Benchmarking of a multi-biomarker low-volume panel for Alzheimer's Disease and related dementia research.

Alzheimer's Disease (AD) biomarker measurement is key to aid in the diagnosis and prognosis of the disease. In the research setting, participant recruitment and retention and optimization of sample use, is one of the main challenges that observational studies face. Thus, obtaining accurate established biomarker measurements for stratification and maximizing use of the precious samples is key. Accurate technologies are currently available for established biomarkers, mainly immunoassays and immunoprecipitation liquid chromatography-mass spectrometry (IP-MS), and some of them are already being used in clinical settings. Although some immunoassays- and IP-MS based platforms provide multiplexing for several different coding proteins there is not a current platform that can measure all the stablished and emerging biomarkers in one run. The NUcleic acid Linked Immuno-Sandwich Assay (NULISA™) is a mid-throughput platform with antibody-based measurements with a sequencing output that requires 15µL of sample volume to measure more than 100 analytes, including those typically assayed for AD. Here we benchmarked and compared the AD-relevant biomarkers including in the NULISA against validated assays, in both CSF and plasma. Overall, we have found that CSF measures of Aß42/40, NfL, GFAP, and p-tau217 are highly correlated and have similar predictive performance when measured by immunoassay, mass-spectrometry or NULISA. In plasma, p-tau217 shows a performance similar to that reported with other technologies when predicting amyloidosis. Other established and exploratory biomarkers (total tau, p-tau181, NRGN, YKL40, sTREM2, VILIP1 among other) show a wide range of correlation values depending on the fluid and the platform. Our results indicate that the multiplexed immunoassay platform produces reliable results for established biomarkers in CSF that are useful in research settings, with the advantage of measuring additional novel biomarkers using minimal sample volume.

An EBV-related CD4 TCR immunotherapy inhibits tumor growth in an HLA-DP5+ nasopharyngeal cancer mouse model.

Adoptive transfer of T cell receptor-engineered T cells (TCR-T) is a promising strategy for immunotherapy against solid tumors. However, the potential of CD4+ T cells in mediating tumor regression has been neglected. Nasopharyngeal cancer is consistently associated with EBV. Here, to evaluate the therapeutic potential of CD4 TCR-T in nasopharyngeal cancer, we screened for CD4 TCRs recognizing EBV nuclear antigen 1 (EBNA1) presented by HLA-DP5. Using mass spectrometry, we identified EBNA1567-581, a peptide naturally processed and presented by HLA-DP5. We isolated TCR135, a CD4 TCR with high functional avidity, that can function in both CD4+ and CD8+ T cells and recognizes HLA-DP5-restricted EBNA1567-581. TCR135-transduced T cells functioned in two ways: directly killing HLA-DP5+EBNA1+ tumor cells after recognizing EBNA1 presented by tumor cells and indirectly killing HLA-DP5-negative tumor cells after recognizing EBNA1 presented by antigen-presenting cells. TCR135-transduced T cells preferentially infiltrated into the tumor microenvironment and significantly inhibited tumor growth in xenograft nasopharyngeal tumor models. Additionally, we found that 62% of nasopharyngeal cancer patients showed 50%-100% expression of HLA-DP on tumor cells, indicating that nasopharyngeal cancer is well suited for CD4 TCR-T therapy. These findings suggest that TCR135 may provide a new strategy for EBV-related nasopharyngeal cancer immunotherapy in HLA-DP5+ patients.

The Impact of Diabetes Mellitus on Patient-Reported Outcomes of Chronic Low Back Pain with Modic Changes at One Year: A Prospective Cohort Study.

STUDY DESIGN: Prospective cohort study. OBJECTIVES: Diabetes mellitus (DM) is associated with unfavourable patient-reported outcomes after spine surgery. Chronic low back pain (CLBP) with Modic Changes (MCs) in the lumbar vertebrae, as observed on MRI, forms a specific subgroup. This study aims to investigate the potential influence of DM on CLBP with MCs. METHODS: This study involved 259 patients with CLBP accompanied MCs. We recorded the patient-reported outcomes (visual analogue scale (VAS), Oswestry Disability Index (ODI), and Roland-Morris Disability Questionnaire (RMDQ)) at baseline, 3, 6, and 12 months. Multivariable linear regression analyses were performed to determine predictors of patient-reported outcomes. RESULTS: 103 patients had DM. Patients with DM exhibited higher VAS (P < .05), ODI (P < .001), and RMDQ (P < .001) scores at 3, 6, and 12 months, while patients without DM experienced more significant improvements in the scores over time (P < .001). Patients with DM reported longer durations of physical exercise (P = .007). Additionally, patients without DM had a significantly higher patient satisfaction index (P < .001) and a lower prevalence of hypertension (P < .001). Notably, significant differences were observed in the distribution of MCs of lumbar vertebrae (P = .034) and Pfirrmann grades of intervertebral disc degeneration between two groups (P < .001). CONCLUSION: Patients with DM demonstrated poorer patient-reported outcomes compared to those without DM in 1-year. DM emerged as an independent predictor of adverse patient-reported outcomes. It can be utilized to enhance the management and treatment of CLBP in patients with MCs.

Emerging roles of RNA binding proteins in intervertebral disc degeneration and osteoarthritis.

The etiology of intervertebral disc degeneration (IDD) and osteoarthritis (OA) is complex and multifactorial. Both predisposing genes and environmental factors are involved in the pathogenesis of IDD and OA. Moreover, epigenetic modifications affect the development of IDD and OA. Dysregulated phenotypes of nucleus pulposus (NP) cells and OA chondrocytes, including apoptosis, extracellular matrix disruption, inflammation, and angiogenesis, are involved at all developmental stages of IDD and OA. RNA binding proteins (RBPs) have recently been recognized as essential post-transcriptional regulators of gene expression. RBPs are implicated in many cellular processes, such as proliferation, differentiation, and apoptosis. Recently, several RBPs have been reported to be associated with the pathogenesis of IDD and OA. This review briefly summarizes the current knowledge on the RNA-regulatory networks controlled by RBPs and their potential roles in the pathogenesis of IDD and OA. These initial findings support the idea that specific modulation of RBPs represents a promising approach for managing IDD and OA.

Etiology of White Matter Hyperintensities in Autosomal Dominant and Sporadic Alzheimer Disease.

Importance: Increased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors. Objective: To estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes. Design, Setting, and Participants: This cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers-the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer's Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019). Main Outcome and Measures: The main outcomes were the independent associations of neurodegeneration (decreases in gray matter volume), parenchymal amyloidosis (assessed by amyloid positron emission tomography), and vessel amyloidosis (evidenced by cerebral microbleeds [CMBs]) with cross-sectional and longitudinal WMH. Results: Data from 3960 MRI sessions among 1141 participants were included: 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years; 137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years; 274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years; 194 [61%] female). Longitudinal increases in WMH volume were greater in individuals with CMBs compared with those without (DIAN: t = 3.2 [P = .001]; ADNI: t = 2.7 [P = .008]), associated with longitudinal decreases in gray matter volume (DIAN: t = -3.1 [P = .002]; ADNI: t = -5.6 [P < .001]; HABS: t = -2.2 [P = .03]), greater in older individuals (DIAN: t = 6.8 [P < .001]; ADNI: t = 9.1 [P < .001]; HABS: t = 5.4 [P < .001]), and not associated with systemic vascular risk (DIAN: t = 0.7 [P = .40]; ADNI: t = 0.6 [P = .50]; HABS: t = 1.8 [P = .06]) in individuals with ADAD and LOAD after accounting for age, gray matter volume, CMB presence, and amyloid burden. In older adults without CMBs at baseline, greater WMH volume was associated with CMB development during longitudinal follow-up (Cox proportional hazards regression model hazard ratio, 2.63; 95% CI, 1.72-4.03; P < .001). Conclusions and Relevance: The findings suggest that increased WMH volume in AD is associated with neurodegeneration and parenchymal and vessel amyloidosis but not with elevated systemic vascular risk. Additionally, increased WMH volume may represent an early sign of vessel amyloidosis preceding the emergence of CMBs.

Comprehensive comparison of three techniques for the treatment of adjacent segment degeneration after lumbar fusion.

Purpose: Adjacent segment degeneration (ASD) following lumbar fusion is technically challenging for spine surgeons. Posterolateral open fusion surgery with pedicle screw fixation is an effective way to treat symptomatic ASD with favorable clinical outcomes; however, it is associated with an increased morbidity rate. Therefore, minimally invasive spine surgery is advocated. This study was designed to compare clinical outcomes among patients with symptomatic ASD who underwent percutaneous transforaminal endoscopic discectomy (PTED) with the transforaminal approach, posterior lumbar interbody fusion (PLIF) with cortical bone trajectory screw fixation (CBT-PLIF), and PLIF with traditional trajectory screw fixation (TT-PLIF). Methods: A retrospective study was conductedon 46 patients (26 men and 20 women; average age 60.8 ± 6.78 years) with symptomatic ASD. The patients were treated with three approaches. The operation time, incision length, time to return to work, complications, and the like were compared among three groups. Intervertebral disc (IVD) space height, angular motion, and vertebral slippage were obtained to assess spine biomechanical stability following surgery. The visual analog scale (VAS) score and Oswestry disability index were evaluated at preoperation and 1-week, 3-month, and the latest follow-ups. Clinical global outcomes were also estimated using modified MacNab criteria. Results: The operation time, incision length, intraoperative blood loss, and time to return to work for the PTED group were significantly decreased compared with those for the other two groups (P < 0.05). The radiological indicators in the CBT-PLIF group and TT-PLIF group had better biomechanical stability compared with those in the PTED groups at the latest follow-up (P < 0.05). The back pain VAS score in the CBT-PLIF group was significantly decreased compared with those in the other two groups at the latest follow-up (P < 0.05). The good-to-excellent rate was 82.35% in the PTED group, 88.89% in the CBT-PLIF group, and 85.00% in the TT-PLIF group. No serious complications were encountered. Two patients experienced dysesthesia in the PTED group; screw malposition was found in one patient in the CBT-PLIF group. One case with a dural matter tear was observed in the TT-PLIF group. Conclusion: All three approaches can treat patients with symptomatic ASD efficiently and safely. Functional recovery was more accelerated in the PTED group compared with the other approaches in the short term; CBT-PLIF and TT-PLIF can provide superior biomechanical stability to the lumbosacral spine following decompression compared with PTED; however, compared with TT-PLIF, CBT-PLIF can significantly reduce back pain caused by iatrogenic muscle injury and improve functional recovery. Therefore, superior clinical outcomes were achieved in the CBT-PLIF group compared with the PTED and TT-PLIF groups in the long term.

Large multi-ethnic genetic analyses of amyloid imaging identify new genes for Alzheimer disease.

Amyloid PET imaging has been crucial for detecting the accumulation of amyloid beta (Aß) deposits in the brain and to study Alzheimer's disease (AD). We performed a genome-wide association study on the largest collection of amyloid imaging data (N = 13,409) to date, across multiple ethnicities from multicenter cohorts to identify variants associated with brain amyloidosis and AD risk. We found a strong APOE signal on chr19q.13.32 (top SNP: APOE ɛ4; rs429358; ß = 0.35, SE = 0.01, P = 6.2 × 10-311, MAF = 0.19), driven by APOE ɛ4, and five additional novel associations (APOE ε2/rs7412; rs73052335/rs5117, rs1081105, rs438811, and rs4420638) independent of APOE ɛ4. APOE ɛ4 and ε2 showed race specific effect with stronger association in Non-Hispanic Whites, with the lowest association in Asians. Besides the APOE, we also identified three other genome-wide loci: ABCA7 (rs12151021/chr19p.13.3; ß = 0.07, SE = 0.01, P = 9.2 × 10-09, MAF = 0.32), CR1 (rs6656401/chr1q.32.2; ß = 0.1, SE = 0.02, P = 2.4 × 10-10, MAF = 0.18) and FERMT2 locus (rs117834516/chr14q.22.1; ß = 0.16, SE = 0.03, P = 1.1 × 10-09, MAF = 0.06) that all colocalized with AD risk. Sex-stratified analyses identified two novel female-specific signals on chr5p.14.1 (rs529007143, ß = 0.79, SE = 0.14, P = 1.4 × 10-08, MAF = 0.006, sex-interaction P = 9.8 × 10-07) and chr11p.15.2 (rs192346166, ß = 0.94, SE = 0.17, P = 3.7 × 10-08, MAF = 0.004, sex-interaction P = 1.3 × 10-03). We also demonstrated that the overall genetic architecture of brain amyloidosis overlaps with that of AD, Frontotemporal Dementia, stroke, and brain structure-related complex human traits. Overall, our results have important implications when estimating the individual risk to a population level, as race and sex will needed to be taken into account. This may affect participant selection for future clinical trials and therapies.

Anticancer and bone-enhanced nano-hydroxyapatite/gelatin/polylactic acid fibrous membrane with dual drug delivery and sequential release for osteosarcoma.

Surgical resection of osteosarcoma is always accompanied by residual metastasis of tumor cells and bone tissue defects. In this work, a novel kind of gelatin/polylactic acid (PLA) coaxial fiber membrane with a shell layer containing doxorubicin-loaded hydroxyapatite (DOX@nHAp) nanoparticles and a core layer containing Icariin (ICA) was developed for antitumor and bone enhancement at the defect site. Physical evaluation displayed that the composite membrane provided moderate hydrophilicity, enhanced tensile strength (Dry: 2-3 MPa, wet: 1-2 MPa) and elasticity (70-100 %), as well as increased specific surface area and pore volume (19.39 m2/g and 0.16 cm3/g). In SBF, DOX@nHAp in the fibers promoted biomineralization on the fiber surface. In in vitro evaluation, approximately 80 % of DOX had a short-term release during the first 8 days, followed by long-term release behavior of ICA for up to 40 days. CCK-8 results confirmed that the membrane could actively support MC3T3-E1 cells proliferation and was conductive to high alkaline phosphatase expression, while the viability of MG-63 cells was effectively inhibited to 50 %. Thus, the dual-loaded fibrous membrane with a coaxial structure and nHAp is a promising system for anticancer and defects reconstruction after osteosarcoma surgery.

Three-dimensional High-definition Exoscope in Minimally Invasive Transforaminal Lumbar Interbody Fusion: A Retrospective Cohort Study.

OBJECTIVES: The operative microscope (OM) has revolutionized the field of modern spine surgery, however, it remains limited by several drawbacks. Recently, the exoscope (EX) system has been designed to assistant spine surgery. It provides a three-dimensional (3D) high-definition (HD) operative experience and becomes an alternative to the OM. The aim of the study was to evaluate the clinical outcomes, advantages and limitations of EX-assisted minimally invasive transforaminal lumbar interbody fusion (EMIS-TLIF) and OM-assisted MIS-TLIF (OMIS-TLIF). METHODS: The clinical outcomes were assessed in 47 patients with lumbar degenerative diseases (LDD) who underwent MIS-TLIF assisted with the OM or EX between January 2019 and September 2020. A total of 22 were treated with EMIS-TLIF, and 25 received OMIS-TLIF. Perioperative parameters (including sex, age, number of fusion levels and body mass index), perioperative parameters (operation time, intraoperative blood loss, postoperative drainage, postoperative hospitalization stay, and duration of follow-up), visual analogue scale (VAS) of back pain, VAS of leg pain, Oswestry disability index (ODI) scores and clinical outcomes were assessed and compared. Image quality, handling of equipment, ergonomics, 3D glasses and educational usefulness were scored according to a questionnaire. RESULTS: Operation time in the OMIS-TLIF group (121.92 ± 16.92 min) was significantly increased compared with that in the EMIS-TLIF group (111.00 ± 19.87 min) (P < 0.05). The VAS of the back pain and ODI scores in the EMIS-TLIF group were significantly lower compared with the OMIS-TLIF group at 1 week postoperatively (P < 0.05). The good-excellent outcomes rate was 90.91% in the EMIS-TLIF group and 88.00% in the OMIS-TLIF group, and there was no significant difference. A total of 44 visits completed the questionnaire. The results of the questionnaire showed that the EX has exhibited advantages regarding handing of equipment, ergonomics and educational usefulness, and comparable image quality as compared with the OM, however, operating surgeons complained uncomfortable sensation when wearing 3D glasses. CONCLUSIONS: The EMIS-TLIF was a safe and effective procedure in the management of LDD as compared with the OMIS-LIF. Meanwhile, EMIS-TLIF might resulted in a short operation time.

Percutaneous Uniplanar Pedicle Screw-Rod System with Injured Vertebra Fixation for Thoracolumbar Burst Fracture and Technique Notes.

OBJECTIVE: To evaluate the efficacy of percutaneous uniplanar pedicle screw (PUPS) combined with injured vertebra fixation for treating thoracolumbar burst fracture and provide technique notes. STUDY DESIGN: A descriptive study. PLACE AND DURATION OF STUDY: Department of Orthopaedics, General Hospital of Central Theater Command, Wuhan, China, from February 2019 to December 2021. METHODOLOGY: Patients who had undergone PUPS internal fixation for thoracolumbar burst fracture were followed up for more than 12 months in the General Hospital of Central Theater Command, Wuhan, China. The operation time, intraoperative blood loss, and hospital stay were recorded. Visual analysis scale (VAS), score of low back pain, ODI (oswestry disability endex), anterior vertebral height (AVH), Cobb angle were documented before and after the operation, Also, the complications and postoperative tail shank angles (TSA) were documented. RESULTS: All 23 patients were followed up for more than 12 months without re-fracture, loosening or breakage of the screw and rod. The operation time, intraoperative blood loss, and hospital stay were 51.34±8.30 minutes, 75.67±16.55 minutes, and 9.86±1.96 days respectively. VAS and ODI scores after the operation were significantly lower than before (p <0.05). The AVH and Cobb angle after operation were significantly better as compared with those before the operation (p <0.05), but no statistically significant difference was found in those two values at 1 week, 3 months, and 12 months after operation (p >0.05). No statistically significant difference was found in TSA after the operation (p >0.05). CONCLUSIONS: PUPS combined with injured vertebra fixation reveals satisfactory efficacy for thoracolumbar burst fracture with well reduction of the fracture, the AVH, and Cobb angle maintenance. KEY WORDS: Percutaneous uniplanar pedicle screw, Minimally invasive surgery, Thoracolumbar vertebral body fracture, Injured vertebra fixation.

Autosomal dominant and sporadic late onset Alzheimer's disease share a common in vivo pathophysiology.

The extent to which the pathophysiology of autosomal dominant Alzheimer's disease corresponds to the pathophysiology of 'sporadic' late onset Alzheimer's disease is unknown, thus limiting the extrapolation of study findings and clinical trial results in autosomal dominant Alzheimer's disease to late onset Alzheimer's disease. We compared brain MRI and amyloid PET data, as well as CSF concentrations of amyloid-ß42, amyloid-ß40, tau and tau phosphorylated at position 181, in 292 carriers of pathogenic variants for Alzheimer's disease from the Dominantly Inherited Alzheimer Network, with corresponding data from 559 participants from the Alzheimer's Disease Neuroimaging Initiative. Imaging data and CSF samples were reprocessed as appropriate to guarantee uniform pipelines and assays. Data analyses yielded rates of change before and after symptomatic onset of Alzheimer's disease, allowing the alignment of the ∼30-year age difference between the cohorts on a clinically meaningful anchor point, namely the participant age at symptomatic onset. Biomarker profiles were similar for both autosomal dominant Alzheimer's disease and late onset Alzheimer's disease. Both groups demonstrated accelerated rates of decline in cognitive performance and in regional brain volume loss after symptomatic onset. Although amyloid burden accumulation as determined by PET was greater after symptomatic onset in autosomal dominant Alzheimer's disease than in late onset Alzheimer's disease participants, CSF assays of amyloid-ß42, amyloid-ß40, tau and p-tau181 were largely overlapping in both groups. Rates of change in cognitive performance and hippocampal volume loss after symptomatic onset were more aggressive for autosomal dominant Alzheimer's disease participants. These findings suggest a similar pathophysiology of autosomal dominant Alzheimer's disease and late onset Alzheimer's disease, supporting a shared pathobiological construct.

Effect of Race on Prediction of Brain Amyloidosis by Plasma Aß42/Aß40, Phosphorylated Tau, and Neurofilament Light.

BACKGROUND AND OBJECTIVES: To evaluate whether plasma biomarkers of amyloid (Aß42/Aß40), tau (p-tau181 and p-tau231), and neuroaxonal injury (neurofilament light chain [NfL]) detect brain amyloidosis consistently across racial groups. METHODS: Individuals enrolled in studies of memory and aging who self-identified as African American (AA) were matched 1:1 to self-identified non-Hispanic White (NHW) individuals by age, APOE ε4 carrier status, and cognitive status. Each participant underwent blood and CSF collection, and amyloid PET was performed in 103 participants (68%). Plasma Aß42/Aß40 was measured by a high-performance immunoprecipitation-mass spectrometry assay. Plasma p-tau181, p-tau231, and NfL were measured by Simoa immunoassays. CSF Aß42/Aß40 and amyloid PET status were used as primary and secondary reference standards of brain amyloidosis, respectively. RESULTS: There were 76 matched pairs of AA and NHW participants (n = 152 total). For both AA and NHW groups, the median age was 68.4 years, 42% were APOE ε4 carriers, and 91% were cognitively normal. AA were less likely than NHW participants to have brain amyloidosis by CSF Aß42/Aß40 (22% vs 43% positive; p = 0.003). The receiver operating characteristic area under the curve of CSF Aß42/Aß40 status with the plasma biomarkers was as follows: Aß42/Aß40, 0.86 (95% CI 0.79-0.92); p-tau181, 0.76 (0.68-0.84); p-tau231, 0.69 (0.60-0.78); and NfL, 0.64 (0.55-0.73). In models predicting CSF Aß42/Aß40 status with plasma Aß42/Aß40 that included covariates (age, sex, APOE ε4 carrier status, race, and cognitive status), race did not affect the probability of CSF Aß42/Aß40 positivity. In similar models based on plasma p-tau181, p-tau231, or NfL, AA participants had a lower probability of CSF Aß42/Aß40 positivity (odds ratio 0.31 [95% CI 0.13-0.73], 0.30 [0.13-0.71], and 0.27 [0.12-0.64], respectively). Models of amyloid PET status yielded similar findings. DISCUSSION: Models predicting brain amyloidosis using a high-performance plasma Aß42/Aß40 assay may provide an accurate and consistent measure of brain amyloidosis across AA and NHW groups, but models based on plasma p-tau181, p-tau231, and NfL may perform inconsistently and could result in disproportionate misdiagnosis of AA individuals.

Sex-Specific Patterns of Body Mass Index Relationship with White Matter Connectivity.

BACKGROUND: Obesity is an increasingly recognized modifiable risk factor for Alzheimer's disease (AD). Increased body mass index (BMI) is related to distinct changes in white matter (WM) fiber density and connectivity. OBJECTIVE: We investigated whether sex differentially affects the relationship between BMI and WM structural connectivity. METHODS: A cross-sectional sample of 231 cognitively normal participants were enrolled from the Knight Alzheimer Disease Research Center. Connectome analyses were done with diffusion data reconstructed using q-space diffeomorphic reconstruction to obtain the spin distribution function and tracts were selected using a deterministic fiber tracking algorithm. RESULTS: We identified an inverse relationship between higher BMI and lower connectivity in the associational fibers of the temporal lobe in overweight and obese men. Normal to overweight women showed a significant positive association between BMI and connectivity in a wide array of WM fibers, an association that reversed in obese and morbidly obese women. Interaction analyses revealed that with increasing BMI, women showed higher WM connectivity in the bilateral frontoparietal and parahippocampal parts of the cingulum, while men showed lower connectivity in right sided corticostriatal and corticopontine tracts. Subgroup analyses demonstrated comparable results in participants with and without positron emission tomography or cerebrospinal fluid evidence of brain amyloidosis, indicating that the relationship between BMI and structural connectivity in men and women is independent of AD biomarker status. CONCLUSION: BMI influences structural connectivity of WM differently in men and women across BMI categories and this relationship does not vary as a function of preclinical AD.

A real-time 3D electromagnetic navigation system for percutaneous transforaminal endoscopic discectomy in patients with lumbar disc herniation: a retrospective study.

BACKGROUND: In this study, we present a novel electromagnetic navigation (EMN) system for percutaneous transforaminal endoscopic discectomy (PTED) procedure. The objective of this study was to investigate the safety and effectiveness of the PTED with the assistance of the EMN system and compare it with the conventional PTED with the assistance of fluoroscopic guidance (C-arm). METHODS: The clinical data of 79 patients (32 in EMN group and 47 in C-arm group) undergoing PTED for lumbar disc herniation (LDH) from January to September of 2019 were analyzed retrospectively. The radiation time, puncture time, operation time, visual analog scale (VAS), Oswestry disability index (ODI), modified MacNab criteria, and radiological parameters were recorded in both groups. RESULTS: Radiation time, puncture time, and operation time were significantly reduced in the EMN group compared with the C-arm group (P < 0.05). Compared with the C-arm group, a steeper learning curve was observed in the EMN group. There were no significant differences between the two groups regarding VAS and ODI scores at different time points (P > 0.05). The satisfaction rates of the EMN and C-arm groups were 90.63 and 87.23%, respectively, but no significant difference was found between the two groups (P > 0.05). There was no significant difference regarding translation and angular motion between the two groups at preoperation and postoperation (P > 0.05). CONCLUSIONS: The EMN system can be applied to facilitate the PETD procedure. It can significantly reduce the intraoperative radiation time, puncture time, and operation time, and reshape the learning curve of PTED. Due to limitations of a retrospective study, results may need validation with larger prospective randomized clinical trials.

A real-time 3D electromagnetic navigation system for percutaneous pedicle screw fixation in traumatic thoraco-lumbar fractures: implications for efficiency, fluoroscopic time, and accuracy compared with those of conventional fluoroscopic guidance.

PURPOSE: Navigation is becoming more useful in percutaneous pedicle screw fixation (PPSF). The aim of this study was to compare the efficiency, fluoroscopic time, accuracy, and clinical outcomes of PPSF with a novel electromagnetic navigation (EMN) system for thoraco-lumbar (TL) fractures with those of PPSF with conventional C-arm fluoroscopic (CF) guidance. METHODS: A retrospective study was conducted. A total of 162 screws were implanted in 29 patients with the assistance of the EMN system (EMN group), and 220 screws were inserted in 40 patients by using CF guidance (CF group). The duration of surgery, placement time per screw, fluoroscopic time per screw, accuracy of pedicle screw placement, and clinical outcomes were compared between the two groups. RESULTS: The duration of surgery and placement time per screw in the EMN group were significantly lower than those in the CF group (P < 0.05). The fluoroscopic time per screw in the CF group was significantly longer than that in the EMN group (P < 0.05). The learning curve of PPSF in the EMN group was steeper than that in the CF group. The accuracy of pedicle screw placement in the EMN group was more precise than that in the CF group (P < 0.05). The VAS scores in the EMN group were significantly lower than those in the CF group at one-week postoperatively (P < 0.05). CONCLUSION: Compared with PPSF by using conventional fluoroscopic guidance, PPSF with the aid of the EMN system can increase the efficiency and accuracy of pedicle screw placement and reduce the fluoroscopic time.

Predicting Symptom Onset in Sporadic Alzheimer Disease With Amyloid PET.

BACKGROUND AND OBJECTIVES: To predict when cognitively normal individuals with brain amyloidosis will develop symptoms of Alzheimer disease (AD). METHODS: Brain amyloid burden was measured by amyloid PET with Pittsburgh compound B. The mean cortical standardized uptake value ratio (SUVR) was transformed into a timescale with the use of longitudinal data. RESULTS: Amyloid accumulation was evaluated in 236 individuals who underwent >1 amyloid PET scan. The average age was 66.5 ± 9.2 years, and 12 individuals (5%) had cognitive impairment at their baseline amyloid PET scan. A tipping point in amyloid accumulation was identified at a low level of amyloid burden (SUVR 1.2), after which nearly all individuals accumulated amyloid at a relatively consistent rate until reaching a high level of amyloid burden (SUVR 3.0). The average time between levels of amyloid burden was used to estimate the age at which an individual reached SUVR 1.2. Longitudinal clinical diagnoses for 180 individuals were aligned by the estimated age at SUVR 1.2. In the 22 individuals who progressed from cognitively normal to a typical AD dementia syndrome, the estimated age at which an individual reached SUVR 1.2 predicted the age at symptom onset (R 2 = 0.54, p < 0.0001, root mean square error [RMSE] 4.5 years); the model was more accurate after exclusion of 3 likely misdiagnoses (R 2 = 0.84, p < 0.0001, RMSE 2.8 years). CONCLUSION: The age at symptom onset in sporadic AD is strongly correlated with the age at which an individual reaches a tipping point in amyloid accumulation.

Three-dimensional high-definition exoscope (Kestrel View II) in anterior cervical discectomy and fusion: a valid alternative to operative microscope-assisted surgery.

BACKGROUND: Operative microscope (OM) has greatly advanced modern spine surgery, but remains limited by several drawbacks. Therefore, a three-dimensional (3D) high-definition (HD) exoscope (EX) (Kestrel View II, Mataka Kohli, Japan) system has been developed and used as an alternative to the OM. The aim of this study was to assess and compare the perioperative data and clinical outcomes of anterior cervical discectomy and fusion (ACDF) procedure with either an EX or OM. METHODS: Forty-eight patients with cervical spondylotic myelopathy (CSM) underwent ACDF assisted by the EX or OM between January 2019 and December 2019. We collected and compared data on operative time, intraoperative bleeding, postoperative hospitalization stay, complications, and clinical outcomes between the two groups. The clinical outcomes were evaluated by using visual analogue scale (VAS) scores, Japanese Orthopedic Association (JOA) scores, the recovery rate of JOA scores, and Odom criteria. RESULTS: The operative time in the EX group was significantly shorter than that in the OM group (P < 0.05). The VAS and JOA scores were significantly improved in both groups after surgery (P < 0.05). In addition, the VAS scores in the EX group were significantly lower than those in the OM group at 1 week postoperatively (P < 0.05). The good-to-excellent outcome rates were 90.48 and 88.89% in the EX group and OM group, respectively, whereas the complication occurrence rates of the EX group and OM group were 4.76 and 11.11%, respectively. CONCLUSIONS: EX-assisted and OM-assisted ACDF resulted in similar clinical outcomes for CSM, while EX-assisted surgery may be related to a short operative time and fewer complications.

Plasma Amyloid-Beta Levels in a Pre-Symptomatic Dutch-Type Hereditary Cerebral Amyloid Angiopathy Pedigree: A Cross-Sectional and Longitudinal Investigation.

Plasma amyloid-beta (Aß) has long been investigated as a blood biomarker candidate for Cerebral Amyloid Angiopathy (CAA), however previous findings have been inconsistent which could be attributed to the use of less sensitive assays. This study investigates plasma Aß alterations between pre-symptomatic Dutch-type hereditary CAA (D-CAA) mutation-carriers (MC) and non-carriers (NC) using two Aß measurement platforms. Seventeen pre-symptomatic members of a D-CAA pedigree were assembled and followed up 3-4 years later (NC = 8; MC = 9). Plasma Aß1-40 and Aß1-42 were cross-sectionally and longitudinally analysed at baseline (T1) and follow-up (T2) and were found to be lower in MCs compared to NCs, cross-sectionally after adjusting for covariates, at both T1(Aß1-40: p = 0.001; Aß1-42: p = 0.0004) and T2 (Aß1-40: p = 0.001; Aß1-42: p = 0.016) employing the Single Molecule Array (Simoa) platform, however no significant differences were observed using the xMAP platform. Further, pairwise longitudinal analyses of plasma Aß1-40 revealed decreased levels in MCs using data from the Simoa platform (p = 0.041) and pairwise longitudinal analyses of plasma Aß1-42 revealed decreased levels in MCs using data from the xMAP platform (p = 0.041). Findings from the Simoa platform suggest that plasma Aß may add value to a panel of biomarkers for the diagnosis of pre-symptomatic CAA, however, further validation studies in larger sample sets are required.

Presymptomatic Dutch-Type Hereditary Cerebral Amyloid Angiopathy-Related Blood Metabolite Alterations.

BACKGROUND: Cerebral amyloid angiopathy (CAA) is one of the major causes of intracerebral hemorrhage and vascular dementia in older adults. Early diagnosis will provide clinicians with an opportunity to intervene early with suitable strategies, highlighting the importance of pre-symptomatic CAA biomarkers. OBJECTIVE: Investigation of pre-symptomatic CAA related blood metabolite alterations in Dutch-type hereditary CAA mutation carriers (D-CAA MCs). METHODS: Plasma metabolites were measured using mass-spectrometry (AbsoluteIDQ® p400 HR kit) and were compared between pre-symptomatic D-CAA MCs (n = 9) and non-carriers (D-CAA NCs, n = 8) from the same pedigree. Metabolites that survived correction for multiple comparisons were further compared between D-CAA MCs and additional control groups (cognitively unimpaired adults). RESULTS: 275 metabolites were measured in the plasma, 22 of which were observed to be significantly lower in theD-CAAMCs compared to D-CAA NCs, following adjustment for potential confounding factors age, sex, and APOE ε4 (p < 00.05). After adjusting for multiple comparisons, only spermidine remained significantly lower in theD-CAAMCscompared to theD-CAA NCs (p  < 0.00018). Plasma spermidine was also significantly lower in D-CAA MCs compared to the cognitively unimpaired young adult and older adult groups (p < 0.01). Spermidinewas also observed to correlate with CSF Aß40 (rs = 0.621, p = 0.024), CSF Aß42 (rs = 0.714, p = 0.006), and brain Aß load (rs = -0.527, p = 0.030). CONCLUSION: The current study provides pilot data on D-CAA linked metabolite signals, that also associated with Aß neuropathology and are involved in several biological pathways that have previously been linked to neurodegeneration and dementia.