Delphi Consensus on Diagnostic Criteria for LUMBAR Syndrome.

OBJECTIVE: To develop consensus on diagnostic criteria for LUMBAR syndrome, the association of segmental infantile hemangiomas that affect the Lower body with Urogenital anomalies, Ulceration, spinal cord Malformations, Bony defects, Anorectal malformations, Arterial anomalies and/or Renal anomalies. STUDY DESIGN: These diagnostic criteria were developed by an expert multidisciplinary and multi-institutional team based on analysis of peer-reviewed data, followed by electronic-Delphi consensus of a panel of 61 international pediatric specialists. RESULTS: After 2 Delphi rounds, a 92% or higher level of agreement was reached for each Delphi statement. 98% of panelists agreed with the diagnostic criteria, and 100% agreed the criteria would be useful in clinical practice. The diagnosis of LUMBAR requires the presence of a segmental, or patterned, infantile hemangioma of the lumbosacral, sacrococcygeal, or pelvic cutaneous regions plus one additional criterion of the urogenital, spinal, bony, anorectal, arterial, or renal organ systems. CONCLUSIONS: These diagnostic criteria will enhance clinical care by improving screening, detection, and overall awareness of this poorly understood neurocutaneous disorder. The criteria can be utilized by a wide variety of pediatric subspecialists. In addition, formal criteria will improve phenotypic uniformity among LUMBAR syndrome cohorts and a patient registry, allowing investigators to assess clinical features, long-term outcomes, and results of genetic sequencing in a standardized manner. Finally, these criteria will serve as a starting point for prospective studies to establish formal screening and management guidelines.

The regional pattern of age-related synaptic loss in the human brain differs from gray matter volume loss: in vivo PET measurement with [11C]UCB-J.

PURPOSE: Aging is a major societal concern due to age-related functional losses. Synapses are crucial components of neural circuits, and synaptic density could be a sensitive biomarker to evaluate brain function. [11C]UCB-J is a positron emission tomography (PET) ligand targeting synaptic vesicle glycoprotein 2A (SV2A), which can be used to evaluate brain synaptic density in vivo. METHODS: We evaluated age-related changes in gray matter synaptic density, volume, and blood flow using [11C]UCB-J PET and magnetic resonance imaging (MRI) in a wide age range of 80 cognitive normal subjects (21-83 years old). Partial volume correction was applied to the PET data. RESULTS: Significant age-related decreases were found in 13, two, and nine brain regions for volume, synaptic density, and blood flow, respectively. The prefrontal cortex showed the largest volume decline (4.9% reduction per decade: RPD), while the synaptic density loss was largest in the caudate (3.6% RPD) and medial occipital cortex (3.4% RPD). The reductions in caudate are consistent with previous SV2A PET studies and likely reflect that caudate is the site of nerve terminals for multiple major tracts that undergo substantial age-related neurodegeneration. There was a non-significant negative relationship between volume and synaptic density reductions in 16 gray matter regions. CONCLUSION: MRI and [11]C-UCB-J PET showed age-related decreases of gray matter volume, synaptic density, and blood flow; however, the regional patterns of the reductions in volume and SV2A binding were different. Those patterns suggest that MR-based measures of GM volume may not be directly representative of synaptic density.

A Cluster Randomized Trial to Reduce Missed Abusive Head Trauma in Pediatric Intensive Care Settings.

OBJECTIVE: To estimate the impact of the PediBIRN (Pediatric Brain Injury Research Network) 4-variable clinical decision rule (CDR) on abuse evaluations and missed abusive head trauma in pediatric intensive care settings. STUDY DESIGN: This was a cluster randomized trial. Participants included 8 pediatric intensive care units (PICUs) in US academic medical centers; PICU and child abuse physicians; and consecutive patients with acute head injures <3 years (n = 183 and n = 237, intervention vs control). PICUs were stratified by patient volumes, pair-matched, and randomized equally to intervention or control conditions. Randomization was concealed from the biostatistician. Physician-directed, cluster-level interventions included initial and booster training, access to an abusive head trauma probability calculator, and information sessions. Outcomes included "higher risk" patients evaluated thoroughly for abuse (with skeletal survey and retinal examination), potential cases of missed abusive head trauma (patients lacking either evaluation), and estimates of missed abusive head trauma (among potential cases). Group comparisons were performed using generalized linear mixed-effects models. RESULTS: Intervention physicians evaluated a greater proportion of higher risk patients thoroughly (81% vs 73%, P = .11) and had fewer potential cases of missed abusive head trauma (21% vs 32%, P = .05), although estimated cases of missed abusive head trauma did not differ (7% vs 13%, P = .22). From baseline (in previous studies) to trial, the change in higher risk patients evaluated thoroughly (67%→81% vs 78%→73%, P = .01), and potential cases of missed abusive head trauma (40%→21% vs 29%→32%, P = .003), diverged significantly. We did not identify a significant divergence in the number of estimated cases of missed abusive head trauma (15%→7% vs 11%→13%, P = .22). CONCLUSIONS: PediBIRN-4 CDR application facilitated changes in abuse evaluations that reduced potential cases of missed abusive head trauma in PICU settings. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03162354.

Synaptic Changes in Parkinson Disease Assessed with in vivo Imaging.

OBJECTIVE: Parkinson disease is characterized by motor and nonmotor symptoms, reduced striatal dopamine signaling, and loss of dopamine neurons in the substantia nigra. It is now known that the pathological process in Parkinson disease may begin decades before the clinical diagnosis and include a variety of neuronal alterations in addition to the dopamine system. METHODS: This study examined the density of all synapses with synaptic vesicle glycoprotein 2A (SV2A) in Parkinson disease subjects with mild bilateral disease (n = 12) and matched normal controls (n = 12) using in vivo high-resolution positron emission tomographic imaging as well as postmortem autoradiography in an independent sample with Parkinson disease (n = 15) and normal controls (n = 13) in the substantia nigra and putamen. RESULTS: A group-by-brain region interaction effect (F10, 22 = 3.52, p = 0.007) was observed in the primary brain areas with in vivo SV2A binding. Post hoc analyses revealed that the Parkinson disease group exhibited lower SV2A in the substantia nigra (-45%; p < 0.001), red nucleus (-31%; p = 0.03), and locus coeruleus (-17%; p = 0.03). Exploratory analyses also revealed lower SV2A binding in clinically relevant cortical areas. Using autoradiography, we confirmed lower SV2A in the substantia nigra (-17%; p < 0.005) and nonsignificant findings in the putamen (-4%; p = 0.06). INTERPRETATION: This work provides the first evidence of synaptic loss in brainstem nuclei involved in the pathogenesis of Parkinson disease in living patients. SV2A imaging holds promise for understanding synaptic changes central to the disease. Ann Neurol 2020;87:329-338.

Neuroradiologic timing of intracranial hemorrhage in abusive head trauma.

Determining the timing of intracranial injuries in general, and abusive head trauma (AHT) in particular, is important to the care of children with traumatic brain injury. Additionally, identifying the time of the injury provides important information as to who might have, and who did not, inflict the trauma. Understanding the appearance and evolution of intracranial findings on neuroimaging has been an important factor in assessing the time of the injury. However, a number of studies in the last two decades have both suggested greater uncertainty about the reliability of this process and advanced our knowledge in this area. In this review, the authors consider the biophysical factors that contribute to the appearance and evolution of intracranial hemorrhage and, in particular, subdural hemorrhage (SDH). The traditional view of SDH is predicated largely on prior studies of intracerebral hemorrhage, although a number of variables make this comparison untenable. Moreover, more recent studies have suggested a number of factors that could alter the density (CT) or signal intensity (MRI) and produce mixed density/intensity SDH. These factors need to be considered in interpreting neuroimaging studies. A number of these recent studies evaluating serial neuroimaging in children with AHT have modified our understanding of intracranial hemorrhage and its evolution in this context. Taken together, the studies to date, having important limitations, provide only broad ranges over which to time injuries. The authors conclude that neuroimaging studies at this time are not likely, in isolation, to be able to accurately pinpoint a specific time of injury; rather, neuroimaging can only provide a range of possible times and should instead be used as a means to supplement or corroborate timing based on clinical presentation and other imaging findings.

Preparing for court testimony.

Pediatric radiologists are frequently summoned to testify in court regarding the imaging of child abuse. This essay provides guidance on how to prepare for trial and what to expect in court. Preparation is paramount and includes meeting with the attorney and reviewing imaging studies, medical records and pertinent reports in anticipation of questioning in court. We also provide guidance to aid in testimony in court. Legal standards for testimony are discussed herein.

Preventing abusive head trauma: can educating parents reduce the incidence?

Abusive head trauma (AHT) is the most lethal form of child abuse; preventing AHT should be a national priority, but research into this area is woefully underfunded. Prevention programs have primarily focused on universal parent education during the neonatal period, a time when parents are a captive audience of the health care establishment whose focus is on the needs of their newborn infant, and who will soon be exposed to the frustration and anger of infant crying. Research has suggested a strong causal link between infant crying and AHT, and parents - particularly fathers and father figures - have been identified as the most common perpetrators of AHT. A number of studies have suggested that educating parents during the postnatal period about the normalcy of inconsolable infant crying and its evolution over the first several months of postnatal life improves parental knowledge about infant crying and a number of positive parenting behaviors, and decreases emergency room visits for crying. In 1998, we began a pilot program in Upstate New York near Buffalo that led to a 47% reduction in AHT incidence. Similar studies have demonstrated 35-75% reductions in incidence, which has led to enthusiasm for this approach to preventing AHT. We, as well as another group, have enacted statewide programs in Pennsylvania and North Carolina; unfortunately, these two large statewide replication trials failed to demonstrate any impact of such an intervention on AHT rates. Serial messages for parents, provided repeatedly over the period of greatest risk for AHT, might be another avenue of research.

Reduced synaptic vesicle protein 2A binding in temporal lobe epilepsy: A [11 C]UCB-J positron emission tomography study.

OBJECTIVE: In this positron emission tomography (PET) study with [11 C]UCB-J, we evaluated synaptic vesicle glycoprotein 2A (SV2A) binding, which is decreased in resected brain tissues from epilepsy patients, in subjects with temporal lobe epilepsy (TLE) and compared the regional binding pattern to [18 F]fluorodeoxyglucose (FDG) uptake. METHODS: Twelve TLE subjects and 12 control subjects were examined. Regional [11 C]UCB-J binding potential (BPND ) values were estimated using the centrum semiovale as a reference region. [18 F]FDG uptake in TLE subjects was quantified using mean radioactivity values. Asymmetry in outcome measures was assessed by comparison of ipsilateral and contralateral regions. Partial volume correction (PVC) with the iterative Yang algorithm was applied based on the FreeSurfer segmentation. RESULTS: In 11 TLE subjects with medial temporal lobe sclerosis (MTS), the hippocampal volumetric asymmetry was 25 ± 11%. After PVC, [11 C]UCB-J BPND asymmetry indices were 37 ± 19% in the hippocampus, with very limited asymmetry in other brain regions. Reductions in [11 C]UCB-J BPND values were restricted to the sclerotic hippocampus when compared to control subjects. The corresponding asymmetry in hippocampal [18 F]FDG uptake was 22 ± 7% and correlated with that of [11 C]UCB-J BPND across subjects (R2  = .38). Hippocampal asymmetries in [11 C]UCB-J binding were 1.7-fold larger than those of [18 F]FDG uptake. SIGNIFICANCE: [11 C]UCB-J binding is reduced in the seizure onset zone of TLE subjects with MTS. PET imaging of SV2A may be a promising biomarker approach in the presurgical selection and evaluation of TLE patients and may improve the sensitivity of molecular imaging for seizure focus detection.

Susceptibility-weighted imaging of retinal hemorrhages in abusive head trauma.

BACKGROUND: Retinal hemorrhages are one of the most important supportive evidences for abusive head trauma (AHT). Susceptibility-weighted imaging (SWI) is highly suited to identify various forms of intracranial hemorrhage in AHT. However its utility in imaging retinal hemorrhage is not well established. OBJECTIVE: SWI is a sensitive sequence for identifying retinal hemorrhage on MRI. MATERIALS AND METHODS: In this retrospective analysis, 26 consecutive infants and young children with a suspected admission diagnosis of AHT underwent indirect ophthalmoscopy and brain MRI protocol for AHT along with SWI. Brain susceptibility-weighted images of 14 age-matched children were used as controls. For detecting retinal hemorrhage, susceptibility-weighted images of patients and controls were reviewed randomly and independently by two neuroradiologists who were blinded to the history and ophthalmology findings. A pediatric ophthalmologist graded the indirect ophthalmoscopy images. RESULTS: A diagnosis of AHT was confirmed in all 26 cases from a multidisciplinary meeting. Indirect ophthalmoscopy images were available in 21 cases. Ophthalmoscopy was positive for retinal hemorrhage in the right eye in 18 cases (85.7%) and in the left eye in 16 cases (76.2%). On SWI, retinal hemorrhage was identified in the right eye in 9/21 cases (42.8%) and in the left eye in 8/21 cases (38.1%) of AHT. Analysis of SWI in 21 cases of AHT demonstrated a sensitivity of 50%, specificity of 100%, positive predictive value of 100% and negative predictive value of 32% for detecting retinal hemorrhage. CONCLUSION: SWI is moderately sensitive and highly specific for identifying retinal hemorrhage in AHT. Further studies are needed to identify steps to improve the efficiency of SWI in detecting retinal hemorrhage.

Correction to: A consensus response on the complete picture: reply to Lynøe and Eriksson.

The original version on this paper contained an error. The COI statement is incorrectly presented.

Consensus statement on abusive head trauma in infants and young children.

Abusive head trauma (AHT) is the leading cause of fatal head injuries in children younger than 2 years. A multidisciplinary team bases this diagnosis on history, physical examination, imaging and laboratory findings. Because the etiology of the injury is multifactorial (shaking, shaking and impact, impact, etc.) the current best and inclusive term is AHT. There is no controversy concerning the medical validity of the existence of AHT, with multiple components including subdural hematoma, intracranial and spinal changes, complex retinal hemorrhages, and rib and other fractures that are inconsistent with the provided mechanism of trauma. The workup must exclude medical diseases that can mimic AHT. However, the courtroom has become a forum for speculative theories that cannot be reconciled with generally accepted medical literature. There is no reliable medical evidence that the following processes are causative in the constellation of injuries of AHT: cerebral sinovenous thrombosis, hypoxic-ischemic injury, lumbar puncture or dysphagic choking/vomiting. There is no substantiation, at a time remote from birth, that an asymptomatic birth-related subdural hemorrhage can result in rebleeding and sudden collapse. Further, a diagnosis of AHT is a medical conclusion, not a legal determination of the intent of the perpetrator or a diagnosis of murder. We hope that this consensus document reduces confusion by recommending to judges and jurors the tools necessary to distinguish genuine evidence-based opinions of the relevant medical community from legal arguments or etiological speculations that are unwarranted by the clinical findings, medical evidence and evidence-based literature.

Childhood Injuries Due to Hay-Hole Falls: A 19-Year Experience at a Rural Pediatric Trauma Center.

OBJECTIVE: Children who live, work, and play on farms with barn design that includes hay-holes are at risk for a particular type of fall. This study retrospectively reviews all children admitted to a pediatric trauma center with injuries due to fall through a hay-hole over a 19-year period. This study is the first to specifically describe hay-hole fall injuries. METHODS: A retrospective review from a 19-year period at a rural pediatric trauma center identified 66 patients who sustained injuries from a hay-hole fall. Charts were reviewed for patient demographics, injuries, interventions, and hospital course. RESULTS: Sixty-six patients sustained injuries from hay-hole falls. Median patient age was 4 years, and median Injury Severity Score was 14. Forty-one percent of patients were admitted to the intensive care unit, and 26% of patients were intubated. Injuries included skull fracture (73%), facial fracture (27%), intracranial hemorrhage (53%), and noncraniofacial injuries (12%). Eighteen percent required a therapeutic intervention. There was 1 fatality (2%). CONCLUSIONS: Hay-hole fall appears to be a distinct injury mechanism, and patients present with different injury patterns than other types of falls. In this study, a high proportion of patients were young, and craniofacial injuries accounted for the majority of injuries. Only a small proportion of patients sustained noncraniofacial injuries. Injury prevention strategies should be targeted to this unique agrarian injury.

Potential Impact of a Validated Screening Tool for Pediatric Abusive Head Trauma.

OBJECTIVE: To conduct a retrospective, theoretical comparison of actual pediatric intensive care unit (PICU) screening for abusive head trauma (AHT) vs AHT screening guided by a previously validated 4-variable clinical prediction rule (CPR) in datasets used by the Pediatric Brain Injury Research Network to derive and validate the CPR. STUDY DESIGN: We calculated CPR-based estimates of abuse probability for all 500 patients in the datasets. Next, we demonstrated a positive and very strong correlation between these estimates of abuse probability and the overall diagnostic yields of our patients' completed skeletal surveys and retinal examinations. Having demonstrated this correlation, we applied mean estimates of abuse probability to predict additional, positive abuse evaluations among patients lacking skeletal survey and/or retinal examination. Finally, we used these predictions of additional, positive abuse evaluations to extrapolate and compare AHT detection (and 2 other measures of AHT screening accuracy) in actual PICU screening for AHT vs AHT screening guided by the CPR. RESULTS: Our results suggest that AHT screening guided by the CPR could theoretically increase AHT detection in PICU settings from 87%-96% (P < .001), and increase the overall diagnostic yield of completed abuse evaluations from 49%-56% (P = .058), while targeting slightly fewer, though not significantly less, children for abuse evaluation. CONCLUSIONS: Applied accurately and consistently, the recently validated, 4-variable CPR could theoretically improve the accuracy of AHT screening in PICU settings.

Venous injury in abusive head trauma.

BACKGROUND: Abusive head trauma (AHT) is an important cause of serious brain injury in infants and young children who have characteristic clinical and imaging findings that are discordant with the clinical history provided. Recent attention has focused on abnormalities of the cranial venous sinuses and cortical veins, both on MRI and at autopsy. Although many have interpreted these to be secondary to the AHT, some have recently argued that these venous abnormalities represent primary cortical sinus and venous thrombosis that leads secondarily to subdural hemorrhage and secondary brain injury. Direct trauma to the veins and sinuses has been reported at autopsy in AHT, but there has been no systematic study of venous abnormalities in cases of AHT. OBJECTIVE: The purpose of this study was to define the incidence and characteristics of venous and sinus abnormalities in AHT. MATERIALS AND METHODS: We included all children <36 months of age who were diagnosed with abusive head trauma between 2001 and 2012 and who had MRI and magnetic resonance (MR) venography as part of their diagnostic workup. We analyzed age, gender and clinical findings. MRI and MR venography were analyzed independently by two neuroradiologists with a focus on abnormalities involving the intracranial veins and venous sinuses. RESULTS: A total of 45 children were included. The median age was 3 months (range 15 days to 31 months) and 28 were boys (62%). Clinical findings included retinal hemorrhage in 71% and extracranial fractures in 55%. CT or MRI demonstrated subdural hemorrhage in 41 (91%); none had subdural effusions. In 31 cases (69%) MR venography demonstrated mass effect on the venous sinuses or cortical draining veins, with either displacement or partial or complete effacement of the venous structures from an adjacent subdural hematoma or brain swelling. We also describe the lollipop sign, which represents direct trauma to the cortical bridging veins and was present in 20/45 (44%) children. CONCLUSION: Evidence of displacement or compression of cortical veins and sinuses from subdural hemorrhage or edema on MR venography was present in the majority of children with abusive head trauma. Evidence of direct trauma to the veins (lollipop sign) was identified in nearly half of cases. It is important to understand the superimposed effects of subdural hematoma and brain swelling on the veins and sinuses to differentiate it from cortical sinus and venous thrombosis.

Imaging of spinal injury in abusive head trauma: a retrospective study.

BACKGROUND: Spinal imaging has been a neglected part of abusive head trauma (AHT) imaging. As most of the radiographs and CT spine are negative in AHT in infants, the cervical spine is assumed to be normal. There is increasing evidence in the role of injury to brainstem and cervical cord in the pathogenesis of AHT. In addition, in courts of law, there is fierce debate about AHT, its mimics and other disparate nontraumatic diagnoses explaining the neuroradiological and skeletal findings. However, this discussion ignores the evidence and significance of spinal injury. We sought to study the cervical spine in an AHT cohort to understand the true prevalence of spinal injuries in AHT and contrast it with cohorts of accidental and nontraumatic groups to give the clinicians a robust diagnostic tool in evaluating AHT. OBJECTIVE: The purpose of this study is to compare the relative incidence of spinal ligamentous and soft-tissue abnormalities on spinal MRI among three groups of children ages <48 months: 1) those with AHT, 2) those with accidental trauma, and 3) those with nontraumatic conditions. MATERIALS AND METHODS: This comparative study included 183 children who underwent spine MRI: 67 with AHT, 46 with accidental trauma and a clinical suspicion of spinal injury, and 70 with nontraumatic conditions. Clinical and radiographic findings were collected in all cases and were analyzed retrospectively to identify MRI evidence of traumatic spinal injuries. The incidence of spinal injuries among the three groups was compared. The incidence of spinal ligamentous injuries was calculated for those with and without radiographic evidence of hypoxic-ischemic encephalopathy. All comparisons were performed using Fisher exact test with P < 0.05 considered statistically significant. RESULTS: Cervical spine ligamentous injuries (predominantly the nuchal, atlanto-occipital and atlanto-axial ligaments) were present in 78% of the AHT group, 46% of the accidental trauma group and 1% of the nontraumatic group; all of these differences were statistically significant. Among the AHT group, ligamentous injuries were statistically correlated with evidence of brain ischemia. CONCLUSION: Injury to the cervical spinal posterior ligamentous complex is common in AHT and even more prevalent than in clinically symptomatic traumatic cases. The high correlation between the radiographic findings of occipitocervical ligamentous injuries and hypoxic-ischemic brain injury is consistent with an interpretation that transient upper occipitocervical spinal cord injury in AHT leads to disordered breathing and results in hypoxic-ischemic encephalopathy. We recommend imaging the entire spine in AHT to properly identify and classify these injuries.

Intracranial venous drainage through spinal veins.

There is extensive collateral networking at the craniocervical junction with a substantial anatomical and functional continuity between the veins, venous sinuses, and venous plexuses of the brain and spine. The predominant pathway for intracranial blood outflow may depend on the level and degree of obstruction. We are presenting an unusual case of predominant egress of intracranial blood through enlarged spinal canal venous collaterals due to thrombosis of the intracranial venous sinuses. Awareness of this unique pattern of venous drainage of the cranium is important and should be considered in the differential diagnosis of spinal arteriovenous malformation (AVM) or arteriovenous fistula (AVF). Magnetic Resonance Venography (MRV) of the brain should be considered to exclude intracranial thrombosis in these cases.

Pediatric Traumatic Injuries Due to Agrarian Hay-Hole Falls.

Hay-holes are a design feature in many traditionally built barns that serve as a portal through which stored hay is passed to the lower level where animals are fed. Unfortunately, children sometimes fall through the hay-hole to the concrete or packed earth below. Available data on the frequency and types of hay-hole injuries is limited. The purpose of this study was to better characterize the resultant injuries and identify prognostic factors that predict outcomes from them. We performed a retrospective review of 53 children admitted to the Penn State Hershey Children's Hospital at the Penn State Hershey Medical Center with injuries due to a fall through a hay-hole over 15 years. Compared to urban trauma, hay-hole falls more frequently involve younger children and craniofacial injuries. Although they may result in significant injuries, they are rarely fatal. Greater fall height is associated with longer length of stay (LOS) but not with a greater frequency of intubation, intracranial hemorrhage, or skull fracture. A re-examination of barn design may help to reduce the frequency of this injury type.

First-in-Human Study of 18F-SynVesT-2: An SV2A PET Imaging Probe with Fast Brain Kinetics and High Specific Binding.

PET imaging of synaptic vesicle glycoprotein 2A allows for noninvasive quantification of synapses. This first-in-human study aimed to evaluate the kinetics, test-retest reproducibility, and extent of specific binding of a recently developed synaptic vesicle glycoprotein 2A PET ligand, (R)-4-(3-(18F-fluoro)phenyl)-1-((3-methylpyridin-4-yl)methyl)pyrrolidine-2-one (18F-SynVesT-2), with fast brain kinetics. Methods: Nine healthy volunteers participated in this study and were scanned on a High Resolution Research Tomograph scanner with 18F-SynVesT-2. Five volunteers were scanned twice on 2 different days. Five volunteers were rescanned with preinjected levetiracetam (20 mg/kg, intravenously). Arterial blood was collected to calculate the plasma free fraction and generate the arterial input function. Individual MR images were coregistered to a brain atlas to define regions of interest for generating time-activity curves, which were fitted with 1- and 2-tissue-compartment (1TC and 2TC) models to derive the regional distribution volume (V T). The regional nondisplaceable binding potential (BP ND) was calculated from 1TC V T, using the centrum semiovale (CS) as the reference region. Results: 18F-SynVesT-2 was synthesized with high molar activity (187 ± 69 MBq/nmol, n = 19). The parent fraction of 18F-SynVesT-2 in plasma was 28% ± 8% at 30 min after injection, and the plasma free fraction was high (0.29 ± 0.04). 18F-SynVesT-2 entered the brain quickly, with an SUVpeak of 8 within 10 min after injection. Regional time-activity curves fitted well with both the 1TC and the 2TC models; however, V T was estimated more reliably using the 1TC model. The 1TC V T ranged from 1.9 ± 0.2 mL/cm3 in CS to 7.6 ± 0.8 mL/cm3 in the putamen, with low absolute test-retest variability (6.0% ± 3.6%). Regional BP ND ranged from 1.76 ± 0.21 in the hippocampus to 3.06 ± 0.29 in the putamen. A 20-min scan was sufficient to provide reliable V T and BP ND Conclusion: 18F-SynVesT-2 has fast kinetics, high specific uptake, and low nonspecific uptake in the brain. Consistent with the nonhuman primate results, the kinetics of 18F-SynVesT-2 is faster than the kinetics of 11C-UCB-J and 18F-SynVesT-1 in the human brain and enables a shorter dynamic scan to derive physiologic information on cerebral blood flow and synapse density.

Synaptic loss and its association with symptom severity in Parkinson's disease.

Parkinson's disease (PD) is the fastest growing neurodegenerative disease, but at present there is no cure, nor any disease-modifying treatments. Synaptic biomarkers from in vivo imaging have shown promise in imaging loss of synapses in PD and other neurodegenerative disorders. Here, we provide new clinical insights from a cross-sectional, high-resolution positron emission tomography (PET) study of 30 PD individuals and 30 age- and sex-matched healthy controls (HC) with the radiotracer [11C]UCB-J, which binds to synaptic vesicle glycoprotein 2A (SV2A), and is therefore, a biomarker of synaptic density in the living brain. We also examined a measure of relative brain perfusion from the early part of the same PET scan. Our results provide evidence for synaptic density loss in the substantia nigra that had been previously reported, but also extend this to other early-Braak stage regions known to be affected in PD (brainstem, caudate, olfactory cortex). Importantly, we also found a direct association between synaptic density loss in the nigra and severity of symptoms in patients. A greater extent and wider distribution of synaptic density loss in PD patients with longer illness duration suggests that [11C]UCB-J PET can be used to measure synapse loss with disease progression. We also demonstrate lower brain perfusion in PD vs. HC groups, with a greater extent of abnormalities in those with longer duration of illness, suggesting that [11C]UCB-J PET can simultaneously provide information on changes in brain perfusion. These results implicate synaptic imaging as a useful PD biomarker for future disease-modifying interventions.