Importance:Factors associated with clinical heterogeneity in Alzheimer disease (AD) lay along a continuum hypothesized to associate with tangle distribution and are relevant for understanding glial activation considerations in therapeutic advancement. Objectives:To examine clinicopathologic and neuroimaging characteristics of disease heterogeneity in AD along a quantitative continuum using the corticolimbic index (CLix) to account for individuality of spatially distributed tangles found at autopsy. Design, Setting, and Participants:This cross-sectional study was a retrospective medical record review performed on the Florida Autopsied Multiethnic (FLAME) cohort accessioned from 1991 to 2020. Data were analyzed from December 2022 to December 2023. Structural magnetic resonance imaging (MRI) and tau positron emission tomography (PET) were evaluated in an independent neuroimaging group. The FLAME cohort includes 2809 autopsied individuals; included in this study were neuropathologically diagnosed AD cases (FLAME-AD). A digital pathology subgroup of FLAME-AD cases was derived for glial activation analyses. Main Outcomes and Measures:Clinicopathologic factors of heterogeneity that inform patient history and neuropathologic evaluation of AD; CLix score (lower, relative cortical predominance/hippocampal sparing vs higher, relative cortical sparing/limbic predominant cases); neuroimaging measures (ie, structural MRI and tau-PET). Results:Of the 2809 autopsied individuals in the FLAME cohort, 1361 neuropathologically diagnosed AD cases were evaluated. A digital pathology subgroup included 60 FLAME-AD cases. The independent neuroimaging group included 93 cases. Among the 1361 FLAME-AD cases, 633 were male (47%; median [range] age at death, 81 [54-96] years) and 728 were female (53%; median [range] age at death, 81 [53-102] years). A younger symptomatic onset (Spearman ρ = 0.39, P < .001) and faster decline on the Mini-Mental State Examination (Spearman ρ = 0.27; P < .001) correlated with a lower CLix score in FLAME-AD series. Cases with a nonamnestic syndrome had lower CLix scores (median [IQR], 13 [9-18]) vs not (median [IQR], 21 [15-27]; P < .001). Hippocampal MRI volume (Spearman ρ = -0.45; P < .001) and flortaucipir tau-PET uptake in posterior cingulate and precuneus cortex (Spearman ρ = -0.74; P < .001) inversely correlated with CLix score. Although AD cases with a CLix score less than 10 had higher cortical tangle count, we found lower percentage of CD68-activated microglia/macrophage burden (median [IQR], 0.46% [0.32%-0.75%]) compared with cases with a CLix score of 10 to 30 (median [IQR], 0.75% [0.51%-0.98%]) and on par with a CLix score of 30 or greater (median [IQR], 0.40% [0.32%-0.57%]; P = .02). Conclusions and Relevance:Findings show that AD heterogeneity exists along a continuum of corticolimbic tangle distribution. Reduced CD68 burden may signify an underappreciated association between tau accumulation and microglia/macrophages activation that should be considered in personalized therapy for immune dysregulation.

To define the risk of curve progression of idiopathic scoliosis (IS) to 35°, 40°, 45°, and 50° based on current curve magnitude and Sanders stage for boys and girls, using a large cohort of patients and encounters, to improve granularity and allow more accurate estimations to guide treatment. Retrospective analysis of a prospectively collected scoliosis database. Generalized estimation equation logistic regression models estimated probabilities of curve progression to 35°, 40°, 45°, and 50° based on starting curve size and Sanders stage. Probabilities and their 95

Progressive supranuclear palsy (PSP) is a neurodegenerative parkinsonian disorder characterized by cell-type-specific tau lesions in neurons and glia. Prior work uncovered transcriptome changes in human PSP brains, although their cell-specificity is unknown. Further, systematic data integration and experimental validation platforms to prioritize brain transcriptional perturbations as therapeutic targets in PSP are currently lacking. In this study, we combine bulk tissue ( n = 408) and single nucleus RNAseq ( n = 34) data from PSP and control brains with transcriptome data from a mouse tauopathy and experimental validations in Drosophila tau models for systematic discovery of high-confidence expression changes in PSP with therapeutic potential. We discover, replicate, and annotate thousands of differentially expressed genes in PSP, many of which reside in glia-enriched co-expression modules and cells. We prioritize DDR2, STOM , and KANK2 as promising therapeutic targets in PSP with striking cross-species validations. We share our findings and data via our interactive application tool PSP RNAseq Atlas ( https://rtools.mayo.edu/PSP_RNAseq_Atlas/ ). Our findings reveal robust glial transcriptome changes in PSP, provide a cross-species systems biology approach, and a tool for therapeutic target discoveries in PSP with potential application in other neurodegenerative diseases.

Glial activation plays a critical role in Alzheimer’s disease (AD) pathogenesis and is associated with amyloid-β plaques and neurofibrillary tangles composed of phosphorylated tau (phospho-tau). With approximately 40%-60% of AD cases having limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), TDP-43 pathology has become more the rule than the exception in AD brains. However, the effect of LATE-NC in AD-related glial activation is unknown. We analyzed the effect of TDP-43 pathology on glial activation in three AD subtypes: hippocampal sparing (HpSp) AD, typical AD, and limbic predominant AD. Twenty cases of each subtype (n = 60 total) were selected from the FLorida Autopsied Multi-Ethnic (FLAME) cohort. Cases were immunohistochemically evaluated on serial sections of the hippocampus in the CA1 and subiculum subsectors, and superior temporal, inferior parietal, and mid-frontal cortices with antibodies to CD68 (phagocytosis), GFAP (astrogliosis), GT-38 (conformation-specific AD-type tau), 6F/3D (amyloid-β), and phospho-Serine 409/410 of TDP-43 (pTDP-43). Digital pathology was employed to quantify immunohistochemical staining. Multivariable regression modeling was utilized to understand the relationship between glial activation and AD pathologies. The level of glial activation, defined as % of immunoreactive surface area for CD68 and GFAP, was lowest in HpSp AD (0.54%, 13%), whereas typical AD (1.3%, 33%) and limbic predominant AD (1.3%, 30%) had similar levels suggesting a ceiling effect, or plateau, of gliosis levels (both p<0.001). HpSp AD was more often male (p<0.001) and younger at disease onset (p<0.001) compared to both typical AD and limbic predominant AD. Multivariable regression modeling of CD68 (subiculum R 2 = 0.60) identified advanced tau to be a significant predictor of CD68 in all brain regions. LATE-NC stage predicted increased CD68 levels in limbic brain regions. Multivariable regression modeling of GFAP (CA1 R 2 = 0.60) showed that Aβ was the strongest predictor of astrogliosis in CA1 and subiculum (p<0.001). Advanced tau in CA1 and parietal cortex, LATE-NC in subiculum and temporal cortex, and APOE4 genotype in CA1 predicted a significant increase in GFAP. These findings highlight the significant role TDP-43 pathology plays in affecting the microenvironment and interplay between neuroinflammation and neurodegeneration and have important implications for therapeutic strategies in AD with co-morbid LATE-NC.

A hallmark of Alzheimer’s disease is amyloid-β (Aβ) deposition in the brain parenchyma as senile plaques which Aß frequently accompanies in the cerebral vasculature as cerebral amyloid angiopathy (CAA). Previous studies demonstrated that the cerebrovascular system is essential for Aβ clearance and interactions exist between cerebrovascular disease and AD. Neuroimaging data, including measures on small vessel disease, amyloid deposits, and microhemorrhages (MCH), can reflect both cerebrovascular disease and AD pathology, thereby serving as intermediate phenotypes of both conditions. We aim to identify genes and co-expression networks in blood associated with these neuroimaging endophenotypes and the biological pathways enriched in these perturbed transcriptional networks. We conducted differential gene expression and Weighted Gene Co-Expression Network analyses (WGCNA) on blood RNA sequencing data of 407 participants from the longitudinally followed Mayo Clinic Study of Aging cohort. The neuroimaging phenotypes include MCH, infarction, and amyloid deposits measured by Pittsburgh compound B positron emission tomography (PiB PET). WGCNA analysis showed a nominally significant association (p<0.05) between several module eigengenes (MEs) and MCH and PiB PET. One module, M42, remained significantly associated with PiB PET after Bonferroni correction for all 43 modules tested. Pathway enrichment analysis of M42 identified two significant pathways (FDR-adjusted p<0.05) including phosphodiesterase I activity and IgE binding. These pathways contain genes such as MS4A2 encoding the high-affinity IgE receptor involved in the immune response. Similarly, ENPP2 in the phosphodiesterase I activity pathway represents an additional candidate gene previously implicated in Alzheimer’s disease. We generated co-expression networks and identified one network module with a statistically significant association between brain amyloid deposits and blood transcriptome data. Further investigations of this network and its enriched pathways are necessary to understand their roles in amyloidosis, CAA, and neurodegeneration. Future studies will include seeking replication of these results in other datasets. Such studies can help elucidate the biological mechanisms of pathogenesis of cerebrovascular damage and amyloid deposits. In addition, in a clinical setting, blood levels of transcripts discovered in this study may serve as predictive or diagnostic biomarkers with mechanistic implications.

African Americans (AA) represent 12% of the United States population ≥65 years-old, but 19% of persons with dementia. Inequalities in social determinants of health may influence access to healthcare resources contributing to increased dementia risk. Modifiable risk factors, including vascular risk factors and depression, may contribute up to 40% of dementia risk and are overrepresented in AA. Accordingly, risk factor modification in AA may improve disparities and decrease dementia risk. Dementia risk factors were evaluated in community-dwelling AA (n = 261) and non-Hispanic White (NHW; n = 193) participants who completed ≥2 research visits in studies of memory and aging at the Mayo Clinic Florida Alzheimer Disease Research Center. The association between modifiable risk factors and cognitive impairment (global Clinical Dementia Rating® [CDR] ≥0.5), and rates of decline in impaired participants (measured using the CDR Sum-of-Boxes; CDR-sb) were compared between AA and NHW, while controlling for demographics, APOEe4 status, and Area Deprivation Index. Modifiable dementia risk factors were common in AA and NHW participants. The ADI was higher in AA denoting greater socioeconomic and environmental deprivation [7.8 (2.3) vs. 4.0 (2.1); p<0.001]. History of stroke/transient ischemic attack (OR, CI 95% = 2.52, 1.08-5.83) was associated with an increased odds of dementia in AA participants only, while depression was associated with an increased odds of dementia in both AA (3.10, 1.52-6.30) and NHW (3.46, 1.14-10.48) participants. Moreover, depression (β, CI 95% = 1.55, 0.5-2.6), p = 0.004) was associated with a faster rate of decline (CDR-sb) in cognitively impaired AA participants. AA participants with depression were disproportionately less likely to report use of antidepressant medications than NHW counterparts (40/45, 89% vs. 21/44, 48%); p<0.001). Modifiable risk factors associated with dementia were common in AA and NHW participants. Depression was associated with dementia in both AA and NHW but uniquely associated with an accelerated rate of cognitive decline in AA participants. Disparities in use of antidepressant medications may contribute to these differences. Optimizing depression treatment in AA communities may improve cognitive trajectories and dementia risk in this population.

Objective:To examine the associations between antidepressant exposure during the third trimester of pregnancy, including individual drugs, drug doses, and antidepressant combinations, and the risk of poor neonatal adaptation (PNA).Patients and Methods:The Rochester Epidemiology Project medical records-linkage system was used to study infants exposed to selective serotonin reuptake inhibitors (SSRIs; n=1014), bupropion, (n=118), serotonin-norepinephrine reuptake inhibitors (n=80), antidepressant combinations (n=20), or other antidepressants (n=22) during the third trimester (April 11, 2000-December 31, 2013). Poor neonatal adaptation was defined based on a review of medical records. Poisson regression was used to examine the risk of PNA with serotonergic antidepressant and drug combinations compared with that with bupropion monotherapy as well as with high- vs standard-dose antidepressants. When possible, analyses were performed using propensity score (PS) weighting.Results:Forty-four infants were confirmed cases of PNA. Serotonin-norepinephrine reuptake inhibitor monotherapy, antidepressant combinations, and paroxetine monotherapy were associated with a significantly higher risk of PNA than bupropion monotherapy in unweighted analyses. High-dose SSRI exposure was associated with a significantly increased risk of PNA in unadjusted (relative risk, 2.61; 95% confidence interval, 1.35-5.04) and PS-weighted models (relative risk, 2.29; 95% confidence interval, 1.17-4.48) compared with standard-dose SSRI exposure. The risk of PNA was significantly higher with high-dose paroxetine and sertraline than with standard doses in the PS-weighted analyses. The other risk factors for PNA included maternal anxiety disorders.Conclusion:Although the frequency of PNA in this cohort was low (3%-4%), the risk of PNA was increased in infants exposed to serotonergic antidepressants, particularly with SSRIs at higher doses, during the third trimester of pregnancy compared with that in infants exposed to standard doses. Potential risk factors for PNA also included third-trimester use of paroxetine (especially at higher doses) and maternal anxiety.

Background: Selective corticolimbic vulnerability to tau pathology in Alzheimer’s disease (AD) underlies clinicopathologic heterogeneity. We aimed to re-express the AD subtype algorithm as a corticolimbic index (CLix) to quantitatively examine heterogeneity and deeply phenotype corticolimbic patterns of AD pathology and glial activation in neuropathologically diagnosed AD.Methods: CLix was developed in AD (n=1361) to collapse spatial distribution of thioflavin-S tangle counts to assign a continuum: relative hippocampal sparing with cortical predominance (<10), representative/typical (≥10 to <30), and limbic predominant (≥30). Presence of atypical, non-amnestic clinical presentation and clinical progression on Mini-Mental State Examination (MMSE) were investigated. Digital pathology measures of AD (tau [AT8, GT-38], amyloid-β [6F/3D]) were performed in hippocampus and association cortices (n=60), which were modeled with TDP-43 staging to predict glial activation burden (astrogliosis: GFAP, phagocytosis: CD68). CLix score was independently validated in an autopsied neuroimaging group (n=93).Findings: Lower CLix score correlated with younger age at symptomatic onset (R=0·39, p<0·001), faster MMSE decline (R=0·27, p<0·001), and associated with non-amnestic clinical presentations (median=13 vs. 21, p<0·001). Lower CLix score correlated with greater hippocampal volume on MRI (R=-0·45, p<0·001) and higher flortaucipir PET uptake (eg, posterior cingulate-precuneus cortex: R=-0·74, p<0·001). Advanced tangle maturity burden (GT-38) differed across all regions (p<0·001). Hippocampal sparing AD exhibited higher cortical tau pathology and reduced cortical phagocytosis. Regression modeling of glial activation (GFAP [R2=0·21–0·56], CD68 [R2=0·23–0·60]) found tau and amyloid-β similarly associated with GFAP and CD68, but TDP-43 stage associated with the greatest glial change.Interpretation: Corticolimbic tangle distribution is correlated with AD clinical phenotype, progression, and neuroimaging changes. Reduced phagocytosis in association cortices of cases with relative hippocampal sparing AD may account for higher tau burden compared to other subtypes. Pending replication, corticolimbic vulnerability and TDP-43 co-pathology should be considered for incorporation into personalized combination therapies targeting chronic immune dysregulation.Funding: This study was supported by the National Institute on Aging (R01-AG054449, R01-AG075802, P30-AG062677, RF1-AG069052, U01-AG057195, R01-AG073282, U01-AG006786, R01-AG034676, R01-AG068206, R01-AG011378, R01 AG041851); the Florida Department of Health, Ed and Ethel Moore Alzheimer’s Disease Research Program (6AZ01, 8AZ06, 20a22); the National Institute of Neurological Disorders and Stroke (R01 NS097495), Alzheimer’s Association (AARG-17-533458); a kind gift from David and Frances Strawn, the Gerstner Family Career Development Award, the Elsie and Marvin Dekelboum Family Foundation, the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic, the Liston Award, the Schuler Foundation, the GHR Foundation, and the Mayo Foundation for Medical Education and Research.Declaration of Interest: NK, IF, ZP, SAL, CMM, CP, DPW, KCA, NCL, JFT, ACW, KMH, SJL, AJS, MLS, SAP, EEC, RSK, ERL, JEC, REC, ATN, RRR, DTJ, KK, and RD and have no conflicts of interest. BDCB is supported by Alzheimer Nederland (#WE.15-2019-13, #WE.03-2021-15, #WE.06-2023-01). CGS receives research support from the NIH (R01-AG068206). OAR receives support from the National Institutes of Health (NIH)/NINDS U54-NS100693, UG3-NS104095, U54- NS110435, Department of Defense (W81XWH- 17-1-0249), Florida State James and Esther King Biomedical Research Program, The Michael J. Fox Foundation, American Parkinson Disease Association Center for Advanced Research and American Brain Foundation. CL receives research support from the National institute of Health (NIH) (P30-AG062677 Research and Education Core). NET receives support from the National Institutes of Health (NIH) (R01- AG061796, U01-AG046139); is associate director of the Mayo Clinic Center for Clinical and Translational Sciences (CTSA) Institutional Career Development (KL2) Core (KL2 TR002379); is member of the Framingham Heart Study Executive Committee (NIH NHLBI 75N92019D00031/75N92019F00125) and NIH TREAT-AD Consortium Executive Advisory Board. TJF receives support from the National Institute of Health (P30AG062677, U01NS100620, U19WU220252), and from the Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy Body Dementia Program. MMM receives research support from NIH. VKR receives research funding from the NIH and the Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy Body Dementia Program, has provided educational content for Medscape, is an Associate Editor for the Journal of Alzheimer’s Disease, is co-PI for a clinical trial supported by the Alzheimer’s Association, and is a site clinician for clinical trials supported by Eisai, the Alzheimer's Treatment and Research Institute at USC, and Transposon Therapeutics, Inc. JGR serves on the DSMB for StrokeNET. BFB receives research support for clinical trials sponsored by Alector, Cognition Therapeutics, and Transposon. He serves on the Scientific Advisory Board of the Tau Consortium. He receives research support from the NIH, the Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy Body Dementia Program, the Little Family Foundation, the Ted Turner and Family LBD Functional Genomics Program, and American Brain Foundation. DSK serves on a Data Safety Monitoring Board for the DIAN study. He served on a Data Safety monitoring Board for a tau therapeutic for Biogen but receives no personal compensation. He is a site investigator in the Biogen aducanumab trials. He is an investigator in a clinical trial sponsored by Lilly Pharmaceuticals and the University of Southern California. He serves as a consultant for Samus Therapeutics, Roche and Alzeca Biosciences but receives no personal compensation. RCP serves as a consultant for Biogen, Inc., Roche, Inc., Merck, Inc., Genentech Inc. (DSMB), Nestle, Inc., and Eisai, Inc., receives publishing royalties from Mild Cognitive Impairment (Oxford University Press, 2003), and UpToDate. CRJ serves on an independent data monitoring board for Roche, has served as a speaker for Eisai, and consulted for Biogen, but he receives no personal compensation from any commercial entity. He receives research support from NIH and the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic. GSD reports no competing interests that are directly relevant to this work. His research is supported by NIH (K23AG064029, U01AG057195, U01NS120901, U19AG032438), the Alzheimer’s Association, and Chan Zuckerberg Initiative. He serves as a consultant for Parabon Nanolabs Inc, and as a Topic Editor (Dementia) for DynaMed (EBSCO). He is the co-Project PI for a clinical trial in anti-NMDAR encephalitis, which receives support from Horizon Pharmaceuticals. He has developed educational materials for PeerView Media, Inc, and Continuing Education Inc. He owns stock in ANI pharmaceuticals. GSD’s institution has received support from Eli Lilly for development and participation in an educational event promoting early diagnosis of symptomatic Alzheimer disease, and in-kind contributions of radiotracer precursors for tau-PET neuroimaging in studies of memory and aging (via Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly). NRGR takes part in multicentre trials supported by AbbVie, Eli Lilly, and Biogen, outside the submitted work, serves on the editorial board of Alzheimer Disease and Therapy; has received publishing royalties from UpToDate, Inc.; receives research support from Biogen, Lilly and Axovant. DWD receives research support from the NIH (P30 -G062677; P50-NS072187; P01-AG003949) from the Mangurian Foundation Lewy Body Dementia Program at Mayo Clinic and the Robert E. Jacoby Professorship; is an editorial board member of Acta Neuropathologica, Annals of Neurology, Brain, Brain Pathology, and Neuropathology, and he is editor in chief of American Journal of Neurodegenerative Disease. VJL serves as consultant for Bayer Schering Pharma, Philips Molecular Imaging, Piramal Imaging, AVID Radiopharmaceuticals, Eisai Inc., Eli Lilly, and GE Healthcare and receives research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals, the NIH (NIA, NCI), and the MN Partnership for Biotechnology and Medical Genomics. PV received speaker fees from Miller Medical Communications, Inc. and receives research support from the NIH. MEM served as a paid consultant for Avid Radiopharmaceuticals, receives grant funding from Eli Lilly and Company, National Institute on Aging, and the State of Florida.Ethical Approval: All research was conducted on postmortem samples that are regarded by the Mayo Clinic Institutional Review Board as exempt from the requirements of research on human subjects. All brains were acquired with appropriate ethical approval, and the study was approved by the Mayo Clinic Institutional Review Board.

Given the overlap of symptoms between Alzheimer’s disease (AD) and other dementias, it is essential to develop widely accessible biomarkers that will ensure an accurate diagnosis of AD to enable its proper treatment. African Americans (AA) are twice more likely to develop AD than non-Hispanic whites (NHW) and yet they remain underrepresented in AD research. The few studies conducted in AA suggest that there are different factors that influence AD in this population; therefore, it is possible that different biomarkers and/or therapies may be needed to effectively treat AD in AA. In this study we are testing the hypothesis that genetic variants that show association with AD-risk in AA and with plasma levels of transcript and proteins may serve as AD biomarkers which are more accessible and less costly than cerebrospinal fluid or neuroimaging biomarkers. In 189 AD cases and 183 cognitively unimpaired (CU) AA participants of the Florida Consortium of African American Alzheimer’s Disease Studies (FCA 3 DS), we performed targeted DNA sequencing of 10 AD-associated loci. Genetic variants were tested for association with plasma transcripts and plasma total tau protein levels previously measured in this cohort using a nanoString® custom panel (Reddy J, et al. 2022) and Simoa assays (Deniz K, et al. 2021), respectively. In receiver operating characteristic (ROC) analyses, the most significant expression/protein quantitative trait loci (eQTL/pQTL) were added sequentially to a base model that included only age and sex to identify eQTL/pQTL that improved the accuracy to correctly classify AD cases vs. CU. Of the 5112 variants identified in the targeted sequencing, 71 were nominally associated (p<0.05) with plasma transcript/protein levels and with AD-risk. ROC analysis of age, sex, eQTL/pQTL in APOE, ABCA7, AKAP9, EPHA1, SORL1 , and TLR4 , and plasma levels of APP, ABCA7, AKAP9, CD14, CLU, and APOE -ɛ4 dosage achieved 77.6% area under the curve (AUC) to discriminate AD vs. CU, a 19.9% improvement over a model that only included age and sex. Plasma transcript levels and eQTL/pQTL are promising diagnostic biomarkers for AD that may improve accessibility and reduce costs for a more accurate diagnosis of AD.

Background.The age of a liver transplant (LT) candidate is one of many variables used in the transplant selection process. Most research about the age at transplant has used prespecified age ranges or categories in assessing associations with transplant outcomes. However, there is a lack of knowledge about the age at transplant and survival. This study aimed to examine associations of age at transplant as a continuous variable, in conjunction with other patient and disease-related factors, with patient and graft survival after LT. Methods.We used the Standard Transplant Analysis and Research data to identify LT recipients between January 2002 and June 2018. Cox regression models with a restricted cubic spline term for age examined associations with graft and patient survival after LT. We assessed the interactions of age with recipients' sex, race/ethnicity, region, indication for transplant, body mass index, model for end-stage liver disease score, diabetes, functional status at transplant, and donor risk index. Results.Age at the time of LT showed a nonlinear association with both graft and patient survival. Each demographic, clinical, transplant-related, and donor-related factor influenced these relationships differently. Conclusions.Our results suggest that some older LT candidates may be better than some younger candidates and that clinicians should not exclusively use age to determine who receives LT.

Purpose Pelvic floor physical therapy (PFPT) is first-line therapy for treatment of pelvic floor tension myalgia (PFTM). Pelvic floor trigger point injections (PFTPI) are added if symptoms are refractive to conservative therapy or if patients experience a flare. The primary objective was to determine if a session of physical therapy with myofascial release immediately following PFTPI provides improved pain relief compared to trigger point injection alone.Methods This was a retrospective cohort analysis of 87 female patients with PFTM who underwent PFTPI alone or PFTPI immediately followed by PFPT. Visual analog scale (VAS) pain scores were recorded pre-treatment and 2 weeks posttreatment. The primary outcome was the change in VAS between patients who received PFTPI alone and those who received PFTPI followed by myofascial release.Results Of the 87 patients in this study, 22 received PFTPI alone and 65 patients received PFTPI followed by PFPT. The median pre-treatment VAS score was 8 for both groups. The median post-treatment score was 6 for the PFTPI only group and 4 for the PFTPI followed by PFPT group, showing a median change in VAS score of 2 and 4, respectively (p = 0.042). Seventy-seven percent of patients in the PFTPI followed by PFPT group had a VAS score improvement of 3 or more, while 45% of patients in the PFTPI only group had a VAS score improvement greater than 3 (p = 0.008).Conclusion PFTPI immediately followed by PFPT offered more improvement in pain for patients with PFTM. This may be due to greater tolerance of myofascial release immediately following injections.

BACKGROUND & AIMS:Recommended surveillance intervals after complete eradication of intestinal metaplasia (CE-IM) after endoscopic eradication therapy (EET) are largely not evidence-based. Using recurrence rates in a multicenter international Barrett's esophagus (BE) CE-IM cohort, we aimed to generate optimal intervals for surveillance.METHODS:Patients with dysplastic BE undergoing EET and achieving CE-IM from prospectively maintained databases at 5 tertiary-care centers in the United States and the United Kingdom were included. The cumulative incidence of recurrence was estimated, accounting for the unknown date of actual recurrence that lies between the dates of current and previous endoscopy. This cumulative incidence of recurrence subsequently was used to estimate the proportion of patients with undetected recurrence for various surveillance intervals over 5 years. Intervals were selected that minimized recurrences remaining undetected for more than 6 months. Actual patterns of post-CE-IM follow-up evaluation are described.RESULTS:A total of 498 patients (with baseline low-grade dysplasia, 115 patients; high-grade dysplasia [HGD], 288 patients; and intramucosal adenocarcinoma [IMCa], 95 patients) were included. Any recurrence occurred in 27.1% and dysplastic recurrence occurred in 8.4% over a median of 2.6 years of follow-up evaluation. For pre-ablation HGD/IMCa, intervals of 6, 12, 18, and 24 months, and then annually, resulted in no patients with dysplastic recurrence undetected for more than 6 months, comparable with current guideline recommendations despite a 33% reduction in the number of surveillance endoscopies. For pre-ablation low-grade dysplasia, intervals of 1, 2, and 4 years balanced endoscopic burden and undetected recurrence risk.CONCLUSIONS:Lengthening post-CE-IM surveillance intervals would reduce the endoscopic burden after CE-IM with comparable rates of recurrent HGD/IMCa. Future guidelines should consider reduced surveillance frequency.

Introduction: Acute nonvariceal upper gastrointestinal bleeding (NVUGIB) is a medical emergency and one of the most common reasons for emergency GI care. The Glasgow-Blatchford score (GBS) has been developed for risk stratification. Our group has previously reported that GBS has very limited accuracy in Middle East North Africa (MENA) region. Our aim was to evaluate whether additional clinical variables improved the accuracy of GBS to predict actual high-risk stigmata or active bleeding during emergency endoscopy and to validate this in a large volume tertiary care setting in the MENA region. Methods: Data were collected retrospectively for a cohort of patients over the age of 16 years who attended the emergency department or were inpatients and underwent esophagogastroduodenoscopy (EGD) for acute NVUGIB from January 2020 through September 2021 at a tertiary hospital in the United Arab Emirates. Our predictor variables included GBS and other potential risk factors as listed in Table. GBS included patients' hemoglobin by gender, blood urea, heart rate, and systolic blood pressure from the time of admission as well as presentation with syncope or melena, and evidence of hepatic disease or cardiac failure. After assessing ability of the GBS to predict Forrest I- II classification by estimating the area under the receiver operating characteristic curve (AUROCC), we examined if other patient demographics and clinical characteristics might improve upon the ability of GBS to detect Forrest I-II classification by fitting several logistic regression models and calculating the AUROCC. Results: Among the 153 patients in our cohort, the median age was 58 years (IQR XMR 11 (IQR 7 to 13). In our cohort, 28 (18.3%) patients had Forrest I-II classification identified during endoscopy. The AUROCC for the ability of GBS to detect Forrest I-II classification was 0.49 (95% CI 0.37 to 0.62). AUROCC for the ability of each patient characteristic to detect Forrest I-II classification is shown in Table. Models that contained age, diastolic blood pressure and nationality/immigration status in addition to GBS provided the highest overall AUROC with confidence intervals significantly higher than GBS alone. Conclusion: Our study did not find evidence that GBS by itself was a useful tool at identifying patients with Forrest I-II classification during endoscopy. Our data suggested younger age, nationality / immigration status along with lower DBP may be better predictors of Forrest I-II classification when considered with GBS. Table 1. - Patients Demographics and Clinical Characteristics with Area under the Receiver Operating Characteristic Curve for Detection of Forrest I-II Classification AUC-1 AUC-2 AUROC-3 AUC-4 Predictor variable Unadjusted GBS-adjusted Age-adjusted GBS- and age-adjusted Glasgow-Blatchford score 0.493 0.704 Age 0.695 0.704 Gender 0.590 0.605 0.724 0.731 Nationality 0.630 0.634 0.737 0.745 Diabetes 0.563 0.565 0.697 0.705 Hypertension 0.609 0.627 0.696 0.706 Dyslipidemia 0.523 0.530 0.698 0.707 Chronic kidney disease 0.577 0.602 0.694 0.704 Ischemic heart disease 0.578 0.566 0.695 0.715 Atrial fibrillation 0.568 0.582 0.704 0.718 Congestive heart failure 0.510 0.519 0.696 0.706 Chronic liver disease 0.526 0.530 0.700 0.708 Cerebrovascular accident 0.563 0.575 0.691 0.702 Malignancy 0.508 0.522 0.696 0.705 Antiplatelets 0.533 0.537 0.696 0.706 Anticoagulant 0.527 0.548 0.699 0.709 Proton pump inhibitor 0.524 0.525 0.695 0.703 Steroid 0.506 0.514 0.695 0.702 NSAIDs 0.520 0.537 0.704 0.712 Admission unit 0.515 0.534 0.700 0.706 Admission time 0.538 0.533 0.699 0.711 Prior GI bleeding 0.517 0.513 0.693 0.705 Hematemesis 0.578 0.572 0.711 0.717 Melena 0.587 0.602 0.716 0.719 Drop in haemoglobin 0.519 0.504 0.693 0.706 PR Bleeding 0.528 0.541 0.698 0.705 Syncope 0.502 0.511 0.694 0.705 Urea 0.532 0.518 0.698 0.706 Initial Hgb 0.498 0.516 0.693 0.701 SBP 0.383 0.448 0.698 0.710 DBP 0.599 0.648 0.738 0.738 Heart rate 0.593 0.599 0.700 0.708 Unstable Pulse 0.570 0.607 0.700 0.705 Blood Transfusion 0.505 0.497 0.698 0.705 AUC=area under the receiver operating characteristic curve, GBS=Glasgow-Blatchford score.AUC-1 estimates were obtained from single variable logistic regression models separately for each predictor variable.AUC-2 estimates were obtained from logistic regression models separately for each predictor variable with GBS included as an additional predictor variable.AUC-3 estimates were obtained from logistic regression models separately for each predictor variable with age included as an additional predictor variable.AUC-4 estimates were obtained from logistic regression models separately for each predictor variable with GBS and age included as an additional predictor variables.

Alzheimer's disease (AD) biomarkers are increasingly more reliable in predicting neuropathology. To facilitate interpretation of phosphorylated tau sites as an early fluid biomarker, we sought to characterize which neurofibrillary tangle maturity levels (pretangle, intermediary 1, mature tangle, intermediary 2, and ghost tangle) are recognized.

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by cell-type-specific tau lesions in neurons and glia. Using bulk brain RNAseq, we previously identified PSP-associated genes and co-expression networks that are enriched with cell-type marker genes. We extended our work to identify cell-type-specific expression perturbations in PSP using a systems approach and in vivo validations in a model system. Single-nucleus RNAseq (snRNAseq) was performed using 33 frozen brain temporal cortex (TCX) samples from PSP and control brains. After quality control (QC), integration, and clustering of nuclei, each cluster was annotated for its cell type. We identified differentially expressed genes (DEG) in PSP and further investigated them using an independent bulk RNAseq dataset comprising 408 PSP and control TCX samples for replication and assessing co-expression patterns. Top DEGs were identified and then validated using external bulk RNAseq datasets from a tau transgenic mouse model. Further, the ability of the validated DEGs to rescue tau-mediated cellular toxicity was evaluated in a tau transgenic Drosophila model. After QC, 30 clusters comprised of 27,284 nuclei were obtained, encompassing two neuronal and six glial cell types. DEGs of each cluster revealed cell-type-specific PSP associations. Notably, many of the up-regulated DEGs in the astroglial clusters were members of the bulk RNAseq co-expression modules that were also up-regulated in PSP and enriched with astrocytic markers. There were also consistent findings for the up-regulated DEGs in the endothelial and microglial clusters, and for down-regulated DEGs in the oligodendroglial clusters. Subsequently, we prioritized 240 DEGs with congruent cell-type-specific perturbations in snRNAseq and bulk RNAseq and validated 29 of those using transgenic mouse model data. Lastly, a significant number of the up-regulated glial genes, when knocked down in a tau transgenic Drosophila model, led to reduced tau-mediated cellular toxicity, suggesting novel potential therapeutic avenues. PSP brains demonstrated robust cell-type-specific gene expression perturbations in the glial cells populations that were validated across different datasets. Importantly, inhibiting the up-regulated expression perturbations rescued tau-mediated toxicity in a Drosophila model. Our findings highlight the cell-type-specific transcriptome changes in PSP and provide potential therapeutic options for primary tauopathies.

Background: Dementia, vascular disease, and cancer increase with age, enabling complex comorbid interactions. Understanding vascular and cancer contributions to dementia risk and neuropathology in oldest-old may improve risk modification and outcomes. Objective: Investigate the contributions of vascular factors and cancer to dementia and neuropathology. Methods: Longitudinal clinicopathologic study of prospectively followed Mayo Clinic participants dying≥95 years-old who underwent autopsy. Participants were stratified by dementia status and compared according to demographics, vascular risk factors, cancer, and neuropathology. Results: Participants (n = 161; 83% female; 99% non-Hispanic whites)≥95 years (95–106 years-old) with/without dementia did not differ based on demographics. APOE ɛ2 frequency was higher in no dementia (20/72 [28%]) versus dementia (11/88 [12%]; p = 0.03), but APOE ɛ4 frequency did not differ. Coronary artery disease was more frequent in no dementia (31/72 [43%]) versus dementia (23/89 [26%]; p = 0.03) associated with 56% lower dementia odds (odds ratio [OR] = 0.44 [confidence interval (CI) = 0.19–0.98]; p = 0.04) and fewer neuritic/diffuse plaques. Diabetes had an 8-fold increase in dementia odds (OR = 8.42 [CI = 1.39–163]; p = 0.02). Diabetes associated with higher cerebrovascular disease (Dickson score; p = 0.05). Cancer associated with 63% lower dementia odds (OR = 0.37 [CI = 0.17–0.78]; p < 0.01) and lower Braak stage (p = 0.01). Conclusion: Cancer exposure in the oldest-old was associated with lower odds of dementia and tangle pathology, whereas history of coronary artery disease was associated with lower odds of dementia and amyloid-β plaque pathology. History of diabetes mellitus was associated with increased odds of dementia and cerebrovascular disease pathology. Cancer-related mechanisms and vascular risk factor reduction strategies may alter dementia risk and neuropathology in oldest-old.

Maryam Alahmad: NO financial relationship with a commercial interest | Noora Alhosani: NO financial relationship with a commercial interest | Khaled Alnuaimi: NO financial relationship with a commercial interest | Colleen Ball: NO financial relationship with a commercial interest | Julia Crook: NO financial relationship with a commercial interest | Talha Malik: NO financial relationship with a commercial interest | Michael Wallace: YES financial relationship with a commercial interest; Veriy: Consulting

BACKGROUND:African Americans (AA) remain underrepresented in Alzheimer's disease (AD) research, despite the prevalence of AD being double in AA compared to non-Hispanic whites. To address this disparity, our group has established the Florida Consortium for African American Alzheimer's Disease Studies (FCA3DS), focusing on the identification of genetic risk factors and novel plasma biomarkers. METHOD:Utilizing FCA3DS whole exome sequence (WES) and plasma RNA samples from AD cases (n=151) and cognitively unimpaired (CU) elderly controls (n=269), we have performed differential gene expression (DGE) and expression quantitative trait locus (eQTL) analyses on 50 transcripts measured with a custom nanoString® panel. We designed this panel to measure, in plasma, cell-free mRNA (cf-mRNA) levels of AD-relevant genes. FINDINGS:Association with higher plasma CLU in CU vs. AD remained significant after Bonferroni correction. Study-wide significant eQTL associations were observed with 105 WES variants in cis with 22 genes, including variants in genes previously associated with AD risk in AA such as ABCA7 and AKAP9. Results from this plasma eQTL analysis identified AD-risk variants in ABCA7 and AKAP9 that are significantly associated with lower and higher plasma mRNA levels of these genes, respectively. Receiver operating characteristic analysis of age, sex APOE-ε4 dosage, CLU, APP, CD14, ABCA7, AKAP9 and APOE mRNA levels, and ABCA7 and AKAP9 eQTLs, achieved 77% area under the curve to discriminate AD vs. CU, an 8% improvement over a model that only included age, sex and APOE-ε4 dosage. INTERPRETATION:Incorporating plasma mRNA levels could contribute to improved predictive value of AD biomarker panels. FUNDING:This work was supported by the National Institute on Aging [RF AG051504, U01 AG046139, R01 AG061796 to NET; P30 AG062677 to JAL and NGR]; Florida Health Ed and Ethel Moore Alzheimer's Disease grants [5AZ03 and 7AZ17 to NET; 7AZ07 to MMC; 8AZ08 to JAL].

Tau neurofibrillary tangles and senile plaques comprised of insoluble amyloid beta are the major histopathological hallmarks of Alzheimer's disease (AD). More than 85% of autopsy-confirmed AD cases also exhibit some degree of cerebral amyloid angiopathy (CAA), which is characterized by amyloid beta peptide deposits predominantly in blood vessels in the meningeal and intracerebral blood vessels. Consequently, CAA predisposes individuals with AD to cerebral infarction and hemorrhages, accounting for ∼20% of cases in the elderly, which could lead to faster cognitive decline through neurovascular pathway dysfunction. We sought to identify cellular composition changes and characterize cell type-specific expression associated with CAA pathology in AD patients.Using 10x Genomics single nuclei RNA sequencing, we profiled nuclei from frozen post-mortem temporal cortex tissue of 80 individuals with neuropathologic diagnosis of AD and varying levels of CAA, ranging from zero to severe CAA pathology. Braak and Thal measures were also obtained. Downstream analyses were performed in R using Seurat v3.2.3. Quality control filtering based on percentage of genes mapped to the mitochondrial genome and number of genes and UMIs detected resulted in 135,092 nuclei for analysis. Differential gene expression analyses were performed using R package MAST.We identified 30 clusters which were annotated using established cell type marker genes. There were 3 oligodendrocyte, 14 neuronal (2 excitatory and 3 inhibitory), 5 microglial, 3 endothelial, 4 astrocyte and 1 oligodendrocyte precursor cell cluster. We observed a significant increase in microglial cell proportions with increasing CAA severity, for 3 of the microglial clusters. Conversely, the excitatory neuronal proportion were decreased in individuals with more severe CAA. Further investigation is ongoing to identify the genes underlying the dysregulation of these cell types in CAA.We observed cellular proportion changes for multiple cell types with increasing CAA severity. Additional analyses to determine the effects of CAA independent of AD severity will be performed by adjusting for Braak and Thal measures. Deeper characterization of cell type-specific expression profiles is expected to provide novel insights into cell-type specific transcriptome changes associated with vascular risk factors in AD.

INTRODUCTION:Cognitive impairment is common in Parkinson's Disease, but the impact of predictive factors on incidence and rate of cognitive decline is incompletely understood. We aimed to determine the effects of sex and APOE allele status on cognitive performance in patients with Parkinson's Disease (PD). MATERIAL AND METHODS:We conducted a retrospective analysis of 325 clinically diagnosed PD patients who underwent one or more cognitive screenings with a Mini-Mental Status Examination (MMSE) or Mattis Dementia Rating Scale (DRS-2). We used proportional odds regression models to estimate odds ratios for higher versus lower cognitive scores in association with age, sex, education, disease duration, and APOE allele status. RESULTS:Higher cognitive scores were independently associated with female sex on the MMSE (OR 2.43; 95% CI 1.14, 5.14) and DRS-2 total (OR 4.14; 95% CI 2.01, 8.53). APOE ε4 dose was associated with lower DRS-2 totals (OR 0.42; 95% CI 0.22, 0.81), but there was no evidence of association with MMSE. Higher education level was also associated with higher scores on the MMSE (OR 1.22; 95% CI 1.07, 1.38) and DRS-2 total (OR 1.31; 95% CI 1.15, 1.50). Disease duration was not associated with cognitive performance on any measure when adjusting for age. CONCLUSION:Male sex and APOE ε4, along with age and lower education level, were associated with poorer cognitive performance among a population of predominantly non-demented PD patients.