AV-1451 positron emission tomography (PET) and magnetic resonance imaging (MRI). Methods: Preprocessed 18F-AV-1451 tau PET, raw T1-weighted structural MR images, demographic information, cerebrospinal fluid (CSF) total tau (t-tau) and phosphorylated tau (p-tau) measurements from 57 elderly individuals with AD were downloaded from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. An iteratively reblurred Van Cittert partial volume correction (PVC) method was applied to all preprocessed PET images. MRI images were used for PET spatial normalization and gray matter volume calculation. 18F-AV-1451 PET standardized uptake value ratio (SUVR) was calculated relative to the cerebellum gray matter. The effect of sex and APOE ε4 status on SUVR and gray matter volume were assessed at both region of interest (ROI) and voxelwise levels. Results: Female APOE ε4 carriers (FACs) had significant higher 18F-AV-1451 SUVRs in the lateral temporal, parietal, posterior cingulate, medial temporal, inferior temporal, entorhinal cortex, amygdala and parahippocampal gyrus regions, and exhibited smaller gray matter volumes in the posterior cingulate, medial temporal, inferior temporal and amygdala regions, as compared to the non-FACs (NFACs) comprised of female APOE ε4 non-carriers, male APOE ε4 carriers and male APOE ε4 non-carriers. Voxelwise analysis revealed forebrain and limbic clusters with greater 18F-AV-1451 SUVRs and lower gray matter volume between FACs compared to the NFACs. Negative correlations between ROI 18F-AV-1451 SUVRs and gray matter volumes were significant after adjusting for age and years of education. Conclusions: Among elderly individuals with AD, sex modified the effects of the APOE ε4 allele on region-specific tau deposition and gray matter volume. FACs had elevated brain region-specific tau PET SUVR and decreased gray matter volume in comparison to NFACs. The study provides a basis for the use of precision medicine in the diagnosis of AD and evaluation of therapeutics using 18F-AV-1451 PET and structural MRI.

Race, socioeconomic deprivation, and hospitalization for COVID-19 in English participants of a national biobank.

Preliminary reports suggest that the Coronavirus Disease 2019 (COVID- 19) pandemic has led to disproportionate morbidity and mortality among historically disadvantaged populations. We investigate the racial and socioeconomic associations of COVID- 19 hospitalization among 418,794 participants of the UK Biobank, of whom 549 (0.13%) had been hospitalized. Both Black participants (odds ratio 3.7; 95%CI 2.5-5.3) and Asian participants (odds ratio 2.2; 95%CI 1.5-3.2) were at substantially increased risk as compared to White participants. We further observed a striking gradient in COVID- 19 hospitalization rates according to the Townsend Deprivation Index - a composite measure of socioeconomic deprivation - and household income. Adjusting for socioeconomic factors and cardiorespiratory comorbidities led to only modest attenuation of the increased risk in Black participants, adjusted odds ratio 2.4 (95%CI 1.5-3.7). These observations confirm and extend earlier preliminary and lay press reports of higher morbidity in non-White individuals in the context of a large population of participants in a national biobank. The extent to which this increased risk relates to variation in pre-existing comorbidities, differences in testing or hospitalization patterns, or additional disparities in social determinants of health warrants further study.

Race, Socioeconomic Deprivation, and Hospitalization for COVID-19 in English participants of a National Biobank.

Preliminary reports suggest that the Coronavirus Disease 2019 (COVID-19) pandemic has led to disproportionate morbidity and mortality among historically disadvantaged populations. The extent to which these disparities are related to socioeconomic versus biologic factors is largely unknown. We investigate the racial and socioeconomic associations of COVID-19 hospitalization among 418,794 participants of the UK Biobank, of whom 549 (0.13%) had been hospitalized. Both black participants (odds ratio 3.4; 95%CI 2.4-4.9) and Asian participants (odds ratio 2.1; 95%CI 1.5-3.2) were at substantially increased risk as compared to white participants. We further observed a striking gradient in COVID-19 hospitalization rates according to the Townsend Deprivation Index - a composite measure of socioeconomic deprivation - and household income. Adjusting for such factors led to only modest attenuation of the increased risk in black participants, adjusted odds ratio 3.1 (95%CI 2.0-4.8). These observations confirm and extend earlier preliminary and lay press reports of higher morbidity in non-white individuals in the context of a large population of participants in a national biobank. The extent to which this increased risk relates to variation in pre-existing comorbidities, differences in testing or hospitalization patterns, or additional disparities in social determinants of health warrants further study.

Preresidency Publication Productivity of U.S. Neurosurgery Interns.

BACKGROUND: Research experience is believed to be an important component of the neurosurgery residency application process. One measure of research productivity is publication volume. The preresidency publication volume of U.S. neurosurgery interns and any potential association between applicant publication volume and the match results of top-ranked residency programs have not been well characterized. OBJECTIVE: In this study, we sought to characterize the preresidency publication volume of U.S. neurosurgery residents in the 2018-2019 intern class using the Scopus database. METHODS: For each intern, we recorded the total number of publications, total number of first or last author publications, total number of neuroscience-related publications, mean number of citations per publication, and mean impact factor of the journal per publication. Preresidency publication volumes of interns at the top-25 programs (based on a composite ranking score according to 4 different ranking metrics) were compared with those at all other programs. RESULTS: We found that 82% of neurosurgery interns included in the analysis (190 interns from 95 programs) had at least 1 publication. The average number of publications per intern among all programs was 6 ± 0.63 (mean ± standard error of the mean). We also found that interns at top-25 neurosurgery residency programs tended to have a higher number of publications (8.3 ± 1.2 vs. 4.8 ± 0.7, P = 0.0137), number of neuroscience-related publications (6.8 ± 1.1 vs. 4.1 ± 0.7, P = 0.0419), and mean number of citations per publication (9.8 ± 1.7 vs. 5.7 ± 0.8, P = 0.0267) compared with interns at all other programs. CONCLUSIONS: Our results provide a general estimate of the preresidency publication volume of U.S. neurosurgery interns and suggest a potential association between publication volume and matching in the top-25 neurosurgery residency programs.

Clinical Trial Publication Trends Within Neurology.

Timely dissemination of results from clinical studies is crucial for the advancement of knowledge and clinical decision making. A large body of research has shown that up to half of clinical trials do not publish their findings. In this study, we sought to determine whether clinical trial publication rates within neurology have increased over time. Focusing on neurology clinical trials completed between 2008 to 2014, we found that while the overall percentage of published trials has not changed (remaining at approximately 50%), time to publication has significantly decreased. Our findings suggest that clinical trials within neurology are being published in a more timely manner.

Sex modulates the ApoE ε4 effect on brain tau deposition measured by 18F-AV-1451 PET in individuals with mild cognitive impairment.

The strongest genetic risk factor for Alzheimer's disease (AD) is the Apolipoprotein E type 4 allele (ApoE ε4). The interaction between sex and ApoE ε4 carrier status on AD risk remains an area of intense investigation. We hypothesized that sex modulates the relationship between ApoE ε4 carrier status and brain tau deposition (a quantitative endophenotype in AD) in individuals with mild cognitive impairment (MCI). Methods: Preprocessed 18F-AV-1451 tau and 18F-AV-45 amyloid PET images, T1-weighted structural magnetic resonance imaging (MRI) scans, demographic information, and cerebrospinal fluid (CSF) total tau (t-tau) and phosphorylated tau (p-tau) measurements from 108 MCI subjects in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database were included. After downloading pre-processed images from ADNI, an iterative reblurred Van Cittertiteration partial volume correction (PVC) method was applied to all PET images. MRIs were used for PET spatial normalization. Regions of interest (ROIs) were defined in standard space, and standardized uptake value ratio (SUVR) images relative to cerebellum were computed. ApoE ε4 by sex interaction analyses on 18F-AV-1451 and CSF tau (t-tau, p-tau) were assessed using generalized linear models. The association between 18F-AV-1451 SUVR and CSF tau (t-tau, p-tau) was assessed. Results: After applying PVC and controlling for age, education level and global cortical 18F-AV-45 SUVR, we found that the entorhinal cortex, amygdala, parahippocampal gyrus, posterior cingulate, and occipital ROIs exhibited a significant ApoE ε4 by sex interaction effect (false discovery rate P < 0.1) among MCI individuals. We also found a significant ApoE ε4 by sex interaction effect on CSF t-tau and p-tau. 18F-AV-1451 SUVR in the 5 ROIs with ApoE ε4 by sex interaction was significantly correlated with CSF p-tau and t-tau. Conclusions: Our findings suggest that women are more susceptible to ApoE ε4-associated accumulation of neurofibrillary tangles in MCI compared to males. Both CSF tau (p-tau, t-tau) and brain tau PET are robust quantitative biomarkers for studying ApoE ε4 by sex effects on brain tau deposition in MCI participants.

Description and Assessment of a Neurosurgery Shadowing and Research Program: A Paradigm for Early and Sustained Exposure to Academic Neurosurgery.

OBJECTIVE: To describe and assess the educational value of a functional neurosurgery clinical shadowing and research tutorial for pre-medical trainees. DESIGN: Program participants observed functional neurosurgery procedures and conducted basic science and clinical research in neurosurgery fields. Former participants completed a brief online survey to evaluate their perspectives and experiences throughout the tutorial. SETTING: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. PARTICIPANTS: 15 pre-medical and post-baccalaureate trainees participated in the tutorial. All former tutorial participants were emailed. RESULTS: 11/15 former participants responded to the survey. Survey results suggest that the tutorial program increased participants' understanding of and interest in neurosurgery and related fields in neuroscience. CONCLUSIONS: The functional neurosurgery medical tutorial provides valuable clinical and research exposure in neurosurgery fields for pre-medical trainees. Our work is a preliminary step in addressing the crucial challenge of training the next generation of neurosurgeon-scientists by providing a pedagogical paradigm for development of formal experiences that integrate original scientific research with clinical neurosurgery exposure.

Insights into Computational Drug Repurposing for Neurodegenerative Disease.

Computational drug repurposing has the ability to remarkably reduce drug development time and cost in an era where these factors are prohibitively high. Several examples of successful repurposed drugs exist in fields such as oncology, diabetes, leprosy, inflammatory bowel disease, among others, however computational drug repurposing in neurodegenerative disease has presented several unique challenges stemming from the lack of validation methods and difficulty in studying heterogenous diseases of aging. Here, we examine existing approaches to computational drug repurposing, including molecular, clinical, and biophysical methods, and propose data sources and methods to advance computational drug repurposing in neurodegenerative disease using Alzheimer's disease as an example.

The effect of ApoE ε4 on longitudinal brain region-specific glucose metabolism in patients with mild cognitive impairment: a FDG-PET study.

While the ApoE ε4 allele is a known risk factor for mild cognitive impairment (MCI) and Alzheimer's disease, brain region specific effects remain elusive. In this study, we investigate whether the ApoE ε4 allele exhibits brain region specific effects in longitudinal glucose uptake among patients with MCI from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Preprocessed FDG PET images, MRIs, and demographic information were downloaded from the ADNI database. An iterative reblurred Van Cittertiteration method was used for partial volume correction (PVC) on all PET images. Structural MRIs were used for PET spatial normalization and region of interest (ROI) definition in standard space. Longitudinal changes in ROI FDG standardized uptake value ratio (SUVR) relative to cerebellum in 24 ApoE ε4 carriers and 24 age-matched ApoE ε4 non-carriers were measured for up to 84-months (median 72 months, SD = 11.2 months) and compared using a generalized linear mixed effects model controlling for gender, education, baseline age, and follow-up period. Additionally, voxelwise analysis was performed by implementing a paired t-test comparing matched baseline and 72 month FDG SUVR images in ApoE carriers and non-carriers separately. Results with PVC were compared with ones from non-PVC based analysis. After applying PVC, the superior fontal, parietal, lateral temporal, medial temporal, caudate, thalamus, and post-cingulate, and amygdala regions had greater longitudinal decreases in FDG uptake in ApoE ε4 carriers with MCI compared to non-carriers with MCI. Similar forebrain and limbic clusters were found through voxelwise analysis. Compared to the PVC based analysis, fewer significant ApoE-associated regions and clusters were found in the non-PVC based PET analysis. Our findings suggest that the ApoE ε4 genotype is associated with a longitudinal decline in glucose uptake in 8 forebrain and limbic brain regions in the context of MCI. In conclusion, this 84-months longitudinal FDG PET study demonstrates a novel ApoE ε4-associated brain-region specific glucose metabolism pattern in patients with MCI. Partial volume correction improved FDG PET quantification.