Arthroscopic subacromial decompression improved outcomes in situationally depressed patients compared to clinically depressed or nondepressed patients.

Background: The purpose of this study is to evaluate patient reported outcomes after arthroscopic extensive débridement of the shoulder with subacromial decompression (SAD) for subacromial impingement using the Patient-Reported Outcomes Measurement Information System (PROMIS) system and evaluate if depression (Dep) (clinical or situational) impacts patients achieving a Minimal Clinically Important Difference (MCID). Methods: Preoperative PROMIS Physical function (PF), Mood, and Dep scores were obtained at the closest date prior to arthroscopic rotator cuff repair and postoperative scores were collected at every clinical visit thereafter. Final PROMIS score used for data analysis was determined by the patients final PROMIS value between 90 to 180 days. Clinical Dep was determined by patients having a formal diagnosis of "Depression or Major Depressive Disorder" at the time of their surgery. Situationally depressed patients, those without a formal diagnosis yet exhibited symptomatic depressive symptoms, were classified by having a PROMIS-Dep cutoff scores larger than 52.5. Results: A total of 136 patients were included for final statistical analysis. 13 patients had a clinical but not situational diagnosis of Dep, 86 patients were identified who had no instance of clinical or situational Dep (nondepressed). 35 patients were situationally depressed. All three cohorts demonstrated a significant improvement in postoperative PROMIS Dep, PI, and PF score relative to their preoperative value (P = .001). Situationally depressed patients achieved greater delta PROMIS-Dep compared to patients with major depressive disorder. Depressed patients had a higher chance of achieving MCID for PROMIS-Dep compared to nondepressed patients (P = .01). Logistic regression analysis demonstrated that underlying Dep did not alter the odds of obtaining MCID compared to nondepressed patients. Nonsmoking patients had significantly greater odds of achieving MCID for PF (P = .02). Discussion: Patients improved after undergoing SAD regardless of underlying Dep or depressive symptoms. Depressed patients exhibited greater change in PROMIS scores compared to nondepressed patients. Smoking remains a risk factor for postoperative outcomes in patients undergoing SAD for subacromial impingement. Identifying and counseling patients with underlying depressive symptoms without a formal major depressive disorder diagnosis may lead to improved outcomes. These findings may help guide clinicians in deciding who would benefit the most from this procedure.

Impact of Sports Participation on Achievement of Clinically Relevant Outcomes 2 Years After ACL Reconstruction.

Background: Clinically relevant threshold values associated with patient-reported outcome measures after orthopaedic procedures such as anterior cruciate ligament reconstruction (ACLR) are important for relating these scores to meaningful postoperative improvement. Purpose/Hypothesis: The purpose of this study was to determine the Patient Acceptable Symptom State (PASS) for the Patient-Reported Outcomes Measurement Information System Computer Adaptive Test (PROMIS-CAT) after ACLR. It was hypothesized that preoperative sport participation would have an impact on PASS achievement. Study Design: Case series; Level of evidence, 4. Methods: Included were consecutive patients who underwent primary assisted ACLR between January 4 and August 1, 2016. Patients were administered the PROMIS-CAT Physical Function (PF) and Pain Interference domains preoperatively and at a minimum 2 years postoperatively, with external anchor questions used to determine the PASS. Receiver operating characteristic (ROC) curves were constructed for the entire study population as well as separately for athletes and nonathletes to determine PROMIS PASS thresholds for each population. A previously published PROMIS-PF minimal clinically important difference was used to evaluate postoperative improvement. A post hoc multivariate nominal logistic multivariate analysis was constructed to assess the effects of preoperative patient characteristics on the likelihood of attaining both the minimal clinically important difference and PASS. Results: In total, 112 patients were included in the study, with 79 (71%) having recreational or higher levels of athletic participation. The PASS for the study population was 56.0 (area under the ROC curve, 0.86) and was unaffected by baseline PROMIS-PF scores but was affected by preoperative athletic participation (56.0 for athletes, 49.0 for nonathletes). A post hoc analysis found 57 patients (51%) achieved the PASS for the PROMIS-PF (cutoff, 56.0), but when the athlete and nonathlete thresholds were applied to their respective patient groups, 66% of athletes and 64% of nonathletes achieved the PASS postoperatively. The multivariate analysis found that sport participation (odds ratio, 6.2; P = .001) but not age, sex, body mass index, or preoperative PROMIS affected the likelihood of achieving the PASS on the PROMIS-PF. Conclusion: Preoperative athletic participation significantly affected the ability to achieve PASS.

Single-Cell Spatial MIST for Versatile, Scalable Detection of Protein Markers.

High-multiplex detection of protein biomarkers across tissue regions has been an attractive spatial biology approach due to significant advantages over traditional immunohistochemistry (IHC) methods. Different from most methods, spatial multiplex in situ tagging (MIST) transfers the spatial protein expression information to an ultrahigh-density, large-scale MIST array. This technique has been optimized to reach single-cell resolution by adoption of smaller array units and 30% 8-arm PEG polymer as transfer medium. Tissue cell nuclei stained with lamin B have been clearly visualized on the MIST arrays and are colocalized with detection of nine mouse brain markers. Pseudocells defined at 10 µm in size have been used to fully profile tissue regions including cells and the intercellular space. We showcased the versatility of our technology by successfully detecting 20 marker proteins in kidney samples with the addition of five minutes atop the duration of standard immunohistochemistry protocols. Spatial MIST is amenable to iterative staining and detection on the same tissue samples. When 25 proteins were co-detected on 1 mouse brain section for each round and 5 rounds were executed, an ultrahigh multiplexity of 125 proteins was obtained for each pseudocell. With its unique abilities, this single-cell spatial MIST technology has the potential to become an important method in advanced diagnosis of complex diseases.

Use of Area Deprivation Index to Predict Minimal Clinically Important Difference for Patient Reported Outcomes Measurement Information System After Arthroscopic Rotator Cuff Repair.

BACKGROUND: Socioeconomic disparities correlate with worse outcomes after arthroscopic rotator cuff repair. However, use of a surrogate to describe socioeconomic disadvantage has been a challenge. The Area Deprivation Index (ADI) is a tool that encompasses 17 socioeconomic variables into a single metric based on census location. HYPOTHESIS: Higher ADI would result in a worse minimal clinically important difference (MCID) for the Patient Reported Outcomes Measurement Information System (PROMIS) and have less improvement in range of motion (ROM) following arthroscopic rotator cuff repair (ARCR). STUDY DESIGN: Cohort study; Level of evidence, 3. METHOD: A retrospective review was performed for patients who underwent arthroscopic rotator cuff repair. Patients in the most socioeconomically disadvantaged quartile (ADIHigh) were compared with the least disadvantaged quartile (ADILow) in the ability to reach MCID. Demographic and surgical features were assessed for attainment of MCID. RESULTS: In total 1382 patients were identified who underwent ARCR, of which a total of 306 patients met final inclusion criteria. A higher percentage of patients within the ADIHigh cohort identified as "Black" or "other" race and had government-issued insurance compared with the ADILow cohort (P < .05). The ADIHigh cohort had significantly worse postoperative forward flexion compared with the ADILow cohort (145.0°± 32.5° vs 156.3°± 23.4°; P = .001) despite starting with comparable preoperative ROM (P = .17). Logistic regression showed that ADI was the only variable significant for predicting achievement of MCID for all 3 PROMIS domains, with the ADIHigh cohort having significantly worse odds of achieving MCID Physical Function (odds ratio [OR], 0.31; P = .001), Pain Interference (OR, 0.21; P = .001), and Depression (OR, 0.28; P = .001). Meanwhile, age, sex, body mass index, and smoking history were nonsignificant. Moreover, "other" for race and Medicare insurance were significant for achievement of MCID Depression but not Physical Function or Pain Interference. Finally, ADI was the main feature for predictive logistic regression modeling. CONCLUSION: ADI served as the only significant predictor for achieving MCID for all 3 PROMIS domains after arthroscopic rotator cuff repair. Patients who face high levels of socioeconomic disadvantage have lower rates of achieving MCID. In addition, patients with greater neighborhood disadvantage demonstrated significantly worse improvement in active forward flexion. Further investigation is required to understand the role of ADI on physical therapy compliance and to identify the barriers that prevent equitable postoperative care.

Effect of Insurance Reimbursement Status on Pre- and Postoperative Patient-Reported Outcomes Measurement Information System (PROMIS) Scores After Arthroscopic Rotator Cuff Repair.

BACKGROUND: Previous studies reported inferior patient-reported outcomes (PROs) after arthroscopic rotator cuff repair for patients receiving workers' compensation (WC) relative to patients with commercial insurance. The extent to which alternative insurance reimbursement, including Medicaid and Medicare, influences outcomes after arthroscopic rotator cuff repair remains understudied. HYPOTHESIS: Compared with patients with commercial insurance reimbursement, patients with WC or government-issued reimbursement would report lower pre- and postoperative Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function (PF) scores, report higher pre- and postoperative PROMIS Depression (D) and Pain Interference (PI) scores, and experience smaller levels of improvement in all PROMIS domains with surgical intervention. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Demographic and surgical data were extracted from the medical record, and PROMIS domains were prospectively collected. Patients were divided into cohorts based on insurance reimbursement status. Differences between insurance-based cohorts for baseline variables, pre- and postoperative PROMIS scores, and change from baseline to final follow-up (delta) for PROMIS scores were evaluated using Kruskal-Wallis or chi-square tests. Mixed-effects linear regression models were performed to assess the influence of insurance while controlling for other variables. Survival analysis was performed to determine time to achieve minimal clinically important difference (MCID) for each PROMIS domain per cohort. RESULTS: 1252 patients underwent arthroscopic rotator cuff repair, met inclusion criteria, and completed PROMIS questionnaires. Statistically significant differences were noted in demographic variables including age (P < .001), sex (P < .001), ethnicity (P < .001), and body mass index (P < .001) between insurance-based cohorts. Unadjusted analysis revealed significantly higher PF scores and lower PI and D scores for the group with commercial insurance relative to those with Medicare, Medicaid, and WC at 6- and 12-month follow-up (P < .01 all comparisons), except for the Medicare versus commercial subcohort analysis for PI at 6 months (P = .28). These differences persisted for the Medicare, Medicaid, and WC groups (P < .03 all comparisons) after adjustment for confounding variables in linear regression. CONCLUSIONS: The baseline characteristics of patients undergoing arthroscopic rotator cuff repair differed based on insurance reimbursement. Patients with commercial insurance reported improved physical function, decreased pain interference, and improved mood (less depression) relative to patients with government-issued and WC insurance, with maximum improvement 6 to 12 months postoperatively. There were few significant differences between insurance groups in change of PROMIS scores from preoperative to postoperative intervals, indicating that differences in the baseline demographic and surgical characteristics of these groups accounted for differences in response to surgery.

Podocyte-Parietal Epithelial Cell Interdependence in Glomerular Development and Disease.

Podocytes and parietal epithelial cells (PECs) are among the few principal cell types within the kidney glomerulus, the former serving as a crucial constituent of the kidney filtration barrier and the latter representing a supporting epithelial layer that adorns the inner wall of Bowman's capsule. Podocytes and PECs share a circumscript developmental lineage that only begins to diverge during the S-shaped body stage of nephron formation-occurring immediately before the emergence of the fully mature nephron. These two cell types, therefore, share a highly conserved gene expression program, evidenced by recently discovered intermediate cell types occupying a distinct spatiotemporal gene expression zone between podocytes and PECs. In addition to their homeostatic functions, podocytes and PECs also have roles in kidney pathogenesis. Rapid podocyte loss in diseases, such as rapidly progressive GN and collapsing and cellular subtypes of FSGS, is closely allied with PEC proliferation and migration toward the capillary tuft, resulting in the formation of crescents and pseudocrescents. PECs are thought to contribute to disease progression and severity, and the interdependence between these two cell types during development and in various manifestations of kidney pathology is the primary focus of this review.

Editorial Commentary: Promising Short-Term Results of Adolescent Transphyseal Anterior Cruciate Ligament Reconstruction With Quadriceps Tendon Autograft Warrant Long-Term Follow-up Study.

Several graft choices have been described for surgeons performing anterior cruciate ligament reconstruction. Bone-patellar tendon-bone autograft has been referred to as the gold standard with which other grafts are compared. Hamstring autograft has been widely used when a soft-tissue graft is desired, such as when physes are open with significant growth remaining, but with greater revision rate than bone-patella tendon-bone in young athletes. Allograft tissue is discouraged in younger patients due to increased re-rupture rate. More recently, quadriceps autograft has been described as another soft tissue graft. Quadriceps tendon grafts do show promise as a soft-tissue graft alternative with a potential drawback of decreased knee extension strength, although longer-term follow-up studies are necessary to evaluate its use in the pediatric population.

Clinically Depressed Patients Having Anterior Cruciate Ligament Reconstruction Show Improved but Inferior Rate of Achieving Minimum Clinically Important Difference for Patient-Reported Outcomes Measurement Information System Compared With Situationally Depressed or Nondepressed Patients.

PURPOSE: To determine whether the preoperative diagnosis of depression predicted worse postoperative outcomes, including physical therapy (PT) compliance, return-to-sport, and patient-reported outcomes using the Patient-Reported Outcomes Measurement Information System (PROMIS) after anterior cruciate ligament (ACL) reconstruction. METHODS: A multisurgeon series of consecutive patients who had undergone ACL reconstruction with minimum 2-year follow-up were included. Chart review was conducted to determine depression diagnosis status, demographic data, rehabilitation PT compliance, return to sports, and patient-reported outcome data using PROMIS. Patients who met the PROMIS threshold for mild depression but did not carry a clinical diagnosis of depression were classified as "situationally depressed." RESULTS: Ninety-five of 115 consecutive patients (81%) met inclusion criteria with an average follow-up of 34 ± 1.9 months. Fourteen patients (15%) had a preoperative diagnosis of depression, whereas 21 (22%) were considered situationally depressed. Clinically depressed patients had a greater rate of PT noncompliance (33.2% ± 17.6% vs 21.9% ± 12.6%; P = .02) and a lower postoperative PROMIS Physical Function (50.8 ± 7.7 vs 57.8 ± 11.0; P = .03 compared with patients without depression. Situationally depressed patients had lower preoperative physical function (35.4 vs 42.5; P = .04) with no differences in postoperative outcomes scores compared to the non-depressed cohort.19/21 (90.5%) of situationally depressed patients had postoperative resolution of their depressive symptoms. CONCLUSIONS: Situationally depressed patients without a clinical diagnosis of depression can expect significant improvements in both pain and function, as well as a resolution of their depressed mood based on PROMIS scores as they progress through recovery after ACL reconstruction. Clinically depressed patients also experience significant improvements; however, their rate of achieving the minimum clinically important difference for PROMIS outcomes may be less than their nondepressed or situationally depressed counterparts. LEVEL OF EVIDENCE: III, prognostic comparative trial.

Recent Advances in Kidney Bioengineering.

Kidney disease is an epidemic that affects more than 600 million people worldwide. The socioeconomic impacts of the disease disproportionately affect Hispanic and non-Hispanic Black Americans, making the disease an issue of social inequality. The urgency of this situation has only become worse during the COVID-19 pandemic, as those who are hospitalized for COVID-19 have an increased risk of kidney failure. For researchers, the kidney is a complex organ that is difficult to accurately model and understand. Traditional cell culture models are not adequate for studying the functional intricacies of the kidney, but recent experiments have offered improvements for understanding these systems. Recent progress includes organoid modeling, 3D bioprinting, decellularization, and microfluidics. Here, we offer a review of the most recent advances in kidney bioengineering.

Podocyte-specific KLF4 is required to maintain parietal epithelial cell quiescence in the kidney.

Podocyte loss triggering aberrant activation and proliferation of parietal epithelial cells (PECs) is a central pathogenic event in proliferative glomerulopathies. Podocyte-specific Krüppel-like factor 4 (KLF4), a zinc-finger transcription factor, is essential for maintaining podocyte homeostasis and PEC quiescence. Using mice with podocyte-specific knockdown of Klf4, we conducted glomerular RNA-sequencing, tandem mass spectrometry, and single-nucleus RNA-sequencing to identify cell-specific transcriptional changes that trigger PEC activation due to podocyte loss. Integration with in silico chromatin immunoprecipitation identified key ligand-receptor interactions, such as fibronectin 1 (FN1)­αVß6, between podocytes and PECs dependent on KLF4 and downstream signal transducer and activator of transcription 3 (STAT3) signaling. Knockdown of Itgb6 in PECs attenuated PEC activation. Additionally, podocyte-specific induction of human KLF4 or pharmacological inhibition of downstream STAT3 activation reduced FN1 and integrin ß 6 (ITGB6) expression and mitigated podocyte loss and PEC activation in mice. Targeting podocyte-PEC crosstalk might be a critical therapeutic strategy in proliferative glomerulopathies.

Preoperative PROMIS Scores Predict Postoperative Outcomes After Primary ACL Reconstruction.

BACKGROUND: PROMIS (Patient-Reported Outcomes Measurement Information System) scores in patients undergoing anterior cruciate ligament (ACL) reconstruction have not been fully described in the literature to date. The ability of preoperative patient-reported outcome scores to directly predict postoperative outcomes in patients who undergo primary ACL reconstruction is unknown. HYPOTHESIS: Postoperative PROMIS physical function (PF), pain interference (PI), and depression (D) scores in patients who undergo ACL reconstruction will show improvement when compared with preoperative scores. Additionally, preoperative PROMIS PF, PI, and D scores will predict which patients will not achieve a minimal clinically important difference (MCID) postoperatively. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 233 patients who underwent primary ACL reconstruction between 2015 and 2016 and had completed PROMIS measures both preoperatively (within 60 days of surgery) and postoperatively (100-240 days after surgery) were included in this study. PROMIS PF, PI, and D scores were compared. Accuracy analyses were performed to determine whether preoperative PROMIS scores from each domain could predict postoperative achievement of MCID in the same domain. Cutoff scores were then calculated. RESULTS: PROMIS PF, PI, and D scores all showed a significant improvement after ACL reconstruction (all P < .001). Preoperative scores from all 3 PROMIS domains showed a strong ability to predict clinically meaningful improvement, as defined by MCID, with areas under the receiver operating characteristic curve from 0.72 to 0.84. Optimal cutoffs for preoperative PROMIS scores showed that patients with a PF score of <42.5, PI score of >56.2, or D score of >44.8 were more likely to achieve MCID. CONCLUSION: PROMIS PF, PI, and D scores improved significantly in patients who underwent primary ACL reconstruction. Preoperative PROMIS PF, PI, and D scores were highly predictive of outcome in the early postoperative period. The reported cutoff scores showed high probability in predicting which patients would and would not achieve a clinically meaningful improvement.

Neurogenic to Gliogenic Fate Transition Perturbed by Loss of HMGB2.

Mouse cortical development relies heavily on a delicate balance between neurogenesis and gliogenesis. The lateral ventricular zone produces different classes of excitatory pyramidal cells until just before birth, when the production of astroglia begins to prevail. Epigenetic control of this fate shift is of critical importance and chromatin regulatory elements driving neuronal or astroglial development play an vital role. Different classes of chromatin binding proteins orchestrate the transcriptional repression of neuronal-specific genes, while allowing for the activation of astrocyte-specific genes. Through proteomic analysis of embryonic neural progenitor cells (NPCs) our group had previously identified high mobility group B2 (HMGB2), a chromatin protein dynamically expressed throughout embryonic development. In the current study using cultures of perinatal NPCs from HMGB2+/+ and HMGB2-/- mice we discovered that vital elements of the polycomb group (PcG) epigenetic complexes polycomb repressive complexes 1 and 2 (PRC1/2) were downregulated during the differentiation process of HMGB2-null NPCs. These epigenetic changes led to downstream changes in specific histone modification levels, specifically the trimethylation of H3K27, and a subsequent shift in the perinatal neurogenesis to gliogenesis fate transition. Collectively these results demonstrate that chromatin binding proteins, such as HMGB2, can have significant effects on the epigenetic landscape of perinatal neural stem/progenitor cells.

Physical Examination of the Knee: Meniscus, Cartilage, and Patellofemoral Conditions.

The knee is one of the most commonly injured joints in the body. Its superficial anatomy enables diagnosis of the injury through a thorough history and physical examination. Examination techniques for the knee described decades ago are still useful, as are more recently developed tests. Proper use of these techniques requires understanding of the anatomy and biomechanical principles of the knee as well as the pathophysiology of the injuries, including tears to the menisci and extensor mechanism, patellofemoral conditions, and osteochondritis dissecans. Nevertheless, the clinical validity and accuracy of the diagnostic tests vary. Advanced imaging studies may be useful adjuncts.

Physical Examination of Knee Ligament Injuries.

The knee is one of the most commonly injured joints in the body. A thorough history and physical examination of the knee facilitates accurate diagnosis of ligament injury. Several examination techniques for the knee ligaments that were developed before advanced imaging remain as accurate or more accurate than these newer imaging modalities. Proper use of these examination techniques requires an understanding of the anatomy and pathophysiology of knee ligament injuries. Advanced imaging can be used to augment a history and examination when necessary, but should not replace a thorough history and physical examination.

Culturing microglia from the neonatal and adult central nervous system.

Microglia are the resident macrophage-like cells of the central nervous system (CNS) and, as such, have critically important roles in physiological and pathological processes such as CNS maturation in development, multiple sclerosis, and spinal cord injury. Microglia can be activated and recruited to action by neuronal injury or stimulation, such as axonal damage seen in MS or ischemic brain trauma resulting from stroke. These immunocompetent members of the CNS are also thought to have roles in synaptic plasticity under non-pathological conditions. We employ protocols for culturing microglia from the neonatal and adult tissues that are aimed to maximize the viable cell numbers while minimizing confounding variables, such as the presence of other CNS cell types and cell culture debris. We utilize large and easily discernable CNS components (e.g. cortex, spinal cord segments), which makes the entire process feasible and reproducible. The use of adult cells is a suitable alternative to the use of neonatal brain microglia, as many pathologies studied mainly affect the postnatal spinal cord. These culture systems are also useful for directly testing the effect of compounds that may either inhibit or promote microglial activation. Since microglial activation can shape the outcomes of disease in the adult CNS, there is a need for in vitro systems in which neonatal and adult microglia can be cultured and studied.

Members of the high mobility group B protein family are dynamically expressed in embryonic neural stem cells.

Neural Stem Cells (NSCs) are a distinct group of cells present in the embryonic and adult mammalian central nervous system (CNS) that are able to differentiate into neurons, astrocytes and oligodendrocytes. As NSC proliferation declines with age, factors that regulate this process need to be defined. To search for NSC regulatory factors, we performed a quantitative shotgun proteomics study that revealed that members of the High Mobility Group B (HMGB) family are highly expressed in NSCs. Using a neurosphere assay, we report the differential expression of HMGB 1, 2, 3, and 4 mRNAs in proliferating NSCs isolated from various time points during embryonic development, as well as the dynamic expression of HMGB1 and B2 mRNAs and proteins in differentiating embryonic NSCs. Expression of HMGB2 underwent the most dramatic changes during the developmental ages examined; as a result, we assessed its role in NSC proliferation and differentiation. We report the predominance of small diameter HMGB2-/- neurospheres in comparison to wild-type, which correlated with increased proliferation in these smaller HMGB2-/- neurospheres. Our data suggest that HMGB2 plays a regulatory role in NSC cell proliferation and maintenance pathways.

Aberrant neural stem cell proliferation and increased adult neurogenesis in mice lacking chromatin protein HMGB2.

Neural stem and progenitor cells (NSCs/NPCs) are distinct groups of cells found in the mammalian central nervous system (CNS). Previously we determined that members of the High Mobility Group (HMG) B family of chromatin structural proteins modulate NSC proliferation and self-renewal. Among them HMGB2 was found to be dynamically expressed in proliferating and differentiating NSCs, suggesting that it may regulate NSC maintenance. We report now that Hmgb2(-/-) mice exhibit SVZ hyperproliferation, increased numbers of SVZ NSCs, and a trend towards aberrant increases in newly born neurons in the olfactory bulb (OB) granule cell layer. Increases in the levels of the transcription factor p21 and the Neural cell adhesion molecule (NCAM), along with down-regulation of the transcription/pluripotency factor Oct4 in the Hmgb2-/- SVZ point to a possible pathway for this increased proliferation/differentiation. Our findings suggest that HMGB2 functions as a modulator of neurogenesis in young adult mice through regulation of NSC proliferation, and identify a potential target via which CNS repair could be amplified following trauma or disease-based neuronal degeneration.

Fibrinogen and beta-amyloid association alters thrombosis and fibrinolysis: a possible contributing factor to Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder in which vascular pathology plays an important role. Since the beta-amyloid peptide (Abeta) is a critical factor in this disease, we examined its relationship to fibrin clot formation in AD. In vitro and in vivo experiments showed that fibrin clots formed in the presence of Abeta are structurally abnormal and resistant to degradation. Fibrin(ogen) was observed in blood vessels positive for amyloid in mouse and human AD samples, and intravital brain imaging of clot formation and dissolution revealed abnormal thrombosis and fibrinolysis in AD mice. Moreover, depletion of fibrinogen lessened cerebral amyloid angiopathy pathology and reduced cognitive impairment in AD mice. These experiments suggest that one important contribution of Abeta to AD is via its effects on fibrin clots, implicating fibrin(ogen) as a potential critical factor in this disease.