Quantifying Inferior Vena Cava Compliance and Distensibility in an In Vivo Ovine Model Using 3D Angiography.

Synthetic vascular grafts overcome some challenges of allografts, autografts, and xenografts but are often more rigid and less compliant than the native vessel into which they are implanted. Compliance matching with the native vessel is emerging as a key property for graft success. The current gold standard for assessing vessel compliance involves the vessel's excision and ex vivo biaxial mechanical testing. We developed an in vivo method to assess venous compliance and distensibility that better reflects natural physiology and takes into consideration the impact of a pressure change caused by flowing blood and by any morphologic changes present. This method is designed as a survival procedure, facilitating longitudinal studies while potentially reducing the need for animal use. Our method involves injecting a 20 mL/kg saline bolus into the venous vasculature, followed by the acquisition of pre and post bolus 3D angiograms to observe alterations induced by the bolus, concurrently with intravascular pressure measurements in target regions. We are then able to measure the circumference and the cross-sectional area of the vessel pre and post bolus. With these data and the intravascular pressure, we are able to calculate the compliance and distensibility with specific equations. This method was used to compare the inferior vena cava's compliance and distensibility in native unoperated sheep to the conduit of sheep implanted with a long-term expanded polytetrafluorethylene (PTFE) graft. The native vessel was found to be more compliant and distensible than the PTFE graft at all measured locations. We conclude that this method safely provides in vivo measurements of vein compliance and distensibility.

Acoustic startle and prepulse inhibition deficits in adult monkeys with neonatal lesions of the hippocampus, amygdala and orbital frontal cortex.

Sensory-motor gating, the process of filtering sensory stimuli to modulate motor responses, is impaired in many psychiatric diseases but especially schizophrenia. Sensory-motor gating assessed with the prepulse inhibition paradigm (PPI) measures startle in response to preceding acoustic stimuli. PPI studies in rodents have consistently found that neonatal hippocampal lesions impair sensory-motor gating in adult animals, but its applicability to primates has yet to be tested. The study examined acoustic startle responses and PPI in adult rhesus monkeys with neonatal lesions of the hippocampus (Neo-Hibo), amygdala (Neo-Aibo), and orbital frontal cortex areas 11 and 13 (Neo-Oasp) and with sham-operations (Neo-C). All monkeys were initially habituated to the startle apparatus and assayed for acoustic startle response curves. Subsequently, PPI was measured with the prepulse occurring at 60, 120, 240, 480, 1000 and 5000 msec prior to the pulse onset. No significant group differences in baseline startle were found. Compared to Neo-C monkeys, Neo-Hibo monkeys showed normal startle curves as well as normal PPI at short prepulse delays but prepulse facilitation (PPF) at longer prepulse intervals. Neo-Aibo monkeys displayed enhanced startle responses with only minor changes in PPI, whereas Neo-Oasp monkeys had severe dampening of startle responses and impaired PPI at shorter prepulse intervals. These results support prior evidence from rodent literature of the involvement of each of these areas in the development of the complex cortico-limbic circuit modulating sensory-motor gating and may shade light on the specific neural structures associated with deficits in PPI reported in neuropsychiatric disorders, such as schizophrenia, autism spectrum disorders, and post-traumatic disorders.

Computational analysis of serum-derived extracellular vesicle miRNAs in juvenile sheep model of single stage Fontan procedure.

Patients with single ventricle heart defects requires a series of staged open-heart procedures, termed Fontan palliation. However, while lifesaving, these operations are associated with significant morbidity and early mortality. The attendant complications are thought to arise in response to the abnormal hemodynamics induced by Fontan palliation, although the pathophysiology underlying these physicochemical changes in cardiovascular and other organs remain unknown. Here, we investigated the microRNA (miRNA) content in serum and serum-derived extracellular vesicles (EVs) by sequencing small RNAs from a physiologically relevant sheep model of the Fontan operation. The differential expression analysis identified the enriched miRNA clusters in (1) serum vs. serum-derived EVs and (2) pre-Fontan EVs vs. post-Fontan EVs. Metascape analysis showed that the overexpressed subset of EV miRNAs by Fontan procedure target liver-specific cells, underscoring a potentially important pathway involved in the liver dysfunction that occurs as a consequence of Fontan palliation. We also found that post-Fontan EV miRNAs were associated with senescence and cell death, whereas pre-Fontan EV miRNAs were associated with stem cell maintenance and epithelial-to-mesenchymal transition. This study shows great potential to identify novel circulating EV biomarkers from Fontan sheep serum that may be used for the diagnosis, prognosis, and therapeutics for patients that have undergone Fontan palliation.

Tissue engineered vascular grafts transform into autologous neovessels capable of native function and growth.

Background: Tissue-engineered vascular grafts (TEVGs) have the potential to advance the surgical management of infants and children requiring congenital heart surgery by creating functional vascular conduits with growth capacity. Methods: Herein, we used an integrative computational-experimental approach to elucidate the natural history of neovessel formation in a large animal preclinical model; combining an in vitro accelerated degradation study with mechanical testing, large animal implantation studies with in vivo imaging and histology, and data-informed computational growth and remodeling models. Results: Our findings demonstrate that the structural integrity of the polymeric scaffold is lost over the first 26 weeks in vivo, while polymeric fragments persist for up to 52 weeks. Our models predict that early neotissue accumulation is driven primarily by inflammatory processes in response to the implanted polymeric scaffold, but that turnover becomes progressively mechano-mediated as the scaffold degrades. Using a lamb model, we confirm that early neotissue formation results primarily from the foreign body reaction induced by the scaffold, resulting in an early period of dynamic remodeling characterized by transient TEVG narrowing. As the scaffold degrades, mechano-mediated neotissue remodeling becomes dominant around 26 weeks. After the scaffold degrades completely, the resulting neovessel undergoes growth and remodeling that mimicks native vessel behavior, including biological growth capacity, further supported by fluid-structure interaction simulations providing detailed hemodynamic and wall stress information. Conclusions: These findings provide insights into TEVG remodeling, and have important implications for clinical use and future development of TEVGs for children with congenital heart disease.

Spontaneous reversal of stenosis in tissue-engineered vascular grafts.

We developed a tissue-engineered vascular graft (TEVG) for use in children and present results of a U.S. Food and Drug Administration (FDA)-approved clinical trial evaluating this graft in patients with single-ventricle cardiac anomalies. The TEVG was used as a Fontan conduit to connect the inferior vena cava and pulmonary artery, but a high incidence of graft narrowing manifested within the first 6 months, which was treated successfully with angioplasty. To elucidate mechanisms underlying this early stenosis, we used a data-informed, computational model to perform in silico parametric studies of TEVG development. The simulations predicted early stenosis as observed in our clinical trial but suggested further that such narrowing could reverse spontaneously through an inflammation-driven, mechano-mediated mechanism. We tested this unexpected, model-generated hypothesis by implanting TEVGs in an ovine inferior vena cava interposition graft model, which confirmed the prediction that TEVG stenosis resolved spontaneously and was typically well tolerated. These findings have important implications for our translational research because they suggest that angioplasty may be safely avoided in patients with asymptomatic early stenosis, although there will remain a need for appropriate medical monitoring. The simulations further predicted that the degree of reversible narrowing can be mitigated by altering the scaffold design to attenuate early inflammation and increase mechano-sensing by the synthetic cells, thus suggesting a new paradigm for optimizing next-generation TEVGs. We submit that there is considerable translational advantage to combined computational-experimental studies when designing cutting-edge technologies and their clinical management.

Effect of the Affordable Care Act on a Safety-Net Burn Center.

We hypothesized that the Patient Protection and Affordable Care Act (ACA) would have beneficial financial effects on our burn center at a safety-net hospital. We performed a retrospective chart review of all burn patients admitted to our center from 2008-2016. These were further divided into three time periods: 2008-2010 (pre-ACA), 2011-2013 (transitional), and 2014-2016 (post-ACA). Cost and reimbursement dollars were adjusted to health personal consumption expenditures price index. Total charges increased from the pre-ACA group ($69,400) to the transitional group ($85,600) and increased again in the post-ACA group ($100,100) (p<.001). When looking at reimbursements relative to charges, actual reimbursement by percentage dropped over each time period. Despite an increase in insured patients, our burn center actually saw a decrease in reimbursements relative to billing.

Angiotensin II receptor I blockade prevents stenosis of tissue engineered vascular grafts.

We previously developed a tissue-engineered vascular graft (TEVG) made by seeding autologous cells onto a biodegradable tubular scaffold, in an attempt to create a living vascular graft with growth potential for use in children undergoing congenital heart surgery. Results of our clinical trial showed that the TEVG possesses growth capacity but that its widespread clinical use is not yet advisable due to the high incidence of TEVG stenosis. In animal models, TEVG stenosis is caused by increased monocytic cell recruitment and its classic ("M1") activation. Here, we report on the source and regulation of these monocytes. TEVGs were implanted in wild-type, CCR2 knockout ( Ccr2-/-), splenectomized, and spleen graft recipient mice. We found that bone marrow-derived Ly6C+hi monocytes released from sequestration by the spleen are the source of mononuclear cells infiltrating the TEVG during the acute phase of neovessel formation. Furthermore, short-term administration of losartan (0.6 g/L, 2 wk), an angiotensin II type 1 receptor antagonist, significantly reduced the macrophage populations (Ly6C+/-/F480+) in the scaffolds and improved long-term patency in TEVGs. Notably, the combined effect of bone marrow-derived mononuclear cell seeding with short-term losartan treatment completely prevented the development of TEVG stenosis. Our results provide support for pharmacologic treatment with losartan as a strategy to modulate monocyte infiltration into the grafts and thus prevent TEVG stenosis.-Ruiz-Rosado, J. D. D., Lee, Y.-U., Mahler, N., Yi, T., Robledo-Avila, F., Martinez-Saucedo, D., Lee, A. Y., Shoji, T., Heuer, E., Yates, A. R., Pober, J. S., Shinoka, T., Partida-Sanchez, S., Breuer, C. K. Angiotensin II receptor I blockade prevents stenosis of tissue engineered vascular grafts.

Quantification of tissue-engineered trachea performance with computational fluid dynamics.

OBJECTIVES/HYPOTHESIS: Current techniques for airway characterization include endoscopic or radiographic measurements that produce static, two-dimensional descriptions. As pathology can be multilevel, irregularly shaped, and dynamic, minimal luminal area (MLA) may not provide the most comprehensive description or diagnostic metric. Our aim was to examine the utilization of computational fluid dynamics (CFD) for the purpose of defining airway stenosis using an ovine model of tissue-engineered tracheal graft (TETG) implantation. STUDY DESIGN: Animal research model. METHODS: TETGs were implanted into sheep, and MLA was quantified with imaging and endoscopic measurements. Graft stenosis was managed with endoscopic dilation and stenting when indicated. Geometries of the TETG were reconstructed from three-dimensional fluoroscopic images. CFD simulations were used to calculate peak flow velocity (PFV) and peak wall shear stress (PWSS). These metrics were compared to values derived from a quantitative respiratory symptom score. RESULTS: Elevated PFV and PWSS derived from CFD modeling correlated with increased respiratory symptoms. Immediate pre- and postimplantation CFD metrics were similar, and implanted sheep were asymptomatic. Respiratory symptoms improved with stenting, which maintained graft architecture similar to dilation procedures. With stenting, baseline PFV (0.33 m/s) and PWSS (0.006 Pa) were sustained for the remainder of the study. MLA measurements collected via bronchoscopy were also correlated with respiratory symptoms. PFV and PWSS found via CFD were correlated (R2 = 0.92 and 0.99, respectively) with respiratory symptoms compared to MLA (R2 = 0.61). CONCLUSIONS: CFD is valid for informed interventions based on multilevel, complex airflow and airway characteristics. Furthermore, CFD may be used to evaluate TETG functionality. LEVEL OF EVIDENCE: NA. Laryngoscope, E272-E279, 2018.

The Heart and Great Vessels.

Cardiovascular disease is the leading cause of mortality worldwide. We have made large strides over the past few decades in management, but definitive therapeutic options to address this health-care burden are still limited. Given the ever-increasing need, much effort has been spent creating engineered tissue to replaced diseased tissue. This article gives a general overview of this work as it pertains to the development of great vessels, myocardium, and heart valves. In each area, we focus on currently studied methods, limitations, and areas for future study.

Designing a tissue-engineered tracheal scaffold for preclinical evaluation.

OBJECTIVE: Recent efforts to tissue engineer long-segment tracheal grafts have been complicated by stenosis and malacia. It has been proposed that both the mechanical characteristics and cell seeding capacity of TETG scaffolds are integral to graft performance. Our aim was to design a tracheal construct that approximates the biomechanical properties of native sheep trachea and optimizes seeding with bone marrow derived mononuclear cells prior to preclinical evaluation in an ovine model. METHODS: A solution of 8% polyethylene terephthalate (PET) and 3% polyurethane (PU) was prepared at a ratio of either 8:2 or 2:8 and electrospun onto a custom stainless steel mandrel designed to match the dimensional measurements of the juvenile sheep trachea. 3D-printed porous or solid polycarbonate C-shaped rings were embedded within the scaffolds during electrospinning. The scaffolds underwent compression testing in the anterior-posterior and lateral-medial axes and the biomechanical profiles compared to that of a juvenile ovine trachea. The most biomimetic constructs then underwent vacuum seeding with ovine bone marrow derived mononuclear cells. Fluorometric DNA assay was used to quantify scaffold seeding. RESULTS: Both porous and solid rings approximated the biomechanics of the native ovine trachea, but the porous rings were most biomimetic. The load-displacement curve of scaffolds fabricated from a ratio of 2:8 PET:PU most closely mimicked that of native trachea in the anterior-posterior and medial-lateral axes. Solid C-ringed scaffolds had a greater cell seeding efficiency when compared to porous ringed scaffolds (Solid: 19 × 104 vs. Porous: 9.6 × 104 cells/mm3, p = 0.0098). CONCLUSION: A long segment tracheal graft composed of 2:8 PET:PU with solid C-rings approximates the biomechanics of the native ovine trachea and demonstrates superior cell seeding capacity of the two prototypes tested. Further preclinical studies using this graft design in vivo would inform the rational design of an optimal TETG scaffold.

The role of myeloid cell-derived PDGF-B in neotissue formation in a tissue-engineered vascular graft.

AIM: Inflammatory myeloid lineage cells mediate neotissue formation in tissue-engineered vascular grafts, but the molecular mechanism is not completely understood. We examined the role of vasculogenic PDGF-B in tissue-engineered vascular graft neotissue development. MATERIALS & METHODS: Myeloid cell-specific PDGF-B knockout mice (PDGF-KO) were generated using bone marrow transplantation, and scaffolds were implanted as inferior vena cava interposition grafts in either PDGF-KO or wild-type mice. RESULTS: After 2 weeks, grafts from PDGF-KO mice had more remaining scaffold polymer and less intimal neotissue development. Increased macrophage apoptosis, decreased smooth muscle cell proliferation and decreased collagen content was also observed. CONCLUSION: Myeloid cell-derived PDGF contributes to vascular neotissue formation by regulating macrophage apoptosis, smooth muscle cell proliferation and extracellular matrix deposition.

Amyloid-Related Imaging Abnormalities in an Aged Squirrel Monkey with Cerebral Amyloid Angiopathy.

Amyloid-related imaging abnormalities (ARIA) in magnetic resonance imaging scans have emerged as indicators of potentially serious side effects in clinical trials of therapeutics for Alzheimer's disease. These anomalies include an edematous type (ARIA-E) that appears as hyperintense (bright) regions by T2-weighted MRI, and a type characterized by the deposition of hemosiderin (ARIA-H) that elicits a hypointense signal, especially in T2* susceptibility weighted images. ARIA in general has been linked to the presence of amyloid-ß (Aß)-type cerebral amyloid angiopathy, an accumulation of misfolded Aß protein in the vascular wall that impairs the integrity of brain blood vessels. However, the pathobiology of ARIA remains poorly understood, in part due to the absence of an animal model of the disorder that would enable a contemporaneous analysis of tissue integrity in the affected region. Here we describe both ARIA-E and ARIA-H in an aged squirrel monkey (Saimiri sciureus), a nonhuman primate model of naturally occurring cerebral amyloid angiopathy. Histopathologic examination of the anomalous region revealed reactive astrocytosis and microgliosis, infiltration of systemic inflammatory/immune cells, damage to axons and myelin, and hemosiderin deposition. The disruption of axons in particular suggests that ARIA-E could have functional consequences for affected regions. The squirrel monkey model can be useful for studying the pathogenesis and long-term effects of ARIA, and for testing the safety and efficacy of emerging therapies for Alzheimer's disease.

Endoscopic management of tissue-engineered tracheal graft stenosis in an ovine model.

OBJECTIVE: To evaluate the safety and efficacy of bronchoscopic interventions in the management of tissue-engineered tracheal graft (TETG) stenosis. STUDY DESIGN: Animal research study. METHODS: TETGs were constructed with seeded autologous bone marrow-derived mononuclear cells on a bioartificial graft. Eight sheep underwent tracheal resection and orthotopic implantation of this construct. Animals were monitored by bronchoscopy and fluoroscopy at 3 weeks, 6 weeks, 3 months, and 4 months. Bronchoscopic interventions, including dilation and stenting, were performed to manage graft stenosis. Postdilation measurements were obtained endoscopically and fluoroscopically. RESULTS: Seven dilations were performed in six animals. At the point of maximal stenosis, the lumen measured 44.6 ± 8.4 mm2 predilation and 50.7 ± 14.1 postdilation by bronchoscopy (P = 0.3517). By fluoroscopic imaging, the airway was 55.9 ± 12.9 mm2 predilation and 65.9 ± 22.4 mm2 postdilation (P = 0.1303). Stents were placed 17 times in six animals. Pre- and poststenting lumen sizes were 62.8 ± 38.8 mm2 and 80.1 ± 54.5 mm2 by bronchoscopy (P = 0.6169) and 77.1 ± 38.9 mm2 and 104 ± 60.7 mm2 by fluoroscopy (P = 0.0825). Mortality after intervention was 67% with dilation and 0% with stenting (P = 0.0004). The average days between bronchoscopy were 8 ± 2 for the dilation group and 26 ± 17 in the stenting group (P = 0.05). One hundred percent of dilations and 29% of stent placements required urgent follow-up bronchoscopy (P = 0.05). CONCLUSION: Dilation has limited efficacy for managing TETG stenosis, whereas stenting has a more lasting clinical effect. LEVEL OF EVIDENCE: NA. Laryngoscope, 127:2219-2224, 2017.

Intravascular Ultrasound Characterization of a Tissue-Engineered Vascular Graft in an Ovine Model.

Patients who undergo implantation of a tissue-engineered vascular graft (TEVG) for congenital cardiac anomalies are monitored with echocardiography, followed by magnetic resonance imaging or angiography when indicated. While these methods provide data regarding the lumen, minimal information regarding neotissue formation is obtained. Intravascular ultrasound (IVUS) has previously been used in a variety of conditions to evaluate the vessel wall. The purpose of this study was to evaluate the utility of IVUS for evaluation of TEVGs in our ovine model. Eight sheep underwent implantation of TEVGs either unseeded or seeded with bone marrow-derived mononuclear cells. Angiography, IVUS, and histology were directly compared. Endothelium, tunica media, and graft were identifiable on IVUS and histology at multiple time points. There was strong agreement between IVUS and angiography for evaluation of luminal diameter. IVUS offers a valuable tool to evaluate the changes within TEVGs, and clinical translation of this application is warranted.

Objective characterization of airway dimensions using image processing.

OBJECTIVES: With the evolution of medical and surgical management for pediatric airway disorders, the development of easily translated techniques of measuring airway dimensions can improve the quantification of outcomes of these interventions. We have developed a technique that improves the ability to characterize endoscopic airway dimensions using common bronchoscopic equipment and an open-source image-processing platform. METHODS: We validated our technique of Endoscopic Airway Measurement (EAM) using optical instruments in simulation tracheas. We then evaluated EAM in a large animal model (Ovis aries, n = 5), comparing tracheal dimensions obtained with EAM to measurements obtained via 3-D fluoroscopic reconstruction. The animal then underwent resection of the measured segment, and direct measurement of this segment was performed and compared to radiographic measurements and those obtained using EAM. RESULTS: The simulation tracheas had a direct measurement of 13.6, 18.5, and 24.2 mm in diameter. The mean difference of diameter in simulation tracheas between direct measurements and measurements obtained using EAM was 0.70 ± 0.57 mm. The excised ovine tracheas had an average diameter of 18.54 ± 0.68 mm. The percent difference in diameter obtained from EAM and from 3-D fluoroscopic reconstruction when compared to measurement of the excised tracheal segment was 4.98 ± 2.43% and 10.74 ± 4.07% respectively. Comparison of these three measurements (EAM, measurement of resected trachea, 3-D fluoroscopic reconstruction) with repeated measures ANOVA demonstrated no statistical significance. CONCLUSIONS: Endoscopic airway measurement (EAM) provides equivalent measurements of the airway with the improved versatility of measuring non-circular and multi-level dimensions. Using optical bronchoscopic instruments and open-source image-processing software, our data supports preclinical and clinical translation of an accessible technique to provide objective quantification of airway diameter.

Cerebral amyloid angiopathy in an aged sooty mangabey (Cercocebus atys).

A 26-y-old male sooty mangabey (Cercocebus atys) was found at necropsy to have a moderate degree of cerebral amyloid ß (Aß) angiopathy in superficial and parenchymal blood vessels of the brain. Senile (Aß) plaques were absent, as were neurofibrillary tangles and other signs of neurodegeneration. Affected blood vessels were arterial, capillary, and, less frequently, venous in nature. Histologically, the Aß40 isoform was more prevalent than was Aß42. As in humans but unlike in squirrel monkeys, the density of lesions in this mangabey increased along a rostral-to-caudal gradient. Therefore mangabeys appear to conform to the general tendency of nonhuman primates by developing cerebral Aß angiopathy in the absence of other indices of Alzheimer-type neuropathology.

Working memory for temporal order is impaired after selective neonatal hippocampal lesions in adult rhesus macaques.

A previous study in this laboratory demonstrated, for the first time, that neonatal lesions of the hippocampus impair monitoring working memory, as measured by a self-order task, but spare recency memory, as measured by the session-unique delayed nonmatching task. To substantiate and extend this novel finding, we assessed working memory in these same animals using a serial order memory task. In humans and non-human primates the serial order memory task has been shown to be dependent upon the integrity of the dorsolateral prefrontal cortex. Additionally, the serial order task has the ability to examine the integrity of non-dorsolateral dependent working memory functions, providing specificity to conclusions drawn from this task. Thus, monkeys with neonatal lesions of the hippocampus and sham-operated control subjects were tested on two versions of the serial order memory task (3 and 4 objects). The results of this study demonstrated that neonatal hippocampal lesions did not impair performance on the 3-object version of the task, confirming our previous finding of intact non-dlPFC dependent working memory. In contrast, these same animals showed a significant impairment on the dlPFC dependent phase of the 4-object serial order task. This finding was further confirmed through a series of probe trials. These results, in combination with our earlier finding, suggest that early lesions of the hippocampus may have impacted the function of the dlPFC or its interactions with the hippocampus.

Effects of neonatal amygdala lesions on fear learning, conditioned inhibition, and extinction in adult macaques.

Fear conditioning studies have demonstrated the critical role played by the amygdala in emotion processing. Although all lesion studies until now investigated the effect of adult-onset damage on fear conditioning, the current study assessed fear-learning abilities, as measured by fear-potentiated startle, in adult monkeys that had received neonatal neurotoxic amygdala damage or sham-operations. After fear acquisition, their abilities to learn and use a safety cue to modulate their fear to the conditioned cue, and, finally, to extinguish their response to the fear conditioned cue were measured with the AX+/BX- Paradigm. Neonatal amygdala damage retarded, but did not completely abolish, the acquisition of a learned fear. After acquisition of the fear signal, four of the six animals with neonatal amygdala lesions discriminated between the fear and safety cues and were also able to use the safety signal to reduce the potentiated-startle response and to extinguish the fear response when the air-blast was absent. In conclusion, the present results support the critical contribution of the amygdala during the early phases of fear conditioning that leads to quick, robust responses to potentially threatening stimuli, a highly adaptive process across all species and likely to be present in early infancy. The neonatal amygdala lesions also indicated the presence of amygdala-independent alternate pathways that are capable to support fear learning in the absence of a functional amygdala. This parallel processing of fear responses within these alternate pathways was also sufficient to support the ability to flexibly modulate the magnitude of the fear responses.

Nonhuman primate models of Alzheimer-like cerebral proteopathy.

Nonhuman primates are useful for the study of age-associated changes in the brain and behavior in a model that is biologically proximal to humans. The Aß and tau proteins, two key players in the pathogenesis of Alzheimer's disease (AD), are highly homologous among primates. With age, all nonhuman primates analyzed to date develop senile (Aß) plaques and cerebral ß-amyloid angiopathy. In contrast, significant tauopathy is unusual in simians, and only humans manifest the profound tauopathy, neuronal degeneration and cognitive impairment that characterize Alzheimer's disease. Primates thus are somewhat paradoxical models of AD-like pathology; on the one hand, they are excellent models of normal aging and naturally occurring Aß lesions, and they can be useful for testing diagnostic and therapeutic agents targeting aggregated forms of Aß. On the other hand, the resistance of monkeys and apes to tauopathy and AD-related neurodegeneration, in the presence of substantial cerebral Aß deposition, suggests that a comparative analysis of human and nonhuman primates could yield informative clues to the uniquely human predisposition to Alzheimer's disease.

Neonatal hippocampal lesions in rhesus macaques alter the monitoring, but not maintenance, of information in working memory.

Neonatal hippocampal damage in rodents impairs medial prefrontal working memory functions. To examine whether similar impairment will follow the same damage in primates, adult monkeys with neonatal hippocampal lesions and sham-operated controls were trained on two working memory tasks. The session-unique delayed nonmatch-to-sample (SU-DNMS) task measures maintenance of information in working memory mediated by the ventral lateral prefrontal cortex. The object self-ordered (Obj-SO) task measures monitoring of information in working memory mediated by the dorsolateral prefrontal cortex. Adult monkeys with neonatal hippocampal lesions performed as well as sham-operated controls on the SU-DNMS task at either the 5- or 30-s delays but were severely impaired on the Obj-SO task. These results extend the earlier findings in rodents by demonstrating that early lesions of the hippocampus in monkeys impair working memory processes known to require the integrity of the dorsolateral prefrontal cortex while sparing lower order working memory processes such as recency. Although the present results suggest that the lack of functional hippocampal inputs may have altered the maturation of the dorsolateral prefrontal cortex, future studies will be needed to determine whether the nature of the observed working memory deficit is due to an absence of the hippocampus, a maldevelopment of the dorsolateral prefrontal cortex, or both.