Timing of Biomarker Changes in Sporadic Alzheimer's Disease in Estimated Years from Symptom Onset.

OBJECTIVE: A clock relating amyloid positron emission tomography (PET) to time was used to estimate the timing of biomarker changes in sporadic Alzheimer disease (AD). METHODS: Research participants were included who underwent cerebrospinal fluid (CSF) collection within 2 years of amyloid PET. The ages at amyloid onset and AD symptom onset were estimated for each individual. The timing of change for plasma, CSF, imaging, and cognitive measures was calculated by comparing restricted cubic splines of cross-sectional data from the amyloid PET positive and negative groups. RESULTS: The amyloid PET positive sub-cohort (n = 118) had an average age of 70.4 ± 7.4 years (mean ± standard deviation) and 16% were cognitively impaired. The amyloid PET negative sub-cohort (n = 277) included individuals with low levels of amyloid plaque burden at all scans who were cognitively unimpaired at the time of the scans. Biomarker changes were detected 15-19 years before estimated symptom onset for CSF Aß42/Aß40, plasma Aß42/Aß40, CSF pT217/T217, and amyloid PET; 12-14 years before estimated symptom onset for plasma pT217/T217, CSF neurogranin, CSF SNAP-25, CSF sTREM2, plasma GFAP, and plasma NfL; and 7-9 years before estimated symptom onset for CSF pT205/T205, CSF YKL-40, hippocampal volumes, and cognitive measures. INTERPRETATION: The use of an amyloid clock enabled visualization and analysis of biomarker changes as a function of estimated years from symptom onset in sporadic AD. This study demonstrates that estimated years from symptom onset based on an amyloid clock can be used as a continuous staging measure for sporadic AD and aligns with findings in autosomal dominant AD. ANN NEUROL 2024;95:951-965.

Suvorexant Acutely Decreases Tau Phosphorylation and Aß in the Human CNS.

OBJECTIVE: In Alzheimer's disease, hyperphosphorylated tau is associated with formation of insoluble paired helical filaments that aggregate as neurofibrillary tau tangles and are associated with neuronal loss and cognitive symptoms. Dual orexin receptor antagonists decrease soluble amyloid-ß levels and amyloid plaques in mouse models overexpressing amyloid-ß, but have not been reported to affect tau phosphorylation. In this randomized controlled trial, we tested the acute effect of suvorexant, a dual orexin receptor antagonist, on amyloid-ß, tau, and phospho-tau. METHODS: Thirty-eight cognitively unimpaired participants aged 45 to 65 years were randomized to placebo (N = 13), suvorexant 10 mg (N = 13), and suvorexant 20 mg (N = 12). Six milliliters of cerebrospinal fluid were collected via an indwelling lumbar catheter every 2 hours for 36 hours starting at 20:00. Participants received placebo or suvorexant at 21:00. All samples were processed and measured for multiple forms of amyloid-ß, tau, and phospho-tau via immunoprecipitation and liquid chromatography-mass spectrometry. RESULTS: The ratio of phosphorylated-tau-threonine-181 to unphosphorylated-tau-threonine-181, a measure of phosphorylation at this tau phosphosite, decreased ~10% to 15% in participants treated with suvorexant 20 mg compared to placebo. However, phosphorylation at tau-serine-202 and tau-threonine-217 were not decreased by suvorexant. Suvorexant decreased amyloid-ß ~10% to 20% compared to placebo starting 5 hours after drug administration. INTERPRETATION: In this study, suvorexant acutely decreased tau phosphorylation and amyloid-ß concentrations in the central nervous system. Suvorexant is approved by the US Food and Drug Administration to treatment insomnia and may have potential as a repurposed drug for the prevention of Alzheimer's disease, however, future studies with chronic treatment are needed. ANN NEUROL 2023;94:27-40.

Change in Cerebrospinal Fluid Tau Microtubule Binding Region Detects Symptom Onset, Cognitive Decline, Tangles, and Atrophy in Dominantly Inherited Alzheimer's Disease.

OBJECTIVE: Identifying cerebrospinal fluid measures of the microtubule binding region of tau (MTBR-tau) species that reflect tau aggregation could provide fluid biomarkers that track Alzheimer's disease related neurofibrillary tau pathological changes. We examined the cerebrospinal fluid (CSF) MTBR-tau species in dominantly inherited Alzheimer's disease (DIAD) mutation carriers to assess the association with Alzheimer's disease (AD) biomarkers and clinical symptoms. METHODS: Cross-sectional and longitudinal CSF from 229 DIAD mutation carriers and 130 mutation non-carriers had sequential characterization of N-terminal/mid-domain phosphorylated tau (p-tau) followed by MTBR-tau species and tau positron emission tomography (tau PET), other soluble tau and amyloid biomarkers, comprehensive clinical and cognitive assessments, and brain magnetic resonance imaging of atrophy. RESULTS: CSF MTBR-tau species located within the putative "border" region and one species corresponding to the "core" region of aggregates in neurofibrillary tangles (NFTs) increased during the presymptomatic stage and decreased during the symptomatic stage. The "border" MTBR-tau species were associated with amyloid pathology and CSF p-tau; whereas the "core" MTBR-tau species were associated stronger with tau PET and CSF measures of neurodegeneration. The ratio of the border to the core species provided a continuous measure of increasing amounts that tracked clinical progression and NFTs. INTERPRETATION: Changes in CSF soluble MTBR-tau species preceded the onset of dementia, tau tangle increase, and atrophy in DIAD. The ratio of 4R-specific MTBR-tau (border) to the NFT (core) MTBR-tau species corresponds to the pathology of NFTs in DIAD and change with disease progression. The dynamics between different MTBR-tau species in the CSF may serve as a marker of tau-related disease progression and target engagement of anti-tau therapeutics. ANN NEUROL 2023;93:1158-1172.

Head-to-head comparison of 10 plasma phospho-tau assays in prodromal Alzheimer's disease.

Plasma phospho-tau (p-tau) species have emerged as the most promising blood-based biomarkers of Alzheimer's disease. Here, we performed a head-to-head comparison of p-tau181, p-tau217 and p-tau231 measured using 10 assays to detect abnormal brain amyloid-ß (Aß) status and predict future progression to Alzheimer's dementia. The study included 135 patients with baseline diagnosis of mild cognitive impairment (mean age 72.4 years; 60.7% women) who were followed for an average of 4.9 years. Seventy-one participants had abnormal Aß-status (i.e. abnormal CSF Aß42/40) at baseline; and 45 of these Aß-positive participants progressed to Alzheimer's dementia during follow-up. P-tau concentrations were determined in baseline plasma and CSF. P-tau217 and p-tau181 were both measured using immunoassays developed by Lilly Research Laboratories (Lilly) and mass spectrometry assays developed at Washington University (WashU). P-tau217 was also analysed using Simoa immunoassay developed by Janssen Research and Development (Janss). P-tau181 was measured using Simoa immunoassay from ADxNeurosciences (ADx), Lumipulse immunoassay from Fujirebio (Fuji) and Splex immunoassay from Mesoscale Discovery (Splex). Both p-tau181 and p-tau231 were quantified using Simoa immunoassay developed at the University of Gothenburg (UGOT). We found that the mass spectrometry-based p-tau217 (p-tau217WashU) exhibited significantly better performance than all other plasma p-tau biomarkers when detecting abnormal Aß status [area under curve (AUC) = 0.947; Pdiff < 0.015] or progression to Alzheimer's dementia (AUC = 0.932; Pdiff < 0.027). Among immunoassays, p-tau217Lilly had the highest AUCs (0.886-0.889), which was not significantly different from the AUCs of p-tau217Janss, p-tau181ADx and p-tau181WashU (AUCrange 0.835-0.872; Pdiff > 0.09), but higher compared with AUC of p-tau231UGOT, p-tau181Lilly, p-tau181UGOT, p-tau181Fuji and p-tau181Splex (AUCrange 0.642-0.813; Pdiff ≤ 0.029). Correlations between plasma and CSF values were strongest for p-tau217WashU (R = 0.891) followed by p-tau217Lilly (R = 0.755; Pdiff = 0.003 versus p-tau217WashU) and weak to moderate for the rest of the p-tau biomarkers (Rrange 0.320-0.669). In conclusion, our findings suggest that among all tested plasma p-tau assays, mass spectrometry-based measures of p-tau217 perform best when identifying mild cognitive impairment patients with abnormal brain Aß or those who will subsequently progress to Alzheimer's dementia. Several other assays (p-tau217Lilly, p-tau217Janss, p-tau181ADx and p-tau181WashU) showed relatively high and consistent accuracy across both outcomes. The results further indicate that the highest performing assays have performance metrics that rival the gold standards of Aß-PET and CSF. If further validated, our findings will have significant impacts in diagnosis, screening and treatment for Alzheimer's dementia in the future.

Medial versus lateral transcondylar screw placement for canine humeral intracondylar fissures: A randomized clinical trial.

OBJECTIVE: To determine the influence of screw direction on complications following transcondylar screw placement for the treatment of canine humeral intracondylar fissures (HIFs). STUDY DESIGN: Equivalence, parallel group, randomized clinical trial. SAMPLE POPULATION: Fifty-two client owned dogs (73 elbows). METHODS: Transcondylar screw placement was randomized to either a medial or lateral approach. The primary outcome was the incidence of postoperative complications. RESULTS: There were 37 cases in the lateral approach group and 36 cases in the medial approach group. There was a significantly greater proportion of postoperative complications following placement of transcondylar screws from a lateral to medial direction (p = .001). There were seven cases with complications (19%) in the medial approach group versus 23 cases with complications (62%) in the lateral approach group. The majority of complications were seromas (n = 13) and surgical site infections (n = 16) with 4 complications requiring further surgery. Implant area moment of inertia (AMI), normalized to bodyweight, was lower in dogs with a major complication (p = .037). CONCLUSION: Transcondylar screws placed from lateral to medial for canine HIFs had a greater proportion of postoperative complications in this randomized clinical trial design. Implants with a lower AMI, relative to bodyweight, were more likely to lead to major complications. CLINICAL SIGNIFICANCE: We recommend placing transcondylar screws from medial to lateral for canine HIFs to reduce the risk of postoperative complications. Relatively small diameter implants had an increased risk of major complications.

Acute sleep loss decreases CSF-to-blood clearance of Alzheimer's disease biomarkers.

INTRODUCTION: Sleep deprivation increases cerebrospinal fluid (CSF) amyloid beta (Aß) and tau levels; however, sleep's effect on Aß and tau in plasma is unknown. METHODS: In a cross-over design, CSF Aß and tau concentrations were measured in five cognitively normal individuals who had blood and CSF collected every 2 hours for 36 hours during sleep-deprived and normal sleep control conditions. RESULTS: Aß40, Aß42, unphosphorylated tau threonine181 (T181), unphosphorylated tau threonine-217 (T217), and phosphorylated T181 (pT181) concentrations increased ∼35% to 55% in CSF and decreased ∼5% to 15% in plasma during sleep deprivation. CSF/plasma ratios of all Alzheimer's disease (AD) biomarkers increased during sleep deprivation while the CSF/plasma albumin ratio, a measure of blood-CSF barrier permeability, decreased. CSF and plasma Aß42/40, pT181/T181, and pT181/Aß42 ratios were stable longitudinally in both groups. DISCUSSION: These findings show that sleep loss alters some plasma AD biomarkers by lowering brain clearance mechanisms and needs to be taken into account when interpreting individual plasma AD biomarkers but not ratios.

CSF Tau phosphorylation at Thr205 is associated with loss of white matter integrity in autosomal dominant Alzheimer disease.

BACKGROUND: Hyperphosphorylation of tau leads to conformational changes that destabilize microtubules and hinder axonal transport in Alzheimer's disease (AD). However, it remains unknown whether white matter (WM) decline due to AD is associated with specific Tau phosphorylation site(s). METHODS: In autosomal dominant AD (ADAD) mutation carriers (MC) and non-carriers (NC) we compared cerebrospinal fluid (CSF) phosphorylation at tau sites (pT217, pT181, pS202, and pT205) and total tau with WM measures, as derived from diffusion tensor imaging (DTI), and cognition. A WM composite metric, derived from a principal component analysis, was used to identify spatial decline seen in ADAD. RESULTS: The WM composite explained over 70% of the variance in MC. WM regions that strongly contributed to the spatial topography were located in callosal and cingulate regions. Loss of integrity within the WM composite was strongly associated with AD progression in MC as defined by the estimated years to onset (EYO) and cognitive decline. A linear regression demonstrated that amyloid, gray matter atrophy and phosphorylation at CSF tau site pT205 each uniquely explained a reduction in the WM composite within MC that was independent of vascular changes (white matter hyperintensities), and age. Hyperphosphorylation of CSF tau at other sites and total tau did not significantly predict WM composite loss. CONCLUSIONS: We identified a site-specific relationship between CSF phosphorylated tau and WM decline within MC. The presence of both amyloid deposition and Tau phosphorylation at pT205 were associated with WM composite loss. These findings highlight a primary AD-specific mechanism for WM dysfunction that is tightly coupled to symptom manifestation and cognitive decline.

CSF tau microtubule binding region identifies tau tangle and clinical stages of Alzheimer's disease.

Tau is a microtubule associated protein in the brain that aggregates in Alzheimer's disease to form pathological tangles and neurites. Insoluble tau aggregates composed of the microtubule binding region (MTBR) of tau are highly associated with the cognitive and clinical symptoms of Alzheimer's disease. In contrast, levels of soluble forms of tau, such as CSF total tau and phosphorylated tau-181 and tau-217, increase prior to tau aggregation in Alzheimer's disease, but these biomarkers do not measure the MTBR of tau. Thus, how CSF MTBR-tau is altered in Alzheimer's disease remains unclear. In this study, we used sequential immunoprecipitation and chemical extraction methods followed by mass spectrometry to analyse MTBR-tau species in Alzheimer's disease and control CSF. We quantified MTBR-tau-specific regions in the CSF and identified that species containing the region beginning at residue 243 were the most highly correlated with tau PET and cognitive measures. This finding suggests that CSF level of tau species containing the upstream region of MTBR may reflect changes in tau pathology that occur in Alzheimer's disease and could serve as biomarkers to stage Alzheimer's disease and track the development of tau-directed therapeutics.

Sleep Deprivation Affects Tau Phosphorylation in Human Cerebrospinal Fluid.

Tau hyperphosphorylation is an early step in tau-mediated neurodegeneration and is associated with intracellular aggregation of tau as neurofibrillary tangles, neuronal and synaptic loss, and eventual cognitive dysfunction in Alzheimer disease. Sleep loss increases the cerebrospinal fluid concentration of amyloid-ß and tau. Using mass spectrometry, we measured tau and phosphorylated tau concentrations in serial samples of cerebrospinal fluid collected from participants who were sleep-deprived, treated with sodium oxybate, or allowed to sleep normally. We found that sleep loss affected phosphorylated tau differently depending on the modified site. These findings suggest a mechanism for sleep loss to increase risk of Alzheimer disease. ANN NEUROL 2020;87:700-709.

Neurofilaments: neurobiological foundations for biomarker applications.

Interest in neurofilaments has risen sharply in recent years with recognition of their potential as biomarkers of brain injury or neurodegeneration in CSF and blood. This is in the context of a growing appreciation for the complexity of the neurobiology of neurofilaments, new recognition of specialized roles for neurofilaments in synapses and a developing understanding of mechanisms responsible for their turnover. Here we will review the neurobiology of neurofilament proteins, describing current understanding of their structure and function, including recently discovered evidence for their roles in synapses. We will explore emerging understanding of the mechanisms of neurofilament degradation and clearance and review new methods for future elucidation of the kinetics of their turnover in humans. Primary roles of neurofilaments in the pathogenesis of human diseases will be described. With this background, we then will review critically evidence supporting use of neurofilament concentration measures as biomarkers of neuronal injury or degeneration. Finally, we will reflect on major challenges for studies of the neurobiology of intermediate filaments with specific attention to identifying what needs to be learned for more precise use and confident interpretation of neurofilament measures as biomarkers of neurodegeneration.

Perceptions of minimally invasive osteosynthesis: A 2018 survey of orthopedic surgeons.

OBJECTIVE: To report perspectives of minimally invasive osteosynthesis (MIO) techniques in veterinary surgical practice in 2018. STUDY DESIGN: Electronic questionnaires. SAMPLE POPULATION: Diplomates and residents of the American College of Veterinary Surgery and European College of Veterinary Surgery and members of the Veterinary Orthopedic Society. METHODS: Survey questions pertaining to MIO and minimally invasive plate osteosynthesis (MIPO) were sent electronically to the sample population. Questions assessed training, current caseload, benefits, and limitations of MIO and MIPO. RESULTS: Two hundred fifty-six veterinary surgeons completed questions pertaining to MIO, and 238 veterinary surgeons completed questions pertaining to MIPO. With regard to MIO, only 16% of respondents reported that they performed MIO regularly or exclusively, and 62% wanted to perform more MIO than they were currently undertaking. Tibial fractures were most commonly selected for MIO/MIPO stabilization techniques in both cats and dogs. Challenges in achieving adequate fracture reduction were identified as the greatest limitations of MIO/MIPO techniques. Forty-three percent of respondents felt there were not enough MIPO training opportunities. CONCLUSION: Currently, MIO/MIPO techniques are performed infrequently, with a large proportion of respondents revealing that they would like to perform more in the future. There is also evidence that additional training opportunities would be welcomed for MIPO. CLINICAL SIGNIFICANCE: The results of our survey provide evidence that, despite the benefits of MIO and MIPO compared with more traditional fracture stabilization approaches, significant barriers must be overcome before the techniques are likely to be more widely adopted.

Risk factors for tibial damage associated with the modified Maquet technique in 174 stifles.

OBJECTIVE: To identify risk factors for tibial damage associated with the modified Maquet technique (MMT) in dogs with cranial cruciate ligament (CCL) disease. STUDY DESIGN: Retrospective study. SAMPLE POPULATION: One hundred and seventy-four stifles from 147 client-owned dogs. METHODS: Medical records of dogs diagnosed with CCL disease and treated with the current version of MMT were reviewed. Dogs were included if immediate postoperative radiographs were available. Cortical hinge fracture or fissure, tibial tuberosity fracture, and diaphyseal fractures of the tibia were recorded. Age, body weight (BW), thickness of the tibial cortical hinge, and angle of opening of the osteotomy were tested as potential risk factors for tibial damage by univariate logistic regression analysis. RESULTS: Tibial damage included intraoperative tibial fissures in 37% of MMTs, intraoperative fractures of the cortical hinge in 3.4% of MMTs, postoperative tibial fractures in 14% of MMTs. Risk factors for intraoperative fissure included BW (P = .0153) and thickness of cortical hinge (P = .0006). The angle of opening of the osteotomy was identified as a risk factor for intraoperative cortical hinge fracture (P = .0034), angles below 11° being preventive. No risk factor was identified for postoperative fracture. CONCLUSION: Based on these results, preventive measures against tibial damage associated with MMT should include: a thickness of cortical hinge based on the equation related to the BW; a length of osteotomy adjusted to the amount of TTA with an osteotomy angle below 10°; and slow advancement of the tibial tuberosity.

A randomized, double-blind, prospective, placebo-controlled study of the efficacy of a diet supplemented with curcuminoids extract, hydrolyzed collagen and green tea extract in owner's dogs with osteoarthritis.

BACKGROUND: We have previously demonstrated that a mixture of Curcuminoids extract, hydrolyzed COllagen and green Tea extract (CCOT) inhibited inflammatory and catabolic mediator's synthesis by bovine and human chondrocytes. A randomly allocated, double-blind, prospective, placebo-controlled study was performed to evaluate the efficacy of a diet containing this CCOT mixture on dogs with naturally occurring osteoarthritis (OA). Therefore, 42 owner's dogs with OA were randomly assigned to receive for 3 months an experimental diet (control) or the same diet supplemented with CCOT. RESULTS: Ground reaction forces did not show statistical differences between groups. After 3 months of feeding, there was a significant reduction of pain at manipulation in the CCOT group, but not in the control group. The evolution for pain at manipulation depended on the diet. The three other parameters evaluated by veterinary subjective assessment (lameness, pain at palpation and joint mobility) did not show statistical differences. Concerning owner subjective assessment, pain severity score worsened in the control group but remained stable in CCOT group. The evolution for pain severity depended on the diet. No statistical difference was found for pain interference, except for the ability to rise to standing from lying down, which was significantly improved in the CCOT compared to the control group. Serum OA biomarkers did not show statistical differences. CONCLUSIONS: Objective variables measured, such as ground reaction forces and OA biomarkers, did not show statistical differences. However, indicators of pain appeared reduced in dogs receiving CCOT mixture for 3 months. The difference of evolution between groups suggests that a greater number of dogs may be necessary to reach a stronger effect on other parameters.

Tau Protein Quantification in Human Cerebrospinal Fluid by Targeted Mass Spectrometry at High Sequence Coverage Provides Insights into Its Primary Structure Heterogeneity.

Tau protein plays a major role in neurodegenerative disorders, appears to be a central biomarker of neuronal injury in cerebrospinal fluid (CSF), and is a promising target for Alzheimer's disease immunotherapies. To quantify tau at high sensitivity and gain insights into its naturally occurring structural variations in human CSF, we coupled absolute quantification using protein standard with the multiplex detection capability of targeted high-resolution mass spectrometry (MS) on a Quadrupole-Orbitrap instrument. Using recombinant tau we developed a step-by-step workflow optimization including an extraction protocol that avoided affinity reagents and achieved the monitoring of 22 tau peptides uniformly distributed along the tau sequence. The lower limits of quantification ranged (LLOQ) from 150 to 1500 pg/mL depending on the peptide. Applied to endogenous CSF tau, up to 19 peptides were detected. Interestingly, there were significant differences in the abundance of peptides depending on their position in the sequence, with peptides from the tau mid-domain appearing significantly more abundant than peptides from the N- and C-terminus domains. This MS-based strategy provided results complementary to those of previous ELISA or Western Blot studies of CSF tau and could be applied to tau monitoring in human CSF cohorts.

Quantitative detection of amyloid-ß peptides by mass spectrometry: state of the art and clinical applications.

Alzheimer's disease (AD) is the most common form of dementia in humans, and a major public health concern with 35 million of patients worldwide. Cerebrospinal fluid (CSF) biomarkers being early diagnostic indicators of AD, it is essential to use the most efficient analytical methods to detect and quantify them accurately. These biomarkers, and more specifically amyloid-ß (Aß) peptides, are measured in routine clinical practice using immunoassays. However, there are several limits to this immunodetection in terms of specificity and multiplexing of the multiple isoforms of the Aß peptides. To overcome these issues, the quantification of these analytes by mass spectrometry (MS) represents an interesting alternative, and several assays have been described over the past years. This article reviews the different Aß peptides quantitative MS-based approaches published so far, compares their pre-analytical phase, and the different quantitative strategies implemented that might be suitable for clinical applications.

Short- and long-term outcomes after arthroscopic treatment of young large breed dogs with medial compartment disease of the elbow.

OBJECTIVES: To report short- and long-term outcomes after arthroscopic treatment in young large breed dogs affected by medial coronoid process disease (MCPD) and identify variables affecting outcome. STUDY DESIGN: Prospective observational case series. ANIMALS: Large breed dogs <3 years old (n = 15; 23 elbows). METHODS: MCPD was confirmed by radiography, computed tomography, and arthroscopy. Dogs were treated by arthroscopy. Variables recorded at time of treatment included radioulnar incongruity (RUI) and degree of cartilage erosion. Variables recorded before, 6 weeks, and ≥23 months after surgery included radiographic score for osteoarthritis, trochlear notch sclerosis, muscle circumference, range of motion (ROM), and the load distribution of vertical ground reaction forces between thoracic and pelvic limbs. RESULTS: A greater load distribution to the pelvic limbs was identified preoperatively in dogs with RUI than in dogs with congruent elbows. Load distribution was not significantly improved at 6 weeks compared with preoperatively. Muscle circumference and vertical impulse distributions were improved at long-term evaluation despite an increased osteoarthritis score. This improvement was more obvious in dogs with RUI or a high degree of cartilage erosion at initial presentation. CONCLUSION: Some evidence of improvement in long-term function was found in dogs with MCPD after arthroscopic treatment. RUI and cartilage erosion at the time of diagnosis were associated with more lameness preoperatively but did not affect the final gait assessment or osteoarthritis score in this small cohort.

Comparison of two minimally invasive approaches to the thoracolumbar spinal canal in dogs.

OBJECTIVE: To describe 2 minimally invasive approaches to the spinal canal for treatment of intervertebral disc disease and compare their efficacy to conventional hemilaminectomy. STUDY DESIGN: Experimental; randomized, controlled design. ANIMALS: Canine cadavers (n = 10; 5 small and 5 large dogs). METHODS: Barium-impregnated agarose gel (BA-gel) was injected into the spinal canal at 3 intervertebral spaces of the thoracolumbar spine in each cadaver. Sites were randomly assigned to 1 of 3 approaches: conventional (standard) hemilaminectomy (SH), endoscopic foraminotomy (EF), or foraminotomy via an illuminated port (FP). Computed tomographic scans were performed before and after the procedures. Procedures were compared for duration, bone window size, incision length, complications and percentage of BA-gel removed via repeated measures ANOVA. RESULTS: The incisions created during EF and FP were similar and smaller to that of a SH. The duration of EF was prolonged compared to FP and SH. The size of the vertebral window created was greater after SH in large dogs, while no difference was found between procedures in small dogs. The amount of simulated disc material removed from the spinal canal did not differ between procedures, regardless of the size of the dog. CONCLUSIONS: The two minimally invasive approaches were feasible in small and large dogs. Both techniques allowed similar removal of simulated disc material and may decrease soft tissue morbidity compared to SH.

Disease staging of Alzheimer's disease using a CSF-based biomarker model.

Biological staging of individuals with Alzheimer's disease (AD) may improve diagnostic and prognostic workup of dementia in clinical practice and the design of clinical trials. In this study, we used the Subtype and Stage Inference (SuStaIn) algorithm to establish a robust biological staging model for AD using cerebrospinal fluid (CSF) biomarkers. Our analysis involved 426 participants from BioFINDER-2 and was validated in 222 participants from the Knight Alzheimer Disease Research Center cohort. SuStaIn identified a singular biomarker sequence and revealed that five CSF biomarkers effectively constituted a reliable staging model (ordered: Aß42/40, pT217/T217, pT205/T205, MTBR-tau243 and non-phosphorylated mid-region tau). The CSF stages (0-5) demonstrated a correlation with increased abnormalities in other AD-related biomarkers, such as Aß-PET and tau-PET, and aligned with longitudinal biomarker changes reflective of AD progression. Higher CSF stages at baseline were associated with an elevated hazard ratio of clinical decline. This study highlights a common molecular pathway underlying AD pathophysiology across all patients, suggesting that a single CSF collection can accurately indicate the presence of AD pathologies and characterize the stage of disease progression. The proposed staging model has implications for enhancing diagnostic and prognostic assessments in both clinical practice and the design of clinical trials.

Evaluation of Exploratory Fluid Biomarker Results from a Phase 1 Senolytic Trial in Mild Alzheimer's Disease.

Senescent cell accumulation contributes to the progression of age-related disorders including Alzheimer's disease (AD). Clinical trials evaluating senolytics, drugs that clear senescent cells, are underway, but lack standardized outcome measures. Our team recently published data from the first open-label trial to evaluate senolytics (dasatinib plus quercetin) in AD. After 12-weeks of intermittent treatment, we reported brain exposure to dasatinib, favorable safety and tolerability, and modest post-treatment changes in cerebrospinal fluid (CSF) inflammatory and AD biomarkers using commercially available assays. Herein, we present more comprehensive exploratory analyses of senolytic associated changes in AD relevant proteins, metabolites, lipids, and transcripts measured across blood, CSF, and urine. These analyses included mass spectrometry for precise quantification of amyloid beta (Aß) and tau in CSF; immunoassays to assess senescence associated secretory factors in plasma, CSF, and urine; mass spectrometry analysis of urinary metabolites and lipids in blood and CSF; and transcriptomic analyses relevant to chronic stress measured in peripheral blood cells. Levels of Aß and tau species remained stable. Targeted cytokine and chemokine analyses revealed treatment-associated increases in inflammatory plasma fractalkine and MMP-7 and CSF IL-6. Urinary metabolites remained unchanged. Modest treatment-associated lipid profile changes suggestive of decreased inflammation were observed both peripherally and centrally. Blood transcriptomic analysis indicated downregulation of inflammatory genes including FOS, FOSB, IL1ß, IL8, JUN, JUNB, PTGS2. These data provide a foundation for developing standardized outcome measures across senolytic studies and indicate distinct biofluid-specific signatures that will require validation in future studies. ClinicalTrials.gov: NCT04063124.