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INTRODUCTION: Vervets are non‐human primates that share high genetic homology with humans and develop amyloid beta (Aβ) pathology with aging. We expand current knowledge by examining Aβ pathology, aging, cognition, and biomarker proteomics. METHODS: Amyloid immunoreactivity in the frontal cortex and temporal cortex/hippocampal regions from archived vervet brain samples ranging from young adulthood to old age was quantified. We also obtained cognitive scores, plasma samples, and cerebrospinal fluid (CSF) samples in additional animals. Plasma and CSF proteins were quantified with platforms utilizing human antibodies. RESULTS: We found age‐related increases in Aβ deposition in both brain regions. Bioinformatic analyses assessed associations between biomarkers and age, sex, cognition, and CSF Aβ levels, revealing changes in proteins related to immune‐related inflammation, metabolism, and cellular processes. DISCUSSION: Vervets are an effective model of aging and early‐stage Alzheimer's disease, and we provide translational biomarker data that both align with previous results in humans and provide a basis for future investigations. Highlights: We found changes in immune and metabolic plasma biomarkers associated with age and cognition.Cerebrospinal fluid (CSF) biomarkers revealed changes in cell signaling indicative of adaptative processes.TNFRSF19 (TROY) and Artemin co‐localize with Alzheimer's disease pathology.Vervets are a relevant model for translational studies of early‐stage Alzheimer's disease. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Tropomyosin related kinase B (TrkB) and C (TrkC) receptor signaling promotes synaptic plasticity and interacts with pathways affected by amyloid beta (Aβ) toxicity. Upregulating TrkB/C signaling could reduce Alzheimer's disease (AD)‐related degenerative signaling, memory loss, and synaptic dysfunction. METHODS: PTX‐BD10‐2 (BD10‐2), a small molecule TrkB/C receptor partial agonist, was orally administered to aged London/Swedish‐APP mutant mice (APPL/S) and wild‐type controls. Effects on memory and hippocampal long‐term potentiation (LTP) were assessed using electrophysiology, behavioral studies, immunoblotting, immunofluorescence staining, and RNA sequencing. RESULTS: In APPL/S mice, BD10‐2 treatment improved memory and LTP deficits. This was accompanied by normalized phosphorylation of protein kinase B (Akt), calcium‐calmodulin–dependent kinase II (CaMKII), and AMPA‐type glutamate receptors containing the subunit GluA1; enhanced activity‐dependent recruitment of synaptic proteins; and increased excitatory synapse number. BD10‐2 also had potentially favorable effects on LTP‐dependent complement pathway and synaptic gene transcription. DISCUSSION: BD10‐2 prevented APPL/S/Aβ‐associated memory and LTP deficits, reduced abnormalities in synapse‐related signaling and activity‐dependent transcription of synaptic genes, and bolstered transcriptional changes associated with microglial immune response. Highlights: Small molecule modulation of tropomyosin related kinase B (TrkB) and C (TrkC) restores long‐term potentiation (LTP) and behavior in an Alzheimer's disease (AD) model.Modulation of TrkB and TrkC regulates synaptic activity‐dependent transcription.TrkB and TrkC receptors are candidate targets for translational therapeutics.Electrophysiology combined with transcriptomics elucidates synaptic restoration.LTP identifies neuron and microglia AD‐relevant human‐mouse co‐expression modules. [ABSTRACT FROM AUTHOR]

INTRODUCTION: In this study, we leverage proteomic techniques to identify communities of proteins underlying Alzheimer's disease (AD) risk among clinically unimpaired (CU) older adults. METHODS: We constructed a protein co‐expression network using 3869 cerebrospinal fluid (CSF) proteins quantified by SomaLogic, Inc., in a cohort of participants along the AD clinical spectrum. We then replicated this network in an independent cohort of CU older adults and related these modules to clinically‐relevant outcomes. RESULTS: We discovered modules enriched for phosphorylation and ubiquitination that were associated with abnormal amyloid status, as well as p‐tau181 (M4: β = 2.44, p < 0.001, M7: β = 2.57, p < 0.001) and executive function performance (M4: β = −2.00, p = 0.005, M7: β = −2.39, p < 0.001). DISCUSSION: In leveraging CSF proteomic data from individuals spanning the clinical spectrum of AD, we highlight the importance of post‐translational modifications for early cognitive and pathological changes. [ABSTRACT FROM AUTHOR]

Background: Vascular dysfunction, blood‐brain barrier (BBB) dysregulation, and neuroinflammation are thought to participate in Alzheimer's disease (AD) pathogenesis, though the mechanism is poorly understood. Among pathways of interest, AD pathology appears to affect vascular endothelial growth factor‐A (VEGFA) signaling in a bidirectional manner. Higher VEGF levels are thought to have a protective role and slow cognitive decline. Neuronal intracellular adhesion molecules (ICAMs) may also be a marker of BBB permeability. ICAMs participate in the immune‐nervous system interactions, synaptic plasticity, and cognition. Method: We used the SomaLogic platform for cerebrospinal fluid (CSF) proteome profiling to investigate the levels of ICAM 1, 2, 3, 5 and VEGFA as markers of vascular dysfunction and neuroinflammation in 83 participants from the Stanford Alzheimer Disease Research Center cohort (54 cognitively unimpaired healthy controls (HC) and 29 with mild cognitive impairment or dementia due to AD). All samples were blinded for analysis. Montreal Cognitive Assessment (MoCA) was used as a measure of global cognition. ANOVA compared the levels of biomarkers in diagnostic groups. Linear regression and interaction terms of group (AD vs HC) by biomarker levels were used to investigate the effect on global cognition. Result: ICAM5 and VEGFA were significantly associated with cognition in our cohort. Both ICAM5 and VEGFA levels were lower in AD compared to HC (Figure 1). Interaction terms of diagnosis by ICAM5 were significant on MoCA (b = ‐59.29, p‐value <.0001), and of diagnosis by VEGFA were also significant on MoCA (b = ‐134.8, p:0.00027), indicating a divergent role for these biomarkers in AD vs. HC (Figure 2). Other ICAMs were not significantly associated with cognition in our cohort. Conclusion: VEGFA and ICAM5 may play an important and dynamic role in AD. More research is needed to understand the interplay between ICAM5 and VEGF and their relationship with AD. References: Tao QQ et al. Aging Dis. 2022; Tubi MA et al. Neurobiol Aging. 2021; Petrelis AM et al. Aging (Albany NY). 2022; Yuan L et al. Aging Dis. 2017; Hino H et al. Brain Res. 1997; Yang H. Comp Funct Genomics. 2012; Birkner K et al. Front Neurol. 2019 [ABSTRACT FROM AUTHOR]

Introduction: Numerous studies have indicated that intra-articular steroid injections to the hip are beneficial for short-term pain relief. However, recent studies have drawn concerns of rapidly progressive osteoarthritis of the hip (RPOH) following intra-articular steroid injections. The prevalence of RPOH following intra-articular steroid injections varies widely in the literature.Objective: To identify the prevalence of RPOH following intra-articular steroid injections, and to compare baseline characteristics between patients with and without RPOH.Design: Case series.Setting: Tertiary academic hospital.Patients: A total of 924 patients (median [interquartile range; IQR] age: 59 [45-70] years; 579 female) who received an intra-articular hip steroid/anesthetic injection from January 2016 to March 2018 and had available pre- and post-injection imaging (prior to surgical intervention) were included in the study.Interventions: Baseline and injection-related data-including demographics, age, body mass index, medical history, laterality, and steroid type-were collected from electronic medical records.Main Outcome Measures: Post-injection RPOH was determined via imaging review by a physiatry fellow, followed by an attending physiatrist and a musculoskeletal radiologist to confirm findings.Results: The majority of patients received unilateral injections into the hip, and the most common steroids used were triamcinolone and methylprednisolone. Review of pre- and post-injection imaging revealed 26 cases of RPOH, for an overall prevalence of 2.8% (95% confidence interval [CI] 1.9%-4.1%). Compared to those without RPOH, patients with RPOH were significantly older (median age [IQR]: 64 [60-73] vs. 59 [44-70] years, p = .003) and had a shorter duration of symptoms prior to their injections (median [IQR]: 3 vs. 12 [6-36] months, p < .001). Adjusted regression analyses showed that age was associated with greater odds of RPOH (odds ratio [OR], 95% CI: 1.04, 1.01 to 1.07; p = .003).Conclusions: The prevalence of RPOH following intra-articular steroid injections into the hip was lower than previously reported but still clinically relevant. This should be considered when counseling patients prior to intra-articular hip steroid injections. [ABSTRACT FROM AUTHOR]

Background: Long‐term maintenance of synaptic adaptations, assessed by long‐term potentiation (LTP), relies on gene induction, and can be impaired by pathological forms of tau protein in Alzheimer's disease and related dementias (ADRD). We have previously shown that alterations in activity‐dependent gene expression profiles present in tauopathy mice are normalized by LM11A‐31 (C31), a small molecule p75 neurotrophin receptor (NTR) signaling modulator. However, altered gene expression levels represent only part of the complexity of the activity‐regulated transcriptional program. Since neuronal stimulation regulates alternative splicing of a number of activity‐regulated transcripts, and its disruption is associated with dysfunctional changes in ADRD, we aim to identify potential alternative splicing events related to tau‐mediated synaptic dysfunction and whether such alterations are influenced by treatment with a p75 NTR modulator. Method: PS19 (P301S) and wildtype mice were treated with vehicle (Veh) or C31 by oral gavage at 6 months of age for 3 consecutive months. Gene translation‐ and protein synthesis‐dependent synaptic plasticity was induced by applying three events of theta burst stimulation (TBS). RNA sequencing on stimulated [(+) TBS] slices was used to generate activity‐related profiles of alternative splicing events at the isoform level. Result: We identified axon guidance, glutamatergic synapse, long‐term potentiation and calcium signaling KEGG pathways among the top significant pathways with isoforms down‐regulated in (+) TBS PS19 relative to (+) WT slices. This isoform downregulation was substantially mitigated in (+) TBS slices from PS19 mice treated with C31 (see figure). For example, CACNA1H‐202, a splice‐variant that encodes a voltage‐gated calcium channel protein required for proper synaptic function, is found among the splice variants down‐regulated in Veh and up‐regulated in C31‐treated (+) TBS PS19 slices. Conversely, Prickle2‐204 isoform, associated with the formation of glutamatergic synapses, is up‐regulated in Veh and down‐regulated in C31‐treated (+) TBS PS19 slices. Currently, we are validating and examining the roles of these key C31‐modulated isoforms in neuronal function and synaptic strength as candidate molecular mechanisms involved in activity‐related effects contributing to tau‐induced neurodegeneration. Conclusion: We identified neuronal activity‐related mRNA isoform modulation by C31, indicating that p75NTR signaling might influence alternative splicing events that compromise synapse function in ADRD. [ABSTRACT FROM AUTHOR]

Background: Triggering receptor expressed on myeloid cells 2 (TREM2) plays a critical role in microglial activation, survival, and apoptosis, as well as in Alzheimer's disease (AD) pathogenesis. We previously reported the MS4A locus as a key modulator for soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF). Here, we pursued the largest CSF study to identify additional novel genetic modifiers of sTREM2. Method: We performed the genome‐wide association study (GWAS) of CSF sTREM2 in 3350 individuals of European ancestry from eight cohorts. To identify functional genes, we performed multi‐ethnic fine mapping with 250 non‐European individuals. Functional validation using peripheral blood mononuclear cell‐derived macrophages was performed. Colocalization and Mendelian randomization (MR) was performed for the causality of sTREM2 in AD. Result: The known MS4A locus and three novel loci were identified at genome‐wide significance. In the MS4A locus, we identified two independent missense variants (p.M178V in MS4A4A and p.A112T in MS4A6A) that drove the association through multi‐ethnic fine mapping. They showed an epistatic effect for sTREM2 and AD risk. The novel TREM2 locus on chromosome 6 contained two rare missense variants (rs142232675 p.D87N, P = 2.71×10‐10; rs75932628 p.R47H, P = 7.16×10‐19) associated with sTREM2 and AD risk. Another novel locus in the intergenic region between TGFBR2 and RBMS3 (rs73823326, P = 3.86×10‐9) included a regulatory variant with a microglia‐specific chromatin loop for promoters of TGFBR2. Using cell‐ based assays we demonstrate that TGFBR2, but not RBMS3, modify sTREM2 levels. The last novel locus NECTIN2 on chromosome 19 (rs11666329, P = 2.52×10‐8) was independent of APOE genotype and colocalized with cis‐eQTL of NECTIN2 in the brain cortex and cis‐pQTL of NECTIN2 in CSF (PP.H4 = 0.83). This variant was also associated with AD risk (P = 1.52×10‐66) and age at onset (P = 3.26×10‐5). Our MR results confirmed the significant protective effect of sTREM2 on reducing AD risk. Conclusion: To our knowledge, this is the largest study to date aiming at identifying genetic modifiers of CSF sTREM2. We provided novel insights for MS4A and TREM2, the two well‐ known gens for AD risk. We also identified TGFBR2 and NECTIN2 as additional modulators involved in TREM2 biology. Our findings provide new insight to unravel sTREM2 modulators and their role in AD. [ABSTRACT FROM AUTHOR]

Background: Plasma glial fibrillary acidic protein (GFAP) is an emerging AD biomarker. We aimed to study how plasma GFAP correlated with age, clinical stage, sex, and the APOE4 status and whether amyloid pathology may mediate these associations. Methods: Cohort of 330 individuals ranging from cognitively unimpaired to dementia due to AD from the Geneva Memory Center. Plasma GFAP was measured using Single molecule array (Simoa) technology. The effect of the variables of interest on plasma GFAP levels was assessed using linear regression models and partial eta squared (eta2p). In a subset of 169 subject with amyloid PET, mediation analysis was performed to test the mediating effect of amyloid levels on the association between variable of interest and plasma GFAP. Results: Age had the strongest effect on plasma GFAP levels (eta2p = 0.39, p< 0.0001), followed by clinical stage (eta2p = 0.10, p< 0.0001), sex (eta2p = 0.06, p< 0.0001), and APOE4 (eta2p = 0.02, p = 0.007). The effect of APOE4 status on plasma GFAP was fully mediated via the cortical amyloid uptake. The bootstrapped indirect effect was 0.09 (p< 0.0001) and the proportion of the effect of APOE4 status on GFAP that goes through the cortical amyloid uptake was 69%. No mediating effect by amyloid was found for age and sex. Conclusion: These results show that in a memory clinic population, i) AD risk factors and severity affected plasma GFAP levels and, ii) the effect of APOE4 on GFAP is amyloid‐dependent whereas that of age and sex is amyloid‐independent. GFAP cut‐offs for the early diagnosis of AD should take age and sex into account. [ABSTRACT FROM AUTHOR]

Background: Early stage Alzheimer disease (AD) is characterized by brain change that includes altered neuronal inhibition and excitation. However, only few data is available for clinical populations. Here, we tested the hypothesis that GABA and glutamate (Glu), the major inhibitory and excitatory neurotransmitters, associate with changes in episodic memory performance, beta‐amyloid (Aß) burden, and genetic risk of AD in old‐aged adults with normal cognition. Method: Thirty old‐aged adults underwent genotyping of the apolipoprotein E epsilon 4 allele (APOE4), MRI and MRSI at 7 Tesla (7T) for estimating GABA and Glu levels (referenced to creatine) in grey and white matter of the posterior cingulate and precuneus region, positron emission tomography with 11C‐Pittsburgh compound‐B for measuring Aß burden, and cognitive testing at two time points for assessing longitudinal change in verbal episodic memory performance. Result: Higher levels of GABA and Glu were associated with higher Aß burden (GABA: ß=0.59; p=0.005; R2=0.41; Glu: ß=0.57; p=0.006; R2=0.30), which was particularly evident in APOE4 carriers (significant interaction of Aß burden and APOE4; GABA: ß=0.93; p<0.001; R2=0.80; Glu: ß=0.81; p<0.001; R2=0.59). GABA classified subjects with high vs. low PiB‐SUVR with good accuracy (AUC=0.77; Figure 1). APOE4 and high Aß burden were associated with declining performance at the Verbal Learning and Memory Test (VLMT), immediate recall. However, these associations were attenuated by GABA and Glu, which both associated with VLMT decline (GABA: ß= ‐0.48; p=0.015; R2=0.18; Glu: ß= ‐0.41; p=0.024; R2=0.15; Figure 2). These associations, however, did not survive adjustment for age, sex and education. All findings were exclusively observable for grey and not white matter levels of GABA and Glu. Conclusion: Our findings may provide clinical evidence of higher inhibitory and excitatory capacity associated with episodic memory decline, genetic risk and pathology of AD. [ABSTRACT FROM AUTHOR]

Background: Although lumbar zygapophyseal joint synovial cysts are fairly well recognized, they are an uncommon cause of lumbosacral radicular pain. Nonoperative treatments include percutaneous aspiration of the cysts under computed tomography or fluoroscopic guidance with a subsequent corticosteroid injection. However, there are mixed results in terms of long-term outcomes and cyst reoccurrence. This study prospectively evaluates percutaneous ruptures of zygapophyseal joint (Z-joint) synovial cysts for the treatment of lumbosacral radicular pain.Objectives: Primary: To determine whether percutaneous rupture of symptomatic Z-joint synovial cysts leads to sustained improvements in radicular pain and function. Secondary: To assess the rates of cyst recurrence and progression to surgical intervention following percutaneous rupture of symptomatic Z-joint synovial cysts.Design: Prospective cohort study.Setting: Outpatient academic spine practice.Participants: Adults with primary radicular pain due to a facet synovial cyst.Methods: Participants underwent fluoroscopically guided percutaneous Z-joint synovial cyst ruptures under standard-of-care practice. Data on pain, physical function, satisfaction, and progression to surgery were collected at 2 weeks, 6 weeks, 3 months, 6 months, and 1 year after rupture. An intention-to-treat analysis was used for assessment of patient-reported outcome measures.Main Outcome Measures: The Numerical Rating Scale, Oswestry Disability Index, and modified North American Spine Society questionnaires were used to measure pain, function, and satisfaction with the procedure, respectively.Results: Thirty-five participants were included in the study, and data were analyzed by an independent researcher. Statistically significant changes in Oswestry Disability Index were reported at 2 weeks, 3 months, and 1 year postintervention (P = .034, .040, and .039, respectively). A statistically and clinically significant relief of current pain was reported at 2 weeks (P = .025) and 6 weeks (P = .014) with respect to baseline. Patients showed significant improvements for best pain at 6 weeks with respect to baseline (P = .031). Patients' worst pain showed the greatest amount of improvement with clinically meaningful changes at all time points compared with baseline. Patient-reported satisfaction was found nearly 70% of the time at all time points. Forty percent (14/35) of participants required repeat cyst rupture, and 31% (11/35) required surgical interventions.Conclusions: There were statistically and clinically significant improvements in pain and function after percutaneous rupture of Z-joint synovial cysts. In addition, the outcomes support previous retrospective studies indicating that approximately 40% of patients will need surgery. This study provides further research to determine the utility of this procedure and to precisely define a subset of ideal candidates.Level Of Evidence: Level II. [ABSTRACT FROM AUTHOR]

Background: P75NTR is a key mediator in the regulation of neuronal plasticity, and modulation of its signaling prevents synaptic dysfunction in Tau.P301S mice, as measured by long‐term potentiation (LTP). Since LTP alters gene expression programs and results in transient post‐translational modifications at synapses, we asked whether tauopathy‐associated alterations in gene co‐expression, in response to stimulation, can be counteracted by p75NTR modulation. Method: LM11A‐31 (C31), a small molecule p75NTR modulator, was orally administered to Wildtype (WT) and Tau.P301S mice for 3 months, at a time when tau pathology was fully developed. RNA sequencing with cell‐type enrichment analysis was performed on unstimulated and stimulated hippocampal slices that underwent theta burst stimulation (TBS) to induce late‐phase LTP and generate activity‐dependent profiles of gene co‐expression networks, using weighted analysis with a soft‐threshold power of 18 to achieve scale‐free topology R2>0.8 and module size 25. Result: The most significantly expressed activity‐dependent transcriptional co‐expression modules related to synaptic function in WT mice, that were down‐regulated in Tau.P301S mice, showed an enrichment for genes in neurons and transcripts selectively expressed in CA1 pyramidal cells. The top significant gene pathways enriched in these modules were glutamatergic synapse, post‐synapse, pre‐synapse, post‐synaptic density, dendritic and neuron spine, with Cacna1h, Gabbr1, Kalrn, Shisa7, and Epha7. All of these were normalized to WT levels with C31 treatment. In addition, significantly up‐regulated co‐expression modules in Tau.P301S relative to WT mice associated with pathways such as complement binding, immune system process, myeloid leukocyte migration and neutrophil chemotaxis were enriched in genes found in microglia, such as Trem2, C1qa, C1qb, C1qc, Tyrobp. Notably, these expression profiles also reverted to WT levels with C31. Further, comparison of mouse and human modules demonstrated that those affected in treated mice have similar up‐ and down‐regulated patterns of expression as those found in human AD. Conclusion: Modulation of p75NTR with C31 normalized tauopathy‐related neuronal and glial transcriptional profiles. These transcriptional alterations are in part concordant with alterations found in human AD‐relevant gene co‐expression networks. [ABSTRACT FROM AUTHOR]

Background: Heterogeneity in the clinical presentation of Alzheimer's disease (AD) underscores the importance of biomarker‐defined diagnosis for use in medicine, research and clinical trials. Therefore, CSF measurement of amyloid and tau is an important tool in the diagnostic toolbox for inferring AD‐related brain pathologies. Because differences in preanalytical handling and in study population demographics render it difficult to apply a set of global concentration cut points for defining normal/abnormal for each analyte, it is critical that analyte cut points representing normal/abnormal be determined in a center‐specific manner. Method: This is a cross‐sectional analysis of CSF collected from participants enrolled in the ongoing prospective cohort study of the Stanford Alzheimer's Disease Research Center. Participants underwent lumbar puncture and cognitive evaluation to receive a diagnosis of cognitively unimpaired (CU), mild cognitive impairment (MCI) or AD. The current study included cognitively normal adults (n=78), individuals with MCI (n=36), and individuals with AD (n=26). Core CSF AD biomarkers p‐tau181, total tau, Aβ42 and Aβ40 were measured (Lumipulse G1200 platform, Fujirebio US, Inc). Cutpoints identifying normal/abnormal amyloid and tau were generated using the Youden method and Amyloid+ was defined as abnormally low CSF Aβ42/Aβ40 while Tau+ was defined as abnormally elevated CSF p‐tau181 and/or total tau. Result: Classification by amyloid and tau biomarkers revealed that in this population, 64.1% (n=50) CU were biomarker negative for tau or amyloid pathology. However, 28.2% (n=22) of the CU were Amyloid+, 5.1% (n=4) were Amyloid+ and Tau+, and 2.6% (n=2) were Tau+ alone. In the MCI diagnostic group, 33.3% (n=12) were Amyloid+ alone, while 30.6% (n=11) were both Amyloid+ and Tau+, and 5.6% (n=2) were Tau+ alone. 30.6% (n=11) were both Amyloid‐ and Tau‐. Within those receiving an AD diagnosis, 23.1% (n=6) had CSF biomarker evidence for being Amyloid+ only, 65.4% (n=17) were both Amyloid+ and Tau+, and 11.5% (n=3) participants had no biomarker evidence for Amyloid+ or Tau+. Conclusion: These results highlight the heterogeneity underlying amyloid and tau pathology in clinically defined diagnostic groups. Biomarker‐defined diagnosis using center‐specific cut points will support accurate diagnosis, treatment, clinical research and enrollment in clinical trials. [ABSTRACT FROM AUTHOR]

Background: Aging is the critical factor of Alzheimer's disease (AD), the most common neurodegenerative disease. Among the pathological changes in the brain associated with AD, protein aggregates are the characteristic pathological hallmark that is composed of misfolded and toxic proteins. A decline in lysosomal proteolytic activity has been linked to protein aggregation and neuronal death, whereas how the lysosomes become defective and exacerbate neurodegeneration in the brain of AD patients is not well understood. Method: One of the hurdles is a lack of human neuron system to acquire deep knowledge of aging and AD. Using a powerful cell reprogramming approach, we developed a new cell model for aging and AD based on the transdifferentiation of human adult fibroblasts into cortical neurons (tNeurons) by bypassing stem‐cell stage. We leveraged cell reprogramming, quantitative proteomics, CRISPR genome editing and drug discovery techniques to achieve a better understanding of how aging and AD affect human neurons, with an emphasis on their impact on the lysosomal pathway. We further used tNeurons as a platform to identify pharmacological candidates that exert neuroprotective effect against lysosomal defects, protein aggregation and neurodegeneration in AD. Result: The transcription factor‐mediated reprogramming approach generated >85% of tNeurons as cortical glutamatergic neurons after 35‐42 days in culture. The tNeurons retained age‐related changes in epigenetic state, DNA damage and protein homeostasis (proteostasis)(Figure 1). The AD tNeurons exhibited an increased levels of Aβ42 peptides and aberrant autophagosome‐lysosome formation in the soma and neurites. Quantitative proteomics further revealed differential expression of proteins in the endosome‐lysosome and autophagy pathway between aged and AD tNeurons. We performed phenotypic and CRISPR screens to identify pharmacological candidates that ameliorate lysosomal defects and protein aggregation in aged and AD tNeurons. Conclusion: This study is anticipated to highlight that the tNeurons provide a tractable system equipped with a capacity to capture signals of human neuronal aging and neurodegenerative diseases. The outcomes provide novel insights into the role of lysosomes in the aging and neurodegenerative process, and its therapeutic implications for AD. [ABSTRACT FROM AUTHOR]

Background: It is not unusual for Alzheimer's Disease (AD) Research Center (ADRC) participants to enroll in additional studies such as the AD Neuroimaging Initiative (ADNI). In such cases, shared access to neuropathologic biospecimens is important to both studies, but dual‐enrollment status is not always known to acting ADRC personnel, and currently there is no centralized method to track dual enrollment. For this study, we aimed to identify individuals enrolled in ADNI and an ADRC, and identify those with autopsy data available through an ADRC but not ADNI. Method: GWAS data were obtained for ADRC participants (N=22,935) through the AD Genetics Consortium (ADGC) and for ADNI participants (N=2,048) through the Laboratory of NeuroImaging (LONI); data were compared in PLINK v1.9 by identity‐by‐descent (IBD). ADRC/ADNI matches were filtered for pi‐hat > 0.8. Genotype data from a custom‐96 SNP microarray for ADRC and ADNI samples banked at the National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD) were also compared to identify additional matches. Year of birth, sex, race, and ethnicity were compared within matches. Participant IDs from matches were reviewed for autopsy data available through the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) and from ADNI, to identify participants with autopsy data available through NACC but not ADNI. We generated counts for matches that had year of death, and among those, how many had neuropathology variables. Result: We identified 364 pairs with matched genetic (pi‐hat>0.99) and available demographic data from GWAS data, and another 52 from NCRAD genotype data. Of these, 143 matched ADRC participants had a year of death. 98 of the 143 had autopsy variables in the NACC UDS. 44 of these 98 were included in the ADNI autopsy data set (2018 version) or pending integration by the ADNI Neuropathology Core (NPC). Thus, 54 ADRC brain donors could be reported to the ADRCs as dually‐enrolled in ADNI, providing the involved ADRCs the opportunity to share these biospecimens with the ADNI NPC. Conclusion: This case study illustrates how identification of dually‐enrolled participants represents a unique opportunity to leverage data collected through multiple studies to enhance AD research. [ABSTRACT FROM AUTHOR]

Background: The Apolipoprotein E ε4 (ApoE4) is the strongest genetic risk factor for Alzheimer's disease (AD). Previous studies have found a link between ApoE4 genotype and tau (T) deposition in the medial temporal lobe (MTL). However, further studies disentangling the influence of genotype on tau deposition and amyloid (A) are still needed. The aim of this study was to assess tau and amyloid deposition depending on subject genotype in a memory clinic cohort. Method: 89 subjects from the Geneva Memory Center underwent amyloid and tau PET imaging, and ApoE genotyping (ApoE2 carriers, ApoE3 homozygotes, ApoE4 carriers). The remaining subjects were classified as ApoE3. Amyloid uptake has been calculated as centiloid values and tau uptake as standardized uptake value ratio (SUVR), normalized to cerebellar uptake. Positivity for each biomarker was based on thresholds published by previous studies. Correlation between amyloid centiloid and tau SUVR in general and by genotype was calculated. ANOVA with Tuckey correction for multiple comparisons was used to assess differences between tau or amyloid PET uptake across different genotypes. Result: 85% of the A+T+ subjects were carriers of the ApoE4 gene. The association between neocortical amyloid and MTL tau stratified by genotype showed that these measures are correlated in ApoE4 carriers (r = 0.52, p = 0.001). The correlation was not significant in non‐carriers. MTL tau SUVR was higher in ApoE4 carriers and significantly different when compared to non‐carriers. Furthermore, tau SUVR from lateral and superior temporal lobes were also significantly different in ApoE4 carriers vs. non‐carriers even when not considering the centiloid value, showing an amyloid‐independent association between tau SUVR and genotype is not limited to the MTL. Centiloid values showed similar differences when comparing ApoE4 carriers with non‐carriers. Conclusion: ApoE4 gene carriers present a significant increase of both tau and amyloid load with respect to non‐carriers. Furthermore, increased tau deposition independent from amyloid load is not limited to the MTL, with the entire temporal lobe showing higher tau pathology in ApoE4 carriers. [ABSTRACT FROM AUTHOR]

Background: Cerebrospinal fluid (CSF) contains a tightly regulated, specialized immune system. Yet, little is known about how aging influences CSF immunity in cognitively typical versus cognitively impaired individuals. Method: Here, we performed single cell RNA sequencing (scRNAseq) on CSF collected from 45 cognitively typical subjects ranging from 54‐82 years old. We then assessed age‐related transcriptomic changes using bioinformatic approaches, including linear and local polynomial regression. We reveal pronounced changes to several CSF immune cell types, underscored by increased expression of lipid processing genes in activated monocytes with age. We then compared CSF immune systems from cognitively typical subjects to 14 subjects with mild cognitive impairment or Alzheimer's disease. Result: Our results indicate disparate age‐related CSF immune system perturbations, including the upregulation of C‐X‐C Motif Chemokine Receptor 6 in clonally expanded T cells of cognitively impaired subjects. Conclusion: These results highlight the utility of CSF immune system changes to identify therapeutic targets of neurodegenerative disease‐associated neuroinflammation. [ABSTRACT FROM AUTHOR]

Background: Ischemia is a well‐established contributor to vascular dementia. Indeed, the most common pathology in people with dementia is mixed, and over half of patients diagnosed with AD have demonstrable vascular pathologies. Ischemia induces an immune response which triggers secondary neurodegeneration remote to the initial lesion, and consequent cognitive decline. Ischemia‐triggered vascular dementia is dependent on B‐lymphocytes driving chronic neuroinflammation in adult mice. However, vascular dementia is most common in the aged, and there are key differences in inflammatory responses with age. Vascular cell adhesion molecule 1 (VCAM1) is an endothelial protein that facilitates vascular‐immune crosstalk via interaction with very late antigen‐4 (VLA‐4). Soluble VCAM1 is elevated in stroke, vascular dementia, and normal aging in both people and mice. In aging mice, anti‐VCAM1 ameliorates age‐induced neuroinflammation and cognitive impairment. Although the mechanism is unclear, this is likely mediated via changes in endothelial cell activation and secretion of pro‐inflammatory mediators. Therefore, we hypothesized that acute anti‐VCAM1 treatment would reduce microgliosis and astrogliosis, while delayed treatment would reduce B and T lymphocyte infiltration in a mouse model of ischemia‐triggered vascular dementia. Method: Adult (3‐month‐old) or aged (10‐month‐old) C57BL/6J mice (n=10‐15/group) underwent permanent distal middle cerebral artery occlusion. Mice were dosed with anti‐VCAM1 antibody either 4 hours or 4 days post‐ischemia, and then sacrificed at 72 hours, 3 weeks or 6 weeks post‐ischemia. Microgliosis and astrogliosis were quantified as percent area immunostained in the lesion border by CD68 and GFAP, respectively. B and T cell infiltration were quantified as percent lesion immunostained by B220, and CD3+ cells in the ischemic lesion, respectively. Result: Acute treatment reduced microgliosis 30% (p=0.0476) and astrogliosis 39% (p<0.03). In adults, delayed anti‐VCAM1 significantly reduced B and T cell infiltration approximately 25% (p=0.0015) and 50% (p=0.0192), respectively. Similarly, in aged mice, delayed anti‐VCAM1 significantly reduced B and T cell infiltration approximately 50% (p=0.0037) and 30% (p=0.0036), respectively. In contrast, early anti‐VCAM1 had little or no effect on B or T cell infiltration. Conclusion: Together, these findings establish VCAM1 as a possible therapeutic target to ameliorate ischemia‐induced neuroinflammation and consequent cognitive decline in a mouse model of vascular dementia. [ABSTRACT FROM AUTHOR]

Athletic pubalgia is a syndrome of persistent groin pain due to chronic repetitive trauma or stress involving the pelvic joints and many musculotendinous structures that cross the anterior pelvis. As a result, the differential diagnosis can be complex, but insertional tendinopathies are the most common. This case report describes a novel approach to the treatment of distal rectus abdominis tendinopathies with ultrasound-guided needle tenotomy and platelet-rich plasma (PRP) injection. After injection, the patient returned to pain-free play at his previous level of intensity. This suggests that PRP may be a useful treatment for this diagnosis. [ABSTRACT FROM AUTHOR]

Addressing the ongoing decline of Pacific Lamprey Entosphenus tridentatus across its range along the west coast of North America requires an understanding of all life history phases. Currently, spawning surveys (redd counts) are a common tool used to monitor returning adult salmonids, but the methods are in their infancy for Pacific Lamprey. To better understand the spawning phase, our objective was to assess temporal spawning trends, redd abundance, habitat use, and spatial patterns of spawning at multiple spatial scales for Pacific Lamprey in the Willamette River basin, Oregon. Although redd density varied considerably across surveyed reaches, the observed temporal patterns of spawning were related to physical habitat and hydrologic conditions. As has been documented in studies in other basins in the Pacific Northwest, we found that redds were often constructed in pool tailouts dominated by gravel, similar to habitat used by spawning salmonids. Across the entire Willamette Basin, Pacific Lampreys appeared to select reaches with alluvial geology, likely because this is where gravel suitable for spawning accumulated. At the tributary scale, spawning patterns were not as strong, and in reaches with nonalluvial geology redds were more spatially clumped than in reaches with alluvial geology. These results can be used to help identify and conserve Pacific Lamprey spawning habitat across the Pacific Northwest. [ABSTRACT FROM AUTHOR]

Pacific LampreyEntosphenus tridentatushas declined across its range along the West Coast of North America, and an understanding of all life history phases is needed to address population recovery. Spawning surveys (redd counts) are common tools currently used to monitor returning adult salmonids, but such methodologies are in their infancy for Pacific Lamprey. Our objective was to assess the minimum spawning survey distance required to detect the presence of Pacific Lamprey redds and obtain precise redd density estimates from these data. To do this, we statistically resampled existing spawning locations of Pacific Lamprey collected during spawning surveys in four streams of the Willamette River Basin, Oregon, during spring of 2013. We found that the minimum survey distance for Pacific Lamprey redd detection was inversely related to the observed redd density and was always less than 1.2 km. Survey distance requirements to obtain precise redd counts (±20% of observed redd densities) were also inversely related to redd density and habitat availability, and varied between 1.3 km and 13.7 km. Our results suggest that spawning surveys are a potential tool for monitoring adult Pacific Lamprey abundance, but the specific objectives of the monitoring programs and acknowledgment of unknowns must be considered prior to implementation into recovery plans. Received January 2, 2014; accepted May 19, 2014 [ABSTRACT FROM AUTHOR]

Abstract: Treatment of Alzheimer's disease (AD) is significantly hampered by the lack of easily accessible biomarkers that can detect disease presence and predict disease risk reliably. Fluid biomarkers of AD currently provide indications of disease stage; however, they are not robust predictors of disease progression or treatment response, and most are measured in cerebrospinal fluid, which limits their applicability. With these aspects in mind, the aim of this article is to underscore the concerted efforts of the Blood-Based Biomarker Interest Group, an international working group of experts in the field. The points addressed include: (1) the major challenges in the development of blood-based biomarkers of AD, including patient heterogeneity, inclusion of the “right” control population, and the blood–brain barrier; (2) the need for a clear definition of the purpose of the individual markers (e.g., prognostic, diagnostic, or monitoring therapeutic efficacy); (3) a critical evaluation of the ongoing biomarker approaches; and (4) highlighting the need for standardization of preanalytical variables and analytical methodologies used by the field. [Copyright &y& Elsevier]

A microscale three-point bend experiment on wood has been carried out. The full 3D strain field of the microscale wood structure has been determined by use of digital volume correlation, based on reconstructed 3D image data acquired with synchrotron radiation micro-computed tomography. The wood specimen, which measures 1.57 × 3.42 × 0.75 mm3, was scanned in different load states along the three-point bend load cycle, from unloaded state to failure. The correlation algorithm is based on a Chebyshev polynomial description of the displacements, which allows a continuous representation of the 3D deformation fields. The methodology of the correlation algorithm is described thoroughly and its performance is tested for a 3D structure that is exposed to a virtual pre-defined deformation. The performance is tested both for noise free volume data as well as for structures with additive noise content. The performance test shows that the correlation algorithm resolves the applied deformation satisfyingly well. In the real experiment, on wood microstructure, the displacement fields show a structural behaviour that is consistent with what is expected for a specimen exposed to three-point bend. However, there are also anomalous effects present in the displacement fields that can be coupled to characteristic features in the cellular structure of the wood. Furthermore, 3D strain calculations based on the obtained displacement data shows a concentration of tensile strain in the region where the specimen eventually collapses. The experimental results show that the use of X-ray-based tomography with high spatial resolution in combination with digital volume correlation can successfully be used to perform 3D strain measurements on wood, at the microscale. [ABSTRACT FROM AUTHOR]

Mycorrhizal fungi are usually identified on the basis of the morphological characters shown by fruit bodies, spores, vegetative mycelia or symbiotic structures. The development of molecular techniques provides a valuable and alternative approach to identify mycorrhizal fungi, especially when it is difficult to gather a sufficient number of data on morphological features. Short arbitrary oligonucleotides were used as primers for the amplification of genomic DNA extracted from spores of arbuscular fungi. The RAPD fingerprints showed banding patterns which allowed us to distinguish between species and even isolates within Glomales. In order to identify mycorrhizal fungi during their symbiotic phase, a nonpolymorphic RAPD band identified as marker for some isolates of Glomus mosseae was purified from agarose gels and cloned in a bluescript vector. The fragment was sequenced and specific primers (PO-M3) were designed for the mycorrhizal fungus. They specifically and successfully amplified the DNA not only from G. mosseae spores, but also from roots of pea, clover, leek and onion plants when they were colonized by G. mosseae isolates. [ABSTRACT FROM AUTHOR]

2,4,5,2′,4′5′-Hexachlorobiphenyl (6-CB) - a polychlorinated biphenyl (PCB) congener resitant to metabolism in most species - has become a major residue in the biosphere including human adipose tissue. Its use as a model of unmetabolizable lipophilic compounds and as a tool in toxicokinetics in the last two decades is reviewed. This extremely water-insoluble compound is transported in plasma by albumin and lipoproteins. Binding to these plasma proteins appears to be important for uptake and release processes in different tissues. The redistribution kinetics of 6-CB as well as its pronounced adipose tissue storage and a very slow excretion with the faeces has been established in long-term animal studies. Excretion is strongly influenced by an increasing or diminishing adipose storage compartment size. Other minor pathways of elimination, e.g., via hair, become also important in the absence of metabolism and renal excretion. 6-CB has revealed the possibility of an almost quantitative transfer of the maternal body burden to the offspring via milk. The use of 6-CB in studies with tissue preparations in vitro is providing insight into transport mechanisms of uptake and release. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is an incurable neurodegenerative disorder in which neuroinflammation plays a critical function. Yet, little is known about the contribution of the adaptive immune response in AD. Here we used integrated analyses of multiple cohorts to identify peripheral and central adaptive immune changes in AD. Method: First, we performed mass cytometry of peripheral blood mononuclear cells and discovered an immune signature of AD consisting of increased numbers of CD8+ T effector memory CD45RA+ (TEMRA) cells. Result: In a second cohort, we found that CD8+ TEMRA cells were negatively associated with cognition. Furthermore, single cell RNA sequencing revealed their enhanced T cell receptor (TCR) signaling. Notably, by utilizing multiple single cell TCR sequencing strategies on a third cohort, we discovered clonally expanded CD8+ TEMRA cells in patient cerebrospinal fluid (CSF). Finally, we used machine learning, cloning, and peptide screens to demonstrate specificity of clonally expanded AD CSF TCRs to two separate Epstein‐Barr virus antigens. Conclusion: These results reveal a novel blood‐CSF adaptive immune response in AD and provide evidence of clonal, antigen‐experienced T cells patrolling the intrathecal space of brains affected by age‐related neurodegeneration. [ABSTRACT FROM AUTHOR]

Background: Aging is a predominant risk factor for numerous chronic diseases that limit healthspan. Mechanisms of aging are thus increasingly recognized as potential therapeutic targets. Blood from young mice reverses aspects of aging and disease across multiple tissues, which supports a hypothesis that age‐related molecular changes in blood could provide novel insights into age‐related disease biology. Method: We measured 2,925 plasma proteins from 4,263 young adults to nonagenarians (18‐95 years old) using an aptamer‐based platform. Result: We identified a proteomic clock that can be used to predict chronological age. Deviations from this plasma proteomic clock are correlated with changes in clinical and functional parameters in healthy subjects and AD patients from the Addneuromed cohort have an older proteomic age than their chronologic age (n=641). We are currently expanding this analysis to 881 healthy controls, MCI and AD subjects of the EMIF‐AD consortium. Thus, this panel of proteins can be used to assess the relative health of an individual and to measure healthspan, analogous to epigenetic clocks based on DNA methylation patterns. In addition, we describe a 46‐protein aging signature that is conserved in humans and mice, allowing deeper investigation of translational aging interventions in mice. Finally, we developed a novel bioinformatics approach, which uncovered marked non‐linear alterations in the human plasma proteome with age. Waves of changes in the proteome in the fourth, seventh, and eighth decades of life reflected distinct biological pathways and revealed differential associations with the genome and proteome of age‐related diseases and phenotypic traits. Conclusion: This new approach to the study of aging led to the identification of unexpected signatures and pathways, which might offer potential targets for age‐related diseases. Our results also have strong implications for the development of diagnostic and prognostic tests. Indeed, the undulating nature of the aging plasma proteome and its interactions with diseases has to be considered when developing proteomic signatures for diagnostic purposes. Such reliable tests are still urgently needed for Alzheimer's disease. [ABSTRACT FROM AUTHOR]