Reliability of a Novel Classification System for Thoracic Disc Herniations.

STUDY DESIGN: This is a cross-sectional survey. OBJECTIVE: The aim was to assess the reliability of a proposed novel classification system for thoracic disc herniations (TDHs). SUMMARY OF BACKGROUND DATA: TDHs are complex entities varying substantially in many factors, including size, location, and calcification. To date, no comprehensive system exists to categorize these lesions. METHODS: Our proposed system classifies 5 types of TDHs using anatomic and clinical characteristics, with subtypes for calcification. Type 0 herniations are small (≤40% of spinal canal) TDHs without significant spinal cord or nerve root effacement; type 1 are small and paracentral; type 2 are small and central; type 3 are giant (>40% of spinal canal) and paracentral; and type 4 are giant and central. Patients with types 1 to 4 TDHs have correlative clinical and radiographic evidence of spinal cord compression. Twenty-one US spine surgeons with substantial TDH experience rated 10 illustrative cases to determine the system's reliability. Interobserver and intraobserver reliability were determined using the Fleiss kappa coefficient. Surgeons were also surveyed to obtain consensus on surgical approaches for the various TDH types. RESULTS: High agreement was found for the classification system, with 80% (range 62% to 95%) overall agreement and high interrater and intrarater reliability (kappa 0.604 [moderate to substantial agreement] and kappa 0.630 [substantial agreement], respectively). All surgeons reported nonoperative management of type 0 TDHs. For type 1 TDHs, most respondents (71%) preferred posterior approaches. For type 2 TDHs, responses were roughly equivalent for anterolateral and posterior options. For types 3 and 4 TDHs, most respondents (72% and 68%, respectively) preferred anterolateral approaches. CONCLUSIONS: This novel classification system can be used to reliably categorize TDHs, standardize description, and potentially guide the selection of surgical approach. Validation of this system with regard to treatment and clinical outcomes represents a line of future study.

Influence of Spinal Deformity Construct Design on Adjacent-Segment Biomechanics.

BACKGROUND: Adjacent level degeneration is a precursor to construct failure in adult spinal deformity surgery, but whether construct design affects adjacent level degeneration risk remains unclear. Here we present a biomechanical profile of common deformity correction constructs and assess adjacent level biomechanics. METHODS: Standard nondestructive flexibility tests (7.5 Nm) were performed on 21 cadaveric specimens: 14 pedicle subtraction osteotomies (PSOs) and 7 anterior column realignment (ACR) constructs. The ranges of motion (ROM) at the adjacent free level in flexion, extension, axial rotation, and lateral bending were measured and analyzed. RESULTS: ACR constructs had a lower ROM change on flexion at the proximal adjacent free level than constructs with PSO (1.02 vs. 1.32, normalized to the intact specimen, P < 0.01). Lateral lumbar interbody fusion adjacent to PSO and 4 rods limits ROM at the free level more effectively than transforaminal interbody fusion and 2 rods in correction constructs with PSO. Use of 2 screws to anchor the ACR interbody further decreased ROM at the proximal adjacent free level on flexion, but adding 4 rods in this setting added no further limitation to adjacent segment motion. CONCLUSIONS: ACR constructs have less ROM change at the adjacent level compared to PSO constructs. Among constructs with ACR, anchoring the ACR interbody with 2 screws reduces motion at the proximal adjacent free level. When PSOs are used, lateral lumbar interbody fusion adjacent to the PSO level has a greater reduction in adjacent-segment motion than transforaminal interbody fusion, suggesting that deformity construct configuration influences proximal adjacent-segment biomechanics.

Are Minimally Invasive Spine Surgeons or Classical Open Spine Surgeons More Consistent with Their Treatment of Adult Spinal Deformity?

OBJECTIVE: Spine surgeons have a heuristic sense of how to surgically restore alignment and address adult spinal deformity (ASD) symptoms, but consensus on the extent of treatment remains unclear. We sought to determine the variability of surgical approaches in treating ASD. METHODS: Sixteen spine surgeons were surveyed on treatment approaches in 10 select ASD cases. We repeated the survey with the same surgeons 4 weeks later, with cases ordered differently. We examined the variability in length of construct, use of interbody spacers, osteotomies, and pelvic fixation frequency. RESULTS: Treatment approaches for each case varied by surgeon, with some surgeons opting for long fusion constructs in cases for which others offered no surgery. There was no consensus among surgeons on the number of levels fused, interbody spacer use, or anterior/posterior osteotomies. Intersurgeon and intrasurgeon variability was 48% (kappa = 0.31) and 59% (kappa = 0.44) for surgeons performing minimally invasive surgery (MIS) versus 37% (kappa = 0.21) and 47% (kappa = 0.30) for those performing open surgery. In the second-round survey, 8 of 15 (53%) surgeons substantially changed the construct length, number of interbody spacers, and osteotomies in at least half the cases they previously reviewed. Surgeons performing MIS versus open surgery were less likely to extend constructs to the pelvis (42.5% vs. 67.5%; P = 0.02), but construct length was not correlated with whether a surgeon performed MIS or open surgery. CONCLUSIONS: Spinal deformity surgeons lack consensus on the optimal surgical approach for treating ASD. Classifying surgeons as performing MIS or open surgery does not mitigate this variability.

Should Somatosensory and Motor Evoked Potential Monitoring Be Used Routinely in All Posterior Cervical Operations for Degenerative Conditions of the Cervical Spine?

OBJECTIVE: Intraoperative neuromonitoring (IONM) is useful during spinal cord operations, but whether IONM is necessary for posterior cervical surgeries for degenerative conditions is unknown. We evaluated the utility of somatosensory evoked potential (SSEP) and motor evoked potential (MEP) monitoring as a tool for predicting new postoperative neurologic deficits during posterior decompression and fusion for degenerative cervical spine conditions. METHODS: We retrospectively reviewed posterior cervical operations performed at our institute over a 4-year period. Patients with postoperative neurologic deficits were identified, and a detailed analysis performed to ascertain whether SSEP or MEP monitoring accurately predicted the onset of new postoperative deficits. RESULTS: Overall, 498 patients were included in the analysis (median age 66 years; range: 22-93 years). SSEP monitoring was performed in all patients, and both SSEP and MEP monitoring were performed in 121 patients (24%). Twenty-one patients (4.2%) had new postoperative neurologic deficits. SSEP had significantly higher specificity (90%) but lower sensitivity (33%) than MEP (74% specificity [P = 0.008], 50% sensitivity [P = 0.01]) for detecting neurologic compromise intraoperatively. For SSEP, the positive predictive value (PPV) and negative predictive value (NPV) in detecting intraoperative changes that translated to new postoperative neurological deficits were 12% and 97%, respectively, whereas for MEP, the PPV and NPV were 6% (P = 0.009) and 98% (P = 0.20), respectively. CONCLUSIONS: IONM during posterior cervical operations for degenerative conditions of the spine is not reliable at predicting new postoperative neurologic deficits in patients treated for degenerative conditions, but may provide peace of mind to the surgeon intraoperatively when no abnormalities are detected.

Surgical anatomy of minimally invasive lateral approaches to the thoracolumbar junction.

OBJECTIVE: The thoracolumbar (TL) junction spanning T11 to L2 is difficult to access because of the convergence of multiple anatomical structures and tissue planes. Earlier studies have described different approaches and anatomical structures relevant to the TL junction. This anatomical study aims to build a conceptual framework for selecting and executing a minimally invasive lateral approach to the spine for interbody fusion at any level of the TL junction with appropriate adjustments for local anatomical variations. METHODS: The authors reviewed anatomical dissections from 9 fresh-frozen cadaveric specimens as well as clinical case examples to denote key anatomical relationships and considerations for approach selection. RESULTS: The retroperitoneal and retropleural spaces reside within the same extracoelomic cavity and are separated from each other by the lateral attachments of the diaphragm to the rib and the L1 transverse process. If the lateral diaphragmatic attachments are dissected and the diaphragm is retracted anteriorly, the retroperitoneal and retropleural spaces will be in direct continuity, allowing full access to the TL junction. The T12-L2 disc spaces can be reached by a conventional lateral retroperitoneal exposure with the rostral displacement of the 11th and 12th ribs. With caudally displaced ribs, or to expose T12-L1 disc spaces, the diaphragm can be freed from its lateral attachments to perform a retrodiaphragmatic approach. The T11-12 disc space can be accessed purely through a retropleural approach without significant mobilization of the diaphragm. CONCLUSIONS: The entirety of the TL junction can be accessed through a minimally invasive extracoelomic approach, with or without manipulation of the diaphragm. Approach selection is determined by the region of interest, degree of diaphragmatic mobilization required, and rib anatomy.

Novel Technique for C1-2 Interlaminar Arthrodesis Utilizing a Modified Sonntag Loop-Suture Graft With Posterior C1-2 Fixation.

OBJECTIVE: Conventional techniques for atlantoaxial fixation and fusion typically pass cables or wires underneath C1 lamina to secure the bone graft between the posterior elements of C1-2, which leads to complications such as cerebrospinal fluid (CSF) leak and neurological injury. With the evolution of fixation hardware, we propose a novel C1-2 fixation technique that avoids the morbidity and complications associated with sublaminar cables and wires. METHODS: This technique entails wedging and anchoring a structural iliac crest graft between C1 and C2 for interlaminar arthrodesis and securing it using a 0-Prolene suture at the time of C1 lateral mass and C2 pars interarticularis screw fixation. RESULTS: We identified 32 patients who underwent surgery for atlantoaxial with our technique. A 60% improvement in pain-related disability from preoperative baseline was demonstrated by Neck Disability Index (p < 0.001). There were no neurologic deficits. Complications included 2 patients CSF leaks related to presenting trauma, 1 patient with surgical site infection, and 1 patient with transient dysphagia. The rate of radiographic atlantoaxial fusion was 96.8% at 6 months, with no evidence of instrumentation failure, graft dislodgement, or graft related complications. CONCLUSION: We demonstrate a novel technique for C1-2 arthrodesis that is a safe and effective option for atlantoaxial fusion.

Global incidence of brain and spinal tumors by geographic region and income level based on cancer registry data.

While obtaining accurate estimates of tumor incidence volume is a difficult technical problem because it requires collating and analyzing data from dozens of world-wide sources curated under different conditions, our study aims to determine the global incidence of brain and spinal tumors. We analyzed 207 tumor registries on five continents, and calculated age-standardized rates to compare tumor incidence between geographic regions and income levels. Based on data available in current cancer registries, the apparent global incidence of malignant brain tumors was 4.25 cases per 100,000 person-years (95% CI [4.21-4.29]), and varied by region from 6.76 [6.71-6.80] in Europe to 2.81 [2.64-2.99] in Africa. Incidence also varied by World Bank income group, ranging from 6.29 [6.26-6.32] cases per 100,000 in high income countries (HICs), to 4.81 [4.77-4.86] in low and middle-income countries (LMICs). Malignant spinal tumors were much less frequent globally (0.098 [0.093-0.104]) and varied similarly by region and income group. The incidence of brain and spinal tumors varies by region and income group, although case ascertainment bias driven by limited resources in low income regions likely plays a role in variance. The burden of neurosurgical disease in LMICs is large, and similar in scale to HICs.

High Sacral Endplate Inclination Vector Forces Are Associated with Pars Fracture-Mediated Lumbosacral Spondylolisthesis.

OBJECTIVE: Lumbar spondylolisthesis can be related to facet arthropathy and disc degeneration or to a fracture of the pars interarticularis, but the mechanistic underpinnings of spondylolisthesis remain unclear. We posit that high sacral slope and body weight increase sacral inclination vector forces, which leads to pars fractures and exacerbates risk for spondylolisthesis. METHODS: To investigate this hypothesis, we measured the sacral slope, body weight, and S1 endplate vector forces for patients who underwent L5-S1 fusion for grade I spondylolisthesis. Patients were stratified based on presence of pars fractures versus facet arthropathy, and statistical analyses were performed to determine whether high sacral endplate inclination vector force is associated with pars fracture-mediated spondylolisthesis. RESULTS: We identified 131 patients who had L5-S1 fusion for spondylolisthesis. The mean age was 56 years, and 57% were female. The body weight of patients ranged from 45.4 to 141.9 kg with an average of 83.8 kg; 32 patients had single-level L5-S1 spondylolisthesis secondary to bilateral L5 pars interarticularis fractures, whereas 99 patients had L5-S1 spondylolisthesis due to facet arthropathy. Patients with pars fractures had steeper sacral slopes (43.2 ± 10.1°) compared with those without pars fractures (36.8 ± 8.1°) (P = 0.0007, odds ratio 2.71). Despite having no significant differences in weight (82.7 ± 17.2 vs. 87.3 ± 17.2 kg, P = 0.189), patients with pars fractures had 49% greater sacral inclination vector forces compared with those without pars fractures (586 ± 158 N vs. 394 ± 90 N, P < 0.0001). CONCLUSIONS: These data suggest that high sacral endplate inclination vector force is a risk factor for developing pars fracture-mediated spondylolisthesis.

Atlantoaxial Fusion Using C1 Sublaminar Cables and C2 Translaminar Screws.

BACKGROUND: Atlantoaxial instability, which can arise in the setting of trauma, degenerative diseases, and neoplasm, is often managed surgically with C1-C2 arthrodesis. Classical C1-C2 fusion techniques require placement of instrumentation in close proximity to the vertebral artery and C2 nerve root. OBJECTIVE: To report a novel C1-C2 fusion technique that utilizes C2 translaminar screws and C1 sublaminar cables to decrease the risk of injury to the vertebral artery and C2 nerve root. METHODS: To facilitate fixation to the atlas, while minimizing the risk of injury to the vertebral artery and to the C2 nerve root, we sought to determine the feasibility of using a soft cable around the C1 arch and affixing it to a rod connected to C2 laminar screws. We reviewed our experience in 3 patients. RESULTS: We used this technique in patients in whom we anticipated difficult C1 screw placement. Three patients were identified through a review of the senior author's cases. Atlantoaxial instability was associated with trauma in 2 patients and chronic degenerative changes in 1 patient. Common symptoms on presentation included pain and limited range of motion. All patients underwent C1-C2 fusion with C2 translaminar screws with sublaminar cable harnessing of the posterior arch of C1. There were no reports of postoperative complications or hardware failure. CONCLUSION: We demonstrate a novel, technically straightforward approach for C1-C2 fusion that minimizes risk to the vertebral artery and to the C2 nerve root, while still allowing for semirigid fixation in instances of both traumatic and chronic degenerative atlantoaxial instability.

Thoracic exophytic ependymoma masquerading as a benign extra-axial tumor.

Spinal tumors are conventionally differentiated based on location in relation to the spinal cord. Benign spinal tumors such as schwannomas and meningiomas are typically extra-axial (intradural extramedullary) lesions, whereas more aggressive primary spinal tumors such as ependymomas are typically intramedullary masses. Rarely, ependymomas can have both intramedullary and extramedullary components (typically referred to as exophytic ependymomas). We report a case of a spinal exophytic ependymoma that radiographically masqueraded as a benign intradural extramedullary lesion causing cord compression and neurologic deficit in a 47-year-old man. The diagnosis of exophytic ependymoma was made intra-operatively, with resultant gross total resection of the extramedullary portion and subtotal resection of the intramedullary portion. Histopathological examination confirmed ependymoma with World Health Organization grade II/IV. Pre-operative suspicion of an exophytic ependymoma influences operative planning and clinical management. We review the literature and discuss clinical management strategies for these interesting spinal tumors.

Rapid Neurological Recovery Following Partial Surgical Resection of Spinal Glioblastoma Multiforme in a Pediatric Patient Presenting With Complete Paraplegia.

Pediatric spinal cord glioblastoma multiforme is a rare entity with a poor prognosis often presenting with lower extremity weakness or paralysis. Previous literature suggests that aggressive surgical resection may provide overall survival benefit; however, there is limited concurrent analysis demonstrating neurological recovery following surgical resection. We report the case of a 9-year-old boy who presented with complete paraplegia and regained the ability to ambulate independently following subtotal surgical resection, radiation, and chemotherapy. The case demonstrates the balance between meaningful neurological recovery and overall survival when deciding on the extent of resection in cases of pediatric spinal glioblastoma multiforme.

Non-Fibrillar Oligomeric Amyloid-ß within Synapses.

Alzheimer's disease (AD) is characterized by memory loss, insidious cognitive decline, profound neurodegeneration, and the extracellular accumulation of amyloid-ß (Aß) peptide in senile plaques and intracellular accumulation of tau in neurofibrillary tangles. Loss and dysfunction of synapses are believed to underlie the devastating cognitive decline in AD. A large amount of evidence suggests that oligomeric forms of Aß associated with senile plaques are toxic to synapses, but the precise sub-synaptic localization of Aß and which forms are synaptotoxic remain unknown. Here, we characterize the sub-synaptic localization of Aß oligomers using three high-resolution imaging techniques, stochastic optical reconstruction microscopy, immunogold electron microscopy, and Förster resonance energy transfer in a plaque-bearing mouse model of AD. With all three techniques, we observe oligomeric Aß inside synaptic terminals. Further, we tested a panel of Aß antibodies using the relatively high-throughput array tomography technique to determine which forms are present in synapses. Our results show that different oligomeric Aß species are present in synapses and highlight the potential of array tomography for rapid testing of aggregation state specific Aß antibodies in brain tissue.

Spinal cord glioblastoma: 25years of experience from a single institution.

Accounting for less than 0.2% of all glioblastomas, high grade gliomas of the spinal cord are very rare. Here, we discuss our approach to managing patients with high grade spinal cord glioma and review the literature on the subject. Six patients with high grade spinal cord gliomas who presented to our institution between 1990 and 2015 were reviewed. Each patient underwent subtotal surgical resection, with a subset receiving adjuvant chemotherapy and radiation. Our primary outcomes of interest were pre-operative and post-operative functional status. One year survival rate was 100%. All patients had stable or improved American Spine Injury Association score immediately after surgery, which was maintained at 3months in 83.3% of patients. Karnofsky Performance Status (KPS) was stable at 3month follow up in 50% of patients, but all had decreased KPS 1year after surgery. A subset of patients received post-operative radiation and chemotherapy with 0% tumor recurrence rate at 3months. We assessed the molecular profiles of tumors from two patients in our series and found that each had mutations in TP53, but had wildtype BRAF, IDH-1, and MGMT. Taken together, our data show that patients with high grade spinal cord gliomas have an excellent survival at 1year, but with some decline in functional status within this period. Further studies are needed to elucidate the natural history of the disease and to explore the role of adjuvant targeted molecular therapies.

Rapid growth of an infectious intracranial aneurysm with catastrophic intracranial hemorrhage.

Infectious intracranial aneurysms are rare vascular lesions that classically occur in patients with infective endocarditis. We present a 49-year-old man with altered mental status and headache with rapid growth and rupture of an infectious intracranial aneurysm with catastrophic intracranial hemorrhage, and review issues related to open neurosurgical and endovascular interventions.

Gene transfer of human Apoe isoforms results in differential modulation of amyloid deposition and neurotoxicity in mouse brain.

Inheritance of the ε4 allele of apolipoprotein E (APOE) is the strongest genetic risk factor associated with the sporadic form of Alzheimer's disease (AD), whereas the rare APOE ε2 allele has the opposite effect. However, the mechanisms whereby APOE confers risk and protection remain uncertain. We used a gene transfer approach to bathe the cortex of amyloid plaque-bearing transgenic mice with virally expressed human APOE. We monitored amyloid-ß (Aß) with multiphoton imaging, in vivo microdialysis, and postmortem array tomography to study the kinetics of human APOE-mediated changes in Aß-related neurotoxicity in a mouse model of AD. We observed that human APOE4 increased the concentrations of oligomeric Aß within the interstitial fluid and exacerbated plaque deposition; the converse occurred after exposure to human APOE2. Peri-plaque synapse loss and dystrophic neurites were also worsened by APOE4 or attenuated by APOE2. Egress of Aß from the central nervous system (CNS) into the plasma was diminished by APOE3 and APOE4 compared to APOE2, in accord with isoform-specific retention of Aß in the CNS. Overall, our data show a differential effect of human APOE isoforms on amyloid deposition and clearance in transgenic mice and, more importantly, on Aß-mediated synaptotoxicity. These results suggest that the APOE genetic risk is mediated by Aß, and that therapeutic approaches aimed at decreasing APOE4, or increasing APOE2, may be beneficial in AD.

Predictors of cranioplasty complications in stroke and trauma patients.

OBJECT: Decompressive craniectomy mandates subsequent cranioplasty. Complications of cranioplasty may be independent of the initial craniectomy, or they may be contingent upon the craniectomy. Authors of this study aimed to identify surgery- and patient-specific risk factors related to the development of surgical site infection and other complications following cranioplasty. METHODS: A consecutive cohort of patients of all ages and both sexes who had undergone cranioplasty following craniectomy for stroke or trauma at a single institution in the period from May 2004 to May 2012 was retrospectively established. Patients who had undergone craniectomy for infectious lesions or neoplasia were excluded. A logistic regression analysis was performed to model and predict determinants related to infection following cranioplasty. RESULTS: Two hundred thirty-nine patients met the study criteria. The overall rate of complication following cranioplasty was 23.85% (57 patients). Complications included, predominantly, surgical site infection, hydrocephalus, and new-onset seizures. Logistic regression analysis identified previous reoperation (OR 3.25, 95% CI 1.30-8.11, p = 0.01) and therapeutic indication for stroke (OR 2.45, 95% CI 1.11-5.39, p = 0.03) as significantly associated with the development of cranioplasty infection. Patient age, location of cranioplasty, presence of an intracranial device, bone flap preservation method, cranioplasty material, booking method, and time interval > 90 days between initial craniectomy and cranioplasty were not predictive of the development of cranioplasty infection. CONCLUSIONS: Cranioplasty complications are common. Cranioplasty infection rates are predicted by reoperation following craniectomy and therapeutic indication (stroke). These variables may be associated with patient-centered risk factors that increase cranioplasty infection risk.

Periampullary duodenal duplication cyst masquerading as a choledochocele.

Enteric duplication cysts are rare congenital anomalies of unclear etiology. While they can occur anywhere in the gastrointestinal tract, they typically occur in the ileum or ileocecal region and very rarely in the duodenum. Here, we report a case of a periampullary duodenal duplication cyst in a 13-year-old male who presented with clinical and laboratory evidence of small bowel obstruction, hepatitis, and pancreatitis. Based on radiologic imaging, the patient was thought to have a type III choledochal cyst (choledochocele) within the duodenal lumen. Intraoperative findings and postoperative pathological evaluation, however, revealed that the lesion was a duodenal duplication cyst masquerading as a choledochal cyst. Interestingly, the duplication cyst was communicating with the common bile duct, simultaneously causing biliary and small bowel obstruction.

Apolipoprotein E4 effects in Alzheimer's disease are mediated by synaptotoxic oligomeric amyloid-ß.

The apolipoprotein E ε4 gene is the most important genetic risk factor for sporadic Alzheimer's disease, but the link between this gene and neurodegeneration remains unclear. Using array tomography, we analysed >50000 synapses in brains of 11 patients with Alzheimer's disease and five non-demented control subjects and found that synapse loss around senile plaques in Alzheimer's disease correlates with the burden of oligomeric amyloid-ß in the neuropil and that this synaptotoxic oligomerized peptide is present at a subset of synapses. Further analysis reveals apolipoprotein E ε4 patients with Alzheimer's disease have significantly higher oligomeric amyloid-ß burden and exacerbated synapse loss around plaques compared with apolipoprotein E ε3 patients. Apolipoprotein E4 protein colocalizes with oligomeric amyloid-ß and enhances synaptic localization of oligomeric amyloid-ß by >5-fold. Biochemical characterization shows that the amyloid-ß enriched at synapses by apolipoprotein E4 includes sodium dodecyl sulphate-stable dimers and trimers. In mouse primary neuronal culture, lipidated apolipoprotein E4 enhances oligomeric amyloid-ß association with synapses via a mechanism involving apolipoprotein E receptors. Together, these data suggest that apolipoprotein E4 is a co-factor that enhances the toxicity of oligomeric amyloid-ß both by increasing its levels and directing it to synapses, providing a link between apolipoprotein E ε4 genotype and synapse loss, a major correlate of cognitive decline in Alzheimer's disease.

Nanoparticles enhance brain delivery of blood-brain barrier-impermeable probes for in vivo optical and magnetic resonance imaging.

Several imaging modalities are suitable for in vivo molecular neuroimaging, but the blood-brain barrier (BBB) limits their utility by preventing brain delivery of most targeted molecular probes. We prepared biodegradable nanocarrier systems made up of poly(n-butyl cyanoacrylate) dextran polymers coated with polysorbate 80 (PBCA nanoparticles) to deliver BBB-impermeable molecular imaging probes into the brain for targeted molecular neuroimaging. We demonstrate that PBCA nanoparticles allow in vivo targeting of BBB-impermeable contrast agents and staining reagents for electron microscopy, optical imaging (multiphoton), and whole brain magnetic resonance imaging (MRI), facilitating molecular studies ranging from individual synapses to the entire brain. PBCA nanoparticles can deliver BBB-impermeable targeted fluorophores of a wide range of sizes: from 500-Da targeted polar molecules to 150,000-Da tagged immunoglobulins into the brain of living mice. The utility of this approach is demonstrated by (i) development of a "Nissl stain" contrast agent for cellular imaging, (ii) visualization of amyloid plaques in vivo in a mouse model of Alzheimer's disease using (traditionally) non-BBB-permeable reagents that detect plaques, and (iii) delivery of gadolinium-based contrast agents into the brain of mice for in vivo whole brain MRI. Four-dimensional real-time two-photon and MR imaging reveal that brain penetration of PBCA nanoparticles occurs rapidly with a time constant of ∼18 min. PBCA nanoparticles do not induce nonspecific BBB disruption, but collaborate with plasma apolipoprotein E to facilitate BBB crossing. Collectively, these findings highlight the potential of using biodegradable nanocarrier systems to deliver BBB-impermeable targeted molecular probes into the brain for diagnostic neuroimaging.