Biochemical, Biomarker, and Behavioral Characterization of the GrnR493X Mouse Model of Frontotemporal Dementia.

Heterozygous loss-of-function mutations in the progranulin gene (GRN) are a major cause of frontotemporal dementia due to progranulin haploinsufficiency; complete deficiency of progranulin causes neuronal ceroid lipofuscinosis. Several progranulin-deficient mouse models have been generated, including both knockout mice and knockin mice harboring a common patient mutation (R493X). However, the GrnR493X mouse model has not been characterized completely. Additionally, while homozygous GrnR493X and Grn knockout mice have been extensively studied, data from heterozygous mice is still limited. Here, we performed more in-depth characterization of heterozygous and homozygous GrnR493X knockin mice, which includes biochemical assessments, behavioral studies, and analysis of fluid biomarkers. In the brains of homozygous GrnR493X mice, we found increased phosphorylated TDP-43 along with increased expression of lysosomal genes, markers of microgliosis and astrogliosis, pro-inflammatory cytokines, and complement factors. Heterozygous GrnR493X mice did not have increased TDP-43 phosphorylation but did exhibit limited increases in lysosomal and inflammatory gene expression. Behavioral studies found social and emotional deficits in GrnR493X mice that mirror those observed in Grn knockout mouse models, as well as impairment in memory and executive function. Overall, the GrnR493X knockin mouse model closely phenocopies Grn knockout models. Lastly, in contrast to homozygous knockin mice, heterozygous GrnR493X mice do not have elevated levels of fluid biomarkers previously identified in humans, including neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in both plasma and CSF. These results may help to inform pre-clinical studies that use this Grn knockin mouse model and other Grn knockout models.

Biochemical, biomarker, and behavioral characterization of the GrnR493X mouse model of frontotemporal dementia.

Heterozygous loss-of-function mutations in the progranulin gene (GRN) are a major cause of frontotemporal dementia due to progranulin haploinsufficiency; complete deficiency of progranulin causes neuronal ceroid lipofuscinosis. Several progranulin-deficient mouse models have been generated, including both knockout mice and knockin mice harboring a common patient mutation (R493X). However, the GrnR493X mouse model has not been characterized completely. Additionally, while homozygous GrnR493X and Grn knockout mice have been extensively studied, data from heterozygous mice is still limited. Here, we performed more in-depth characterization of heterozygous and homozygous GrnR493X knockin mice, which includes biochemical assessments, behavioral studies, and analysis of fluid biomarkers. In the brains of homozygous GrnR493X mice, we found increased phosphorylated TDP-43 along with increased expression of lysosomal genes, markers of microgliosis and astrogliosis, pro-inflammatory cytokines, and complement factors. Heterozygous GrnR493X mice did not have increased TDP-43 phosphorylation but did exhibit limited increases in lysosomal and inflammatory gene expression. Behavioral studies found social and emotional deficits in GrnR493X mice that mirror those observed in Grn knockout mouse models, as well as impairment in memory and executive function. Overall, the GrnR493X knockin mouse model closely phenocopies Grn knockout models. Lastly, in contrast to homozygous knockin mice, heterozygous GrnR493X mice do not have elevated levels of fluid biomarkers previously identified in humans, including neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in both plasma and CSF. These results may help to inform pre-clinical studies that use this Grn knockin mouse model and other Grn knockout models.

Low circulating adropin concentrations predict increased risk of cognitive decline in community-dwelling older adults.

The secreted peptide adropin is highly expressed in human brain tissues and correlates with RNA and proteomic risk indicators for dementia. Here we report that plasma adropin concentrations predict risk for cognitive decline in the Multidomain Alzheimer Preventive Trial (ClinicalTrials.gov Identifier, NCT00672685; mean age 75.8y, SD = 4.5 years, 60.2% female, n = 452). Cognitive ability was evaluated using a composite cognitive score (CCS) that assessed four domains: memory, language, executive function, and orientation. Relationships between plasma adropin concentrations and changes in CCS (∆CCS) were examined using Cox Proportional Hazards Regression, or by grouping into tertiles ranked low to high by adropin values and controlling for age, time between baseline and final visits, baseline CCS, and other risk factors (e.g., education, medication, APOE4 status). Risk of cognitive decline (defined as a ∆CCS of - 0.3 or more) decreased with increasing plasma adropin concentrations (hazard ratio = 0.873, 95% CI 0.780-0.977, P = 0.018). Between adropin tertiles, ∆CCS was significantly different (P = 0.01; estimated marginal mean ± SE for the 1st to 3rd tertile, - 0.317 ± 0.064; - 0.275 ± 0.063; - 0.042 ± 0.071; n = 133,146, and 130, respectively; P < 0.05 for 1st vs. 2nd and 3rd adropin tertiles). Normalized plasma Aß42/40 ratio and plasma neurofilament light chain, indicators of neurodegeneration, were significantly different between adropin tertile. These differences were consistent with reduced risk of cognitive decline with higher plasma adropin levels. Overall, these results suggest cognitive decline is reduced in community-dwelling older adults with higher circulating adropin levels. Further studies are needed to determine the underlying causes of the relationship and whether increasing adropin levels can delay cognitive decline.

Low circulating adropin levels in late-middle aged African Americans with poor cognitive performance.

We recently reported accelerated cognitive decline in Europeans aged > 70 years with low circulating adropin levels. Adropin is a small, secreted peptide that is highly expressed in the human nervous system. Expression profiling indicate relationships between adropin expression in the human brain and pathways that affect dementia risk. Moreover, increased adropin expression or treatment using synthetic adropin improves cognition in mouse models of aging. Here we report that low circulating adropin concentrations associate with poor cognition (worst quintile for a composite score derived from the MMSE and semantic fluency test) in late-middle aged community-dwelling African Americans (OR = 0.775, P < 0.05; age range 45-65 y, n = 352). The binomial logistic regression controlled for sex, age, education, cardiometabolic disease risk indicators, and obesity. Previous studies using cultured cells from the brains of human donors suggest high expression in astrocytes. In snRNA-seq data from the middle temporal gyrus (MTG) of human donors, adropin expression is higher in astrocytes relative to other cell types. Adropin expression in all cell-types declines with advance age, but is not affected by dementia status. In cultured human astrocytes, adropin expression also declines with donor age. Additional analysis indicated positive correlations between adropin and transcriptomic signatures of energy metabolism and protein synthesis that are adversely affected by donor age. Adropin expression is also suppressed by pro-inflammatory factors. Collectively, these data indicate low circulating adropin levels are a potential early risk indicator of cognitive impairment. Declining adropin expression in the brain is a plausible link between aging, neuroinflammation, and risk of cognitive decline.

Antisense oligonucleotides targeting the miR-29b binding site in the GRN mRNA increase progranulin translation.

Heterozygous GRN (progranulin) mutations cause frontotemporal dementia (FTD) due to haploinsufficiency, and increasing progranulin levels is a major therapeutic goal. Several microRNAs, including miR-29b, negatively regulate progranulin protein levels. Antisense oligonucleotides (ASOs) are emerging as a promising therapeutic modality for neurological diseases, but strategies for increasing target protein levels are limited. Here, we tested the efficacy of ASOs as enhancers of progranulin expression by sterically blocking the miR-29b binding site in the 3' UTR of the human GRN mRNA. We found 16 ASOs that increase progranulin protein in a dose-dependent manner in neuroglioma cells. A subset of these ASOs also increased progranulin protein in iPSC-derived neurons and in a humanized GRN mouse model. In FRET-based assays, the ASOs effectively competed for miR-29b from binding to the GRN 3' UTR RNA. The ASOs increased levels of newly synthesized progranulin protein by increasing its translation, as revealed by polysome profiling. Together, our results demonstrate that ASOs can be used to effectively increase target protein levels by partially blocking miR binding sites. This ASO strategy may be therapeutically feasible for progranulin-deficient FTD as well as other conditions of haploinsufficiency.

The use of robot-assisted surgery for the unstable traumatic spine: A retrospective cohort study.

Background: Robotic assistance has been shown to increase instrumentation placement accuracy in open and minimally invasive spinal fusion. These gains have been achieved without increases in operative times, blood loss, or hospitalization duration. However, most work has been done in the degenerative population and little is known of the utility of robotic assistance when applied to spinal trauma. This is largely due to the uncertainty stemming from the disruption of normal anatomy by the traumatic injury. Since the robot depends upon registration for instrumentation guidance according to the fiducials it uses, trauma can introduce unique challenges. The present study sought to evaluate the safety and efficacy of robotic assistance in a consecutive cohort of spine trauma patients. Methods: All patients with Thoracolumbar Injury Classification and Severity Scale (TLICS) >4 who underwent robot-assisted spinal fusion using the Globus ExcelsiusGPS at a single tertiary care center for trauma between 2020 and 2022 were identified. Demographic, clinical, and surgical data were collected and analyzed; the primary endpoints were operative time, fluoroscopy time, estimated blood loss, postoperative complications, admission time, and 90-day readmission rate. The paired t-test was used to compare differences between mean values when looking at the number of surgical levels. Results: Forty-two patients undergoing robot-assisted spinal surgery were included (mean age 61.3±17.1 year; 47% female. Patients were stratified by the number of operative levels, 2 (n = 10), 3-4 (n = 11), 5 to 6 (n = 13), or >6 (n = 8). There appeared to be a positive correlation between number of levels instrumented and odds of postoperative complications, admission duration, fluoroscopy time, and estimated blood loss. There were no instances of screw malposition or breach. Conclusions: This initial experience suggests robotic assistance can be safely employed in the spine trauma population. Additional experiences in larger patient populations are necessary to delineate those traumatic pathologies most amenable to robotic assistance.

Staphylococcus schleiferi subspecies coagulans septic shock in an immunocompetent male following canine otitis externa.

Staphylococcus schleiferi bacteremia is an underappreciated cause of septic shock in the critical care department. Although nominally a coagulase variable Staphylococcus and associated with otitis externa infections in canine species, it has been associated with the metastatic infection including osteomyelitis, endocarditis, nephritis, and meningitis in humans. This report records a possible zoonotic case of S. schleiferi subspecies coagulans bacteremia following canine otitis externa associated with septic shock and endovascular infection precipitating intensive care admission for vasopressor support in an immunocompetent male.

Complications of the Prone Transpsoas Lateral Lumbar Interbody Fusion for Degenerative Lumbar Spine Disease: A Multicenter Study.

BACKGROUND AND OBJECTIVES: The prone transpsoas (PTP) approach for lateral lumbar interbody fusion (LLIF) is a novel technique for degenerative lumbar spine disease. However, there is a paucity of information in the literature on the complications of this procedure, with all published data consisting of small samples. We aimed to report the intraoperative and postoperative complications of PTP in the largest study to date. METHODS: A retrospective electronic medical record review was conducted at 11 centers to identify consecutive patients who underwent LLIF through the PTP approach between January 1, 2021, and December 31, 2021. The following data were collected: intraoperative characteristics (operative time, estimated blood loss [EBL], intraoperative complications [anterior longitudinal ligament (ALL) rupture, cage subsidence, vascular and visceral injuries]), postoperative complications, and hospital stay. RESULTS: A total of 365 patients were included in the study. Among these patients, 2.2% had ALL rupture, 0.3% had cage subsidence, 0.3% had a vascular injury, 0.3% had a ureteric injury, and no other visceral injuries were reported. Mean operative time was 226.2 ± 147.9 minutes. Mean EBL was 138.4 ± 215.6 mL. Mean hospital stay was 2.7 ± 2.2 days. Postoperative complications included new sensory symptoms-8.2%, new lower extremity weakness-5.8%, wound infection-1.4%, cage subsidence-0.8%, psoas hematoma-0.5%, small bowel obstruction and ischemia-0.3%, and 90-day readmission-1.9%. CONCLUSION: In this multicenter case series, the PTP approach was well tolerated and associated with a satisfactory safety profile.

Targeting nonsense-mediated RNA decay does not increase progranulin levels in the Grn R493X mouse model of frontotemporal dementia.

A common cause of frontotemporal dementia (FTD) are nonsense mutations in the progranulin (GRN) gene. Because nonsense mutations activate the nonsense-mediated RNA decay (NMD) pathway, we sought to inhibit this RNA turnover pathway as a means to increase progranulin levels. Using a knock-in mouse model harboring a common patient mutation, we tested whether either pharmacological or genetic inhibition of NMD upregulates progranulin in these GrnR493X mice. We first examined antisense oligonucleotides (ASOs) targeting an exonic region in GrnR493X mRNA predicted to block its degradation by NMD. As we previously reported, these ASOs effectively increased GrnR493X mRNA levels in fibroblasts in vitro. However, following CNS delivery, we found that none of the 8 ASOs we tested increased Grn mRNA levels in the brains of GrnR493X mice. This result was obtained despite broad ASO distribution in the brain. An ASO targeting a different mRNA was effective when administered in parallel to wild-type mice. As an independent approach to inhibit NMD, we examined the effect of loss of an NMD factor not required for embryonic viability: UPF3b. We found that while Upf3b deletion effectively perturbed NMD, it did not increase Grn mRNA levels in Grn+/R493X mouse brains. Together, our results suggest that the NMD-inhibition approaches that we used are likely not viable for increasing progranulin levels in individuals with FTD caused by nonsense GRN mutations. Thus, alternative approaches should be pursued.

Helical coils augment embolization of the middle meningeal artery for treatment of chronic subdural hematoma: A technical note.

Embolization of the middle meningeal artery (MMA) is a safe and effective adjunct in the treatment of chronic subdural hematoma. While prior authors describe the use of coils to assist embolization by preventing reflux through eloquent collaterals, we de- scribe the use of coils to further open the MMA, allowing the administration of greater amounts of embolisate for a more robust embolization. The objective of this study was to demonstrate that helical coils can safely open the MMA following the administration of polyvinyl alcohol (PVA) particles. This allows for more embolisate to be administered into the MMA for more effective treatment. A retrospective review was conducted at our institution including intraoperative images and postoperative clinical and radiographic follow up. Failure rates using MMA embolization with PVA and helical coil augmentation were compared to failure rates in the literature of MMA embolization with PVA or ethylene vinyl-alcohol copolymer alone. A total of 8 cases were reviewed in which this technique was implemented. There were no immediate complications after treatment. All patients that underwent helical coil embolization following the administration of PVA had increased amount of embolisate delivered into the MMA. All patients at follow up had resolution of the subdural hematoma on outpatient imaging. Helical coil embolization allows for more embolisate administration into the MMA and provides a technical advantage for patients that fail traditional techniques of embolization. Case series are taking place to further test this hypothesis and identify the ideal patient population that may gain maximal yield from this novel technique.

Radiographic alignment outcomes after the single-position prone transpsoas approach: a multi-institutional retrospective review of 363 cases.

OBJECTIVE: The aim of this paper was to evaluate the changes in radiographic spinopelvic parameters in a large cohort of patients undergoing the prone transpsoas approach to the lumbar spine. METHODS: A multicenter retrospective observational cohort study was performed for all patients who underwent lateral lumber interbody fusion via the single-position prone transpsoas (PTP) approach. Spinopelvic parameters from preoperative and first upright postoperative radiographs were collected, including lumbar lordosis (LL), pelvic incidence (PI), and pelvic tilt (PT). Functional indices (visual analog scale score), and patient-reported outcomes (Oswestry Disability Index) were also recorded from pre- and postoperative appointments. RESULTS: Of the 363 patients who successfully underwent the procedure, LL after fusion was 50.0° compared with 45.6° preoperatively (p < 0.001). The pelvic incidence-lumbar lordosis mismatch (PI-LL) was 10.5° preoperatively versus 2.9° postoperatively (p < 0.001). PT did not significantly change (0.2° ± 10.7°, p > 0.05). CONCLUSIONS: The PTP approach allows significant gain in lordotic augmentation, which was associated with good functional results at follow-up.

TNFR-1 and GDF-15 Are Associated With Plasma Neurofilament Light Chain and Progranulin Among Community-Dwelling Older Adults: A Secondary Analysis of the MAPT Study.

There is growing evidence that cognitive decline can be affected by both nutritional aspects and inflammation. Plasma neurodegenerative biomarkers stand out as minimally invasive useful measures to monitor the potential risk of cognitive decline. This study aimed to investigate the associations between biomarkers of neurodegeneration, nutrition, and inflammation among community-dwelling older adults, and to verify if associations differed according to apolipoprotein E (APOE) ε4 status. This cross-sectional analysis included 475 participants ≥70 years old from the Multidomain Alzheimer Preventive Trial (MAPT), mean age 76.8 years (SD = 4.5), 59.4% women. Biomarkers of neurodegeneration (plasma amyloid-ß 42/40-Aß 42/40, neurofilament light chain-NfL, progranulin), nutrition (erythrocyte docosahexaenoic acid, eicosapentaenoic acid, omega-3 index; plasma homocysteine-Hcy, 25 hydroxyvitamin D), inflammation (plasma tumor necrosis factor receptor 1-TNFR-1, monocyte chemoattractant protein 1-MCP-1, interleukin 6-IL-6), and cellular stress (plasma growth differentiation factor 15-GDF-15) were assessed. Linear regression analyses were performed to investigate the associations between nutritional and inflammatory biomarkers (independent variables) and neurodegenerative biomarkers (dependent variables), with adjustments for age, sex, education, body mass index, physical activity, allocation to MAPT groups, and APOE ε4 status. After adjusting for confounders, Aß 42/40 was not associated with nutritional or inflammatory markers. NfL was positively associated with GDF-15, TNFR-1, IL-6, and Hcy. Progranulin was positively associated with GDF-15, TNFR-1, and MCP-1. Analyses restricted to APOE ε4 carriers (n = 116; 26.9%) or noncarriers were mostly similar. Our cross-sectional study with community-dwelling older adults corroborates previous evidence that inflammatory pathways are associated to plasma markers of neurodegeneration. Clinical Trials Registration Number: NCT00672685.

The efficacy and safety of a shortened duration of antimicrobial therapy for group A Streptococcus bacteremia.

OBJECTIVES: To determine if shorter courses of antibiotic therapy for group A Streptococcus (GAS) bacteremia are associated with excess mortality. METHODS: In this retrospective study of consecutive cases of GAS bacteremia in tropical Australia, the duration of antibiotic therapy was correlated with 90-day all-cause mortality. RESULTS: There were 286 episodes of GAS bacteremia; the patients' median (interquartile range) age was 60 (48-71) years and 169/286 (59.1%) patients identified as an Indigenous Australian. There were 227/286 (79.4%) patients with a significant comorbidity. The all-cause 90-day mortality was 16/286 (5.6%); however, 12/16 (81.3%) patients died while still receiving their initial course of antibiotics and only 7/16 (43.8%) deaths were directly attributable to the GAS infection. After excluding patients who died while taking their initial course of antibiotics and those in whom the duration of therapy was uncertain, there was no difference in 90-day mortality between patients receiving ≤5 days of intravenous antibiotics and those receiving longer courses (1/137 [0.7%] vs 3/107 [2.8%], P-value = 0.32) nor in patients receiving ≤10 days of total therapy and those receiving longer courses (1/67 [1.5%] vs 3/178 [1.7%], P-value = 1.0). CONCLUSION: Even among patients with significant comorbidity, shorter antibiotic courses for GAS bacteremia are not associated with excess mortality.

Chronic sleep loss disrupts rhythmic gene expression in Drosophila.

Genome-wide profiling of rhythmic gene expression has offered new avenues for studying the contribution of circadian clock to diverse biological processes. Sleep has been considered one of the most important physiological processes that are regulated by the circadian clock, however, the effects of chronic sleep loss on rhythmic gene expression remain poorly understood. In the present study, we exploited Drosophila sleep mutants insomniac 1 (inc 1 ) and wide awake D2 (wake D2 ) as models for chronic sleep loss. We profiled the transcriptomes of head tissues collected from 4-week-old wild type flies, inc 1 and wake D2 at timepoints around the clock. Analysis of gene oscillation revealed a substantial loss of rhythmicity in inc 1 and wake D2 compared to wild type flies, with most of the affected genes common to both mutants. The disruption of gene oscillation was not due to changes in average gene expression levels. We also identified a subset of genes whose loss of rhythmicity was shared among animals with chronic sleep loss and old flies, suggesting a contribution of aging to chronic, sleep-loss-induced disruption of gene oscillation.

Deficiency of the frontotemporal dementia gene GRN results in gangliosidosis.

Haploinsufficiency of GRN causes frontotemporal dementia (FTD). The GRN locus produces progranulin (PGRN), which is cleaved to lysosomal granulin polypeptides. The function of lysosomal granulins and why their absence causes neurodegeneration are unclear. Here we discover that PGRN-deficient human cells and murine brains, as well as human frontal lobes from GRN-mutation FTD patients have increased levels of gangliosides, glycosphingolipids that contain sialic acid. In these cells and tissues, levels of lysosomal enzymes that catabolize gangliosides were normal, but levels of bis(monoacylglycero)phosphates (BMP), lipids required for ganglioside catabolism, were reduced with PGRN deficiency. Our findings indicate that granulins are required to maintain BMP levels to support ganglioside catabolism, and that PGRN deficiency in lysosomes leads to gangliosidosis. Lysosomal ganglioside accumulation may contribute to neuroinflammation and neurodegeneration susceptibility observed in FTD due to PGRN deficiency and other neurodegenerative diseases.

Prone-lateral access to the lumbar spine: single-level corpectomy with approach discussion.

The lateral lumbar interbody fusion has evolved as newly envisioned access corridors become feasible with technological advances. Prone lateral access has evolved as a single-access approach to combine the benefits of minimally invasive surgery with direct and indirect decompression of the neural elements with synergistic anterior and posterior column correction. In this video, the authors discuss the pearls, pitfalls, and adjuvant technologies they use in a high-volume prone lateral center via case demonstration of a prone lateral corpectomy. The video can be found here: https://stream.cadmore.media/r10.3171/2022.3.FOCVID2216.

Progranulin Preserves Autophagy Flux and Mitochondrial Function in Rat Cortical Neurons Under High Glucose Stress.

Chronic hyperglycemia in type II diabetes results in impaired autophagy function, accumulation of protein aggregates, and neurodegeneration. However, little is known about how to preserve autophagy function under hyperglycemic conditions. In this study, we tested whether progranulin (PGRN), a neurotrophic factor required for proper lysosome function, can restore autophagy function in neurons under high-glucose stress. We cultured primary cortical neurons derived from E18 Sprague-Dawley rat pups to maturity at 10 days in vitro (DIV) before incubation in high glucose medium and PGRN for 24-72 h before testing for autophagy flux, protein turnover, and mitochondrial function. We found that although PGRN by itself did not upregulate autophagy, it attenuated impairments in autophagy seen under high-glucose conditions. Additionally, buildup of the autophagosome marker light chain 3B (LC3B) and lysosome marker lysosome-associated membrane protein 2A (LAMP2A) changed in both neurons and astrocytes, indicating a possible role for glia in autophagy flux. Protein turnover, assessed by remaining advanced glycation end-product levels after a 6-h incubation, was preserved with PGRN treatment. Mitochondrial activity differed by complex, although PGRN appeared to increase overall activity in high glucose. We also found that activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and glycogen synthase kinase 3ß (GSK3ß), kinases implicated in autophagy function, increased with PGRN treatment under stress. Together, our data suggest that PGRN prevents hyperglycemia-induced decreases in autophagy by increasing autophagy flux via increased ERK1/2 kinase activity in primary rat cortical neurons.

Serum neurofilament light levels are predictive of all-cause mortality in late middle-aged individuals.

BACKGROUND: Blood biomarkers can offer valuable and easily accessible indicators of normal biological processes, pathogenic conditions, and responses to therapeutic interventions. Recent studies found that levels of neurofilament light chain (NfL) in the blood are associated with mortality in three European cohorts of older adults (median ages 73, 93, and 100 years). Whether similar associations exist in younger adults and in other ethnic groups is currently not known. METHODS: We utilized a cohort study that included 294 African Americans (baseline ages 49-65). Serum NfL levels were measured using a Meso Scale Discovery-based assay. Vital status was determined by matching through the National Death Index. FINDINGS: Seventy-two participants (24.5%) died during the 14-15 years of follow up (2000-2014). Baseline serum NfL levels were significantly higher in the decedent group (86.1±65.7 pg/ml vs. 50.1±28.0 pg/ml, p < 0·001). In binomial logistic regression models adjusted for age, gender, education, baseline smoking status, BMI, and total comorbidities (0-11), serum NfL levels remained a strong predictor of all-cause mortality, and sensitivity analyses employing multiple additional covariates did not substantively change the relationship. Further, Kaplan-Meier curves based on serum NfL quartiles showed reduced survival in groups with higher serum NfL levels. INTERPRETATION: This study found a positive association between serum NfL levels and mortality in late middle-aged and older individuals. While our findings support that serum NfL levels may be a useful biomarker for all-cause mortality, further studies are needed to understand the biological mechanisms underlying this association. FUNDING: National Institute on Aging, Saint Louis University.

Investigating the combination of plasma amyloid-beta and geroscience biomarkers on the incidence of clinically meaningful cognitive decline in older adults.

We investigated combining a core AD neuropathology measure (plasma amyloid-beta [Aß] 42/40) with five plasma markers of inflammation, cellular stress, and neurodegeneration to predict cognitive decline. Among 401 participants free of dementia (median [IQR] age, 76 [73-80] years) from the Multidomain Alzheimer Preventive Trial (MAPT), 28 (7.0%) participants developed dementia, and 137 (34.2%) had worsening of clinical dementia rating (CDR) scale over 4 years. In the models utilizing plasma Aß alone, a tenfold increased risk of incident dementia (nonsignificant) and a fivefold increased risk of worsening CDR were observed as each nature log unit increased in plasma Aß levels. Models incorporating Aß plus multiple plasma biomarkers performed similarly to models included Aß alone in predicting dementia and CDR progression. However, improving Aß model performance for composite cognitive score (CCS) decline, a proxy of dementia, was observed after including plasma monocyte chemoattractant protein 1 (MCP1) and growth differentiation factor 15 (GDF15) as covariates. Participants with abnormal Aß, GDF15, and MCP1 presented higher CCS decline (worsening cognitive function) compared to their normal-biomarker counterparts (adjusted ß [95% CI], - 0.21 [- 0.35 to - 0.06], p = 0.005). In conclusion, our study found limited added values of multi-biomarkers beyond the basic Aß models for predicting clinically meaningful cognitive decline among non-demented older adults. However, a combined assessment of inflammatory and cellular stress status with Aß pathology through measuring plasma biomarkers may improve the evaluation of cognitive performance.