Hippocampal rotation is associated with ventricular atrial size.

BACKGROUND: Fetal ventriculomegaly is a source of apprehension for expectant parents and may present prognostic uncertainty for physicians. Accurate prenatal counseling requires knowledge of its cause and associated findings as the differential diagnosis is broad. We have observed an association between ventriculomegaly and incomplete hippocampal inversion. OBJECTIVE: To determine whether ventricular size is related to incomplete hippocampal inversion. MATERIALS AND METHODS: We retrospectively evaluated pre- and postnatal brain MRIs in normal subjects (mean GA, 31 weeks; mean postnatal age, 27 days) and patients with isolated ventriculomegaly (mean GA, 31 weeks; mean postnatal age, 68 days) at a single academic medical center. Lateral ventricular diameter, multiple qualitative and quantitative markers of hippocampal inversion, and evidence of intraventricular hemorrhage were documented. RESULTS: Incomplete hippocampal inversion and ventricular size were associated in both normal subjects (n=51) and patients with ventriculomegaly (n=32) (P<0.05). Severe ventriculomegaly was significantly associated with adverse clinical outcome in postnatal (P=0.02) but not prenatal (P=0.43) groups. In all additional cases of isolated ventriculomegaly, clinical outcome was normal over the time of assessment (mean 1±1.9 years; range 0.01 to 10 years). CONCLUSION: Lateral ventricular atrial diameter and incomplete hippocampal inversion are associated. Less hippocampal inversion correlates with larger atria. For every 1-mm increase in fetal ventricular size, the odds of incomplete hippocampal inversion occurring increases by a factor of 1.6 in normal controls and 1.4 in patients with ventriculomegaly.

Pregnancy and Child Outcomes Following Fetal Intracranial Hemorrhage.

BACKGROUND: The prenatal and early postnatal outcomes of fetal intracranial hemorrhage (ICH) prenatally diagnosed by fetal magnetic resonance imaging (MRI) have not been well described. METHODS: A retrospective study of cases with fetal ICH diagnosed by fetal MRI at Children's National Hospital, Washington, DC, from 2012 to 2020 was conducted. Maternal characteristics, prenatal imaging, pregnancy outcome, and child developmental outcomes were recorded. Abnormal outcomes were categorized as mild for required physical/occupational therapy without other delays, moderate for intermediate multidomain developmental delays, and severe if nonambulatory, nonverbal, or intellectual disability. RESULTS: Fifty-seven cases with fetal ICH were included. The mean (S.D.) maternal age was 31.1 (6.9) years, gestational age at fetal evaluation was 28.1 (5.3) weeks, and gestational age at birth was 38.2 (1.3) weeks. Pregnancy outcomes were 75% (n = 43) live birth, 14% (n = 8) termination of pregnancy, and 11% (n = 6) intrauterine demise (IUD). Live births decreased from 90% to 33% and IUD increased 10% to 22% when comparing unilateral intraventricular hemorrhage with more extensive hemorrhages. Among the 37 live-born infants with clinical follow-up to age 1.8 (1.6) years, neurodevelopmental outcome was normal in 57%, mildly abnormal in 24%, moderately abnormal in 14%, and severely abnormal in 5%. In five cases, an etiology was identified: two had placental pathologies, two had genetic findings (fetal neonatal alloimmune thrombocytopenia and COL4A1 mutation), and one had congenital cytomegalovirus infection. CONCLUSION: Perinatal and early child outcomes following fetal ICH have a wide spectrum of outcomes. Fetal MRI description of ICH location may aid in pregnancy and postnatal outcome prediction.

Autonomic markers of extubation readiness in premature infants.

BACKGROUND: In premature infants, extubation failure is common and difficult to predict. Heart rate variability (HRV) is a marker of autonomic tone. Our aim is to test the hypothesis that autonomic impairment is associated with extubation readiness. METHODS: Retrospective study of 89 infants <28 weeks. HRV metrics 24 h prior to extubation were compared for those with and without extubation success within 72 h. Receiver-operating curve analysis was conducted to determine the predictive ability of each metric, and a predictive model was created. RESULTS: Seventy-three percent were successfully extubated. The success group had significantly lower oxygen requirement, higher sympathetic HRV metrics, and a lower parasympathetic HRV metric. α1 (measure of autocorrelation, related to sympathetic tone) was the best predictor of success-area under the curve (AUC) of .73 (p = 0.001), and incorporated into a predictive model had an AUC of 0.81 (p < 0.0001)-sensitivity of 81% and specificity of 78%. CONCLUSIONS: Extubation success is associated with HRV. We show an autonomic imbalance with low sympathetic and elevated parasympathetic tone in those who failed. α1, a marker of sympathetic tone, was noted to be the best predictor of extubation success especially when incorporated into a clinical model. IMPACT: This article depicts autonomic markers predictive of extubation success. We depict an autonomic imbalance in those who fail extubation with heightened parasympathetic and blunted sympathetic signal. We describe a predictive model for extubation success with a sensitivity of 81% and specificity of 78%.

Fetal brain MRI: neurometrics, typical diagnoses, and resolving common dilemmas.

This review presents a practical approach to imaging the fetal brain by MRI. Herein, we demonstrate how to measure brain structures and fluid spaces, and discuss the importance of comparing measurements to normative biometric references at a corresponding gestational age. We present some common imaging dilemmas of the technical aspects of fetal MRI with regard to typical regions of abnormality including the cerebrum, the ventricular system, and the posterior fossa, and discuss how to resolve them.

Isolated Absent Septum Pellucidum: A Retrospective Study of Fetal Diagnosis and Postnatal Outcomes.

BACKGROUND: Absent septum pellucidum (ASP) is a brain abnormality often associated with neuroanatomic abnormalities including septo-optic dysplasia (SOD). We aimed to determine how frequently prenatally diagnosed isolated ASP is confirmed by postnatal imaging and to examine clinical outcomes for ASP. METHODS: This was a retrospective study of maternal-fetal dyads referred to Children's National Hospital from January 1, 2012, to June 30, 2019. We included cases with fetal diagnosis of isolated or complex ASP. Diagnosis was based on ASP and the presence or absence of additional neuroanatomic findings. Data included obstetric and birth history, genetic testing, imaging, and neurodevelopmental outcomes. RESULTS: ASP was diagnosed in 35 fetuses. Of 17 fetuses with isolated ASP, 10 had postnatal evaluation. In five (50%) isolated ASP cases, postnatal imaging revealed additional brain abnormalities. The five children with postnatally confirmed isolated ASP had lower rates of hydrocephalus (0% vs 54%) and abnormal feeding (0% vs 20%), hearing (0% vs 14%), and vision (0% vs 14%) than those with complex ASP (n = 17). Children with isolated ASP had lower rates of developmental delay (33% vs 50%) and seizures (11% vs 30%) than children with complex ASP. One child with prenatal isolated ASP was diagnosed with SOD (10%). CONCLUSIONS: Few children with prenatally diagnosed isolated ASP had SOD diagnosed postnatally. Overall, children with isolated ASP demonstrate better outcomes than children with complex ASP. Fetal magnetic resonance imaging is a useful tool to evaluate the septum pellucidum and may reveal additional abnormalities that can impact prognosis and affect prenatal counseling.

Outcome of Agenesis of the Corpus Callosum Diagnosed by Fetal MRI.

BACKGROUND: Fetal magnetic resonance imaging (MRI) is increasingly utilized for prenatal diagnosis of agenesis of the corpus callosum (ACC). This study aimed to (1) describe cases of ACC diagnosed by fetal MRI, (2) determine the frequency of postnatal confirmation by MRI, and (3) understand postnatal outcomes of infants with ACC. METHODS: Maternal records from Children's National Hospital between January 2012 and June 2019 with a prenatal neurological consultation, fetal MRI, and ACC on imaging were included. Maternal, prenatal, and postnatal infant data were collected. Each case was categorized as complete or partial ACC and isolated or complex ACC by fetal MRI and group comparisons of outcomes were analyzed. RESULTS: A total of 127 maternal-fetal dyads with ACC were categorized into 45 isolated-complete, 17 isolated-partial, 46 complex-complete, and 19 complex-partial ACC. Of 75 live births, 72 had postnatal evaluations. In 43 of 59 (73%) cases with postnatal neuroimaging, prenatal ACC subcategory was confirmed. Children with isolated or complex and with partial or complete ACC had similar rates of developmental delays and epilepsy. Complex ACC cases had worse outcomes than isolated ACC, with complex ACC having more postnatal dysmorphisms and abnormal feeding and vision compared with isolated ACC. Similar neurodevelopmental outcomes were seen for partial and complete ACC. CONCLUSIONS: Children with isolated or complex ACC and with partial or complete ACC have a range of neurodevelopmental outcomes. Fetal and postnatal brain MRI is a valuable tool to understand differences of the corpus callosum that can guide genetic testing, prenatal counseling, and postnatal care.

Autonomic development in preterm infants is associated with morbidity of prematurity.

BACKGROUND: Previous studies have described an association between preterm birth and maturation of the autonomic nervous system (ANS); however, this may be impacted by multiple factors, including prematurity-related complications. Our aim was to evaluate for the effect of prematurity-related morbidity on ANS development in preterm infants in the NICU. METHODS: We compared time and frequency domains of heart rate variability (HRV) as a measure of ANS tone in 56 preterm infants from 2 NICUs (28 from each). One cohort was from a high-morbidity regional referral NICU, the other from a community-based inborn NICU with low prematurity-related morbidity. Propensity score matching was used to balance the groups by a 1:1 nearest neighbor design. ANS tone was analyzed. RESULTS: The two cohorts showed parallel maturational trajectory of the alpha 1 time-domain metric, with the cohort from the high-morbidity NICU having lower autonomic tone. The maturational trajectories between the two cohorts differed in all other time-domain metrics (alpha 2, RMS1, RMS2). There was no difference between groups by frequency-domain metrics. CONCLUSIONS: Prematurity-associated morbidities correlate with autonomic development in premature infants and may have a greater impact on the extrauterine maturation of this system than birth gestational age. IMPACT: Autonomic nervous system development measured by time-domain metrics of heart rate variability correlate with morbidities associated with premature birth. This study builds upon our previously published work that showed that development of autonomic tone was not impacted by gestational age at birth. This study adds to our understanding of autonomic nervous system development in a preterm extrauterine environment. Our study suggests that gestational age at birth may have less impact on autonomic nervous system development than previously thought.

In infants with congenital heart disease autonomic dysfunction is associated with pre-operative brain injury.

BACKGROUND: Brain injury is a serious and common complication of critical congenital heart disease (CHD). Impaired autonomic development (assessed by heart rate variability (HRV)) is associated with brain injury in other high-risk neonatal populations. OBJECTIVE: To determine whether impaired early neonatal HRV is associated with pre-operative brain injury in CHD. METHODS: In infants with critical CHD, we evaluated HRV during the first 24 h of cardiac ICU (CICU) admission using time-domain (RMS 1, RMS 2, and alpha 1) and frequency-domain metrics (LF, nLF, HF, nHF). Pre-operative brain magnetic resonance imaging (MRI) was scored for injury using an established system. Spearman's correlation coefficient was used to determine the association between HRV and pre-operative brain injury. RESULTS: We enrolled 34 infants with median birth gestational age of 38.8 weeks (IQR 38.1-39.1). Median postnatal age at pre-operative brain MRI was 2 days (IQR 1-3 days). Thirteen infants had MRI evidence of brain injury. RMS 1 and RMS 2 were inversely correlated with pre-operative brain injury. CONCLUSIONS: Time-domain metrics of autonomic function measured within the first 24 h of admission to the CICU are associated with pre-operative brain injury, and may perform better than frequency-domain metrics under non-stationary conditions such as critical illness. IMPACT: Autonomic dysfunction, measured by heart rate variability (HRV), in early transition is associated with pre-operative brain injury in neonates with critical congenital heart disease. These data extend our earlier findings by providing further evidence for (i) autonomic dysfunction in infants with CHD, and (ii) an association between autonomic dysfunction and brain injury in critically ill neonates. These data support the notion that further investigation of HRV as a biomarker for brain injury risk is warranted in infants with critical CHD.

Taenia-tela choroidea complex and choroid plexus location help distinguish Dandy-Walker malformation and Blake pouch cysts.

BACKGROUND: Dandy-Walker malformation and Blake pouch cysts can have overlapping imaging features. The choroid plexus and associated taenia-tela choroidea complex are displaced inferolaterally in Dandy-Walker malformation and below the vermis in Blake pouch cysts. OBJECTIVE: To determine the normal fetal and postnatal MR appearance of the choroid plexus and taenia-tela choroidea complex, and whether their location can help distinguish Dandy-Walker malformation from Blake pouch cysts. MATERIALS AND METHODS: In this retrospective study, we evaluated brain MR exams from normal-appearing fetuses (gestational age 19-38 weeks) and infants, fetal and postnatal exams in Blake pouch cysts and Dandy-Walker malformation, and ambiguous cases equivocal for mild Dandy-Walker malformation and Blake pouch cysts. We documented choroid plexus and the taenia-tela choroidea complex location and axial and sagittal angles in each case. Then we contrasted and compared the original and updated fetal diagnoses based on taenia-tela choroidea complex and choroid plexus positions. RESULTS: The choroid plexus location and the taenia-tela choroidea complex location and angles varied significantly among normal exams, Blake pouch cyst exams and Dandy-Walker malformation exams (P<0.01). Dandy-Walker malformation showed inferolateral displacement of the taenia-tela choroidea complex and choroid plexus distant from the vermis. Adding the taenia-tela choroidea complex and choroid plexus into the assessment improved diagnostic accuracy, especially in ambiguous cases. CONCLUSION: The location of the taenia-tela choroidea complex and choroid plexus provided additional diagnostic neuroimaging clues that could be used in conjunction with other conventional findings to distinguish Dandy-Walker malformation and Blake pouch cysts. Normal, Blake pouch cyst, and Dandy-Walker malformation cases differed with regard to taenia-tela choroidea complex and choroid plexus position. Inferolateral taenia-tela choroidea complex displacement distant from the vermian margin was characteristic of Dandy-Walker malformation.

The Role of Fetal MRI for Suspected Anomalies of the Posterior Fossa.

BACKGROUND: Posterior fossa anomalies can be diagnostic dilemmas during the fetal period. The prognosis for different diagnoses of the posterior fossa varies widely. We investigated whether fetal magnetic resonance imaging (MRI) and prenatal neurology consultation led to an alternate prognosis for fetuses referred due to concern for a fetal posterior fossa anomaly and concordance between pre- and postnatal diagnoses. METHODS: This is a retrospective study of cases referred to the Prenatal Pediatrics Institute at Children's National Hospital from January 2012 to June 2018 due to concern for posterior fossa anomaly. Each encounter was scored for change in prognosis based upon clinical and fetal MRI report. Postnatal imaging was compared with prenatal imaging when available. RESULTS: In total, 180 cases were referred for fetal posterior fossa anomalies based on outside obstetric ultrasound and had both fetal MRI and a neurology consultation. Fetal MRI and neurology consultation resulted in a change in fetal prognosis in 70% of cases. The most common referral diagnosis in our cohort was Dandy-Walker continuum, but it was not often confirmed by fetal MRI. In complex cases, posterior fossa diagnosis and prognosis determined by fetal MRI impacted choices regarding pregnancy management. Postnatal imaging was obtained in 57 (47%) live-born infants. Fetal and postnatal prognoses were similar in 60%. CONCLUSIONS: Fetal diagnosis affects pregnancy management decisions. The fetal-postnatal imaging agreement of 60% highlights the conundrum of balancing the timing of fetal MRI to provide the most accurate diagnosis of the posterior fossa abnormalities in time to make pregnancy management decisions.

How prenatal head ultrasound reference ranges affect evaluation of possible fetal microcephaly.

OBJECTIVES: Different fetal ultrasound (US) nomograms of the head circumference (HC) have been established; however, comparisons between the detection rates of microcephaly among US nomograms are few and inconsistent. We aimed to compare the prenatal diagnostic rate of fetal microcephaly (FM) among four widely used US nomograms of the fetal HC, when applied to the same group of fetuses. METHODS: We retrospectively identified singleton pregnancies complicated by fetal HC < 5th percentile for gestational age (GA) by US, without other risk factors for FM and with normal fetal brain MRI. Raw values of HC by US were converted to z-scores using four nomograms (Chervenak = A, Hadlock = B, Gelber = C, Papageorghiou = D). Z-scores value of the HC were classified as normal, possible normal, or microcephaly if values were >-2, ≤ -2 and >-3, or ≤ -3, respectively and compared among the four nomograms. RESULTS: Fifty one fetuses at a mean (±SD) GA of 28 (±4) weeks were included. The four nomograms resulted in different z-score values of the fetal HC for the same subject (p < .001) and none of them showed 100% agreement. Reference C and D showed the highest agreement in classifying subjects as normal, possible normal, or with microcephaly (simple Kappa = 0.8915, % agreement = 94.1%), while A and B had the lowest agreement (simple Kappa = 0.0977, % agreement = 51.0%). CONCLUSIONS: Despite the use of similar prenatal cutoff z-score values of the fetal HC, the four nomograms led to different diagnostic rates of FM. More consistent diagnostic criteria are therefore needed to define FM, especially in the absence of other risk factors for FM and normal fetal brain MRI, since the prenatal diagnosis can affect pregnancy management.

Autonomic nervous system maturation in the premature extrauterine milieu.

BACKGROUND: In premature infants, we investigated whether the duration of extrauterine development influenced autonomic nervous system (ANS) maturation. METHODS: We performed a longitudinal cohort study of ANS maturation in preterm infants. Eligibility included birth gestational age (GA) < 37 weeks, NICU admission, and expected survival. The cohort was divided into three birth GA groups: Group 1 (≤29 weeks), Group 2 (30-33 weeks), and Group 3 (≥34 weeks). ECG data were recorded weekly and analyzed for sympathetic and parasympathetic tone using heart rate variability (HRV). Quantile regression modeled the slope of ANS maturation among the groups by postnatal age to term-equivalent age (TEA) (≥37 weeks). RESULTS: One hundred infants, median (Q1-Q3) birth GA of 31.9 (28.7-33.9) weeks, were enrolled: Group 1 (n = 35); Group 2 (n = 40); and Group 3 (n = 25). Earlier birth GA was associated with lower sympathetic and parasympathetic tone. However, the rate of autonomic maturation was similar, and at TEA there was no difference in HRV metrics across the three groups. The majority of infants (91%) did not experience significant neonatal morbidities. CONCLUSION: Premature infants with low prematurity-related systemic morbidity have maturational trajectories of ANS development that are comparable across a wide range of ex-utero durations regardless of birth GA. IMPACT: Heart rate variability can evaluate the maturation of the autonomic nervous system. Metrics of both the sympathetic and parasympathetic nervous system show maturation in the premature extrauterine milieu. The autonomic nervous system in preterm infants shows comparable maturation across a wide range of birth gestational ages. Preterm newborns with low medical morbidity have maturation of their autonomic nervous system while in the NICU. Modern NICU advances appear to support autonomic development in the preterm infant.

Exposures influencing the developing central autonomic nervous system.

Autonomic nervous system function is critical for transition from in-utero to ex-utero life and is associated with neurodevelopmental and neuropsychiatric outcomes later in life. Adverse prenatal and neonatal conditions and exposures can impair or alter ANS development and, as a result, may also impact long-term neurodevelopmental outcomes. The objective of this article is to provide a broad overview of the impact of factors that are known to influence autonomic development during the fetal and early neonatal period, including maternal mood and stress during and after pregnancy, fetal growth restriction, congenital heart disease, toxic exposures, and preterm birth. We touch briefly on the typical development of the ANS, then delve into both in-utero and ex-utero maternal and fetal factors that may impact developmental trajectory of the ANS and, thus, have implications in transition and in long-term developmental outcomes. While many types of exposures and conditions have been shown to impact development of the autonomic nervous system, there is still much to be learned about the mechanisms underlying these influences. In the future, more advanced neuromonitoring tools will be required to better understand autonomic development and its influence on long-term neurodevelopmental and neuropsychological function, especially during the fetal period.

Placental Pathology and Neuroimaging Correlates in Neonates with Congenital Heart Disease.

Congenital heart disease (CHD) is an independent risk factor for brain injury, including stroke, and poor neurodevelopmental outcomes, and placental abnormalities may represent an additional risk factor for brain injury in neonates. The incidence and scope of placental pathology and relationship to fetal brain abnormalities in pregnancies complicated by fetal CHD has not been explored to our knowledge. In order to determine the prevalence of placental pathology findings and whether placental findings are associated with postnatal brain injury in pregnancies complicated by fetal CHD, we reviewed placental pathology reports for 51 pregnancies complicated by CHD and scored available postnatal, pre-operative brain MRI for brain pathology. Overall, 57% of CHD infants had abnormal placental pathology. Pregnancies complicated by CHD with aortic obstruction (AO) were significantly more likely than those with no obstruction to have abnormal placental pathology (79% vs. 44%). There was a trend toward more severe brain lesions amongst patients with brain lesions and placental abnormality (55% moderate/severe) compared to those without placental abnormality (11% moderate/severe). These data suggest that placental abnormalities are common in CHD and may have a compounding effect on brain lesions in this high-risk population.

Neuronal c-Abl activation leads to induction of cell cycle and interferon signaling pathways.

BACKGROUND: Expression of active c-Abl in adult mouse forebrain neurons in the AblPP/tTA mice resulted in severe neurodegeneration, particularly in the CA1 region of the hippocampus. Neuronal loss was preceded and accompanied by substantial microgliosis and astrocytosis. In contrast, expression of constitutively active Arg (Abl-related gene) in mouse forebrain neurons (ArgPP/tTA mice) caused no detectable neuronal loss or gliosis, although protein expression and kinase activity were at similar levels to those in the AblPP/tTA mice. METHODS: To begin to elucidate the mechanism of c-Abl-induced neuronal loss and gliosis, gene expression analysis of AblPP/tTA mouse forebrain prior to development of overt pathology was performed. Selected results from gene expression studies were validated with quantitative reverse transcription PCR , immunoblotting and bromodeoxyuridine (BrdU) labeling, and by immunocytochemistry. RESULTS: Two of the top pathways upregulated in AblPP/tTA mice with c-Abl expression for 2 weeks were cell cycle and interferon signaling. However, only the expression of interferon signaling pathway genes remained elevated at 4 weeks of c-Abl induction. BrdU incorporation studies confirm that, while the cell cycle pathway is upregulated in AblPP/tTA mice at 2 weeks of c-Abl induction, the anatomical localization of the pathway is not consistent with previous pathology seen in the AblPP/tTA mice. Increased expression and activation of STAT1, a known component of interferon signaling and interferon-induced neuronal excitotoxicity, is an early consequence of c-Abl activation in AblPP/tTA mice and occurs in the CA1 region of the hippocampus, the same region that goes on to develop severe neurodegenerative pathology and neuroinflammation. Interestingly, no upregulation of gene expression of interferons themselves was detected. CONCLUSIONS: Our data suggest that the interferon signaling pathway may play a role in the pathologic processes caused by c-Abl expression in neurons, and that the AblPP/tTA mouse may be an excellent model for studying sterile inflammation and the effects of interferon signaling in the brain.

c-Abl in neurodegenerative disease.

The c-Abl tyrosine kinase participates in a variety of cellular functions, including regulation of the actin cytoskeleton, regulation of the cell cycle, and the apoptotic/cell cycle arrest response to stress, and the Abl family of kinases has been shown to play a crucial role in development of the central nervous system. Recent studies have shown c-Abl activation in human Alzheimer's and Parkinson's diseases and c-Abl activation in mouse models and neuronal culture in response to amyloid beta fibrils and oxidative stress. Overexpression of active c-Abl in adult mouse neurons results in neurodegeneration and neuroinflammation. Based on this evidence, a potential role for c-Abl in the pathogenesis of neurodegenerative disease is discussed, and we attempt to place activation of c-Abl in context with other known contributors to neurodegenerative pathology.

Neuronal c-Abl overexpression leads to neuronal loss and neuroinflammation in the mouse forebrain.

Several immunocytochemical studies have revealed that Abelson tyrosine kinase (c-Abl) is associated with both neuritic plaques and neurofibrillary tangles in the brains of patients with Alzheimer's disease (AD). Additionally, c-Abl has been shown to phosphorylate tau on tyrosine 394. The activity of c-Abl is also involved in the control of the cell cycle and apoptosis. To examine the consequences of c-Abl activation in the adult brain, we have constructed two lines of transgenic mice expressing either a constitutively active form of c-Abl (AblPP/tTA mice) or its sister protein, Arg (ArgPP/tTA mice), with a neuron-specific promoter (CamKIIα) regulated by doxycycline (Tet-Off). Expression of active c-Abl in adult mouse forebrain neurons results in severe neurodegeneration, particularly in the CA1 region of the hippocampus. Neuronal loss was preceded and accompanied by substantial microgliosis and astrocyctosis. Despite careful examination, no c-Abl expression is found in glial cells, indicating that neuronal c-Abl expression is responsible for the gliosis. In contrast, ArgPP/tTA mice have no evidence of neuronal loss or gliosis, even though protein expression and kinase activity levels are similar to those in the AblPP/tTA mice. Given the evidence of c-Abl activation in the human AD brain combined with the pathological phenotype of AblPP/tTA mice, it is likely that aberrant c-Abl activity may play a role in neurodegenerative disease.