Neuroimaging Outcomes Research Articles

A Case Series Characterizing Pilomyxoid Astrocytomas in Childhood

The term pilomyxoid astrocytoma (PMA) was added to the World Health Organization Classification of Tumours of the central nervous system in 2007. Pilomyxoid tumors are grade II tumors, considered to be variants of pilocytic astrocytomas. We attempted to determine if positron emission tomography (PET), proliferative index (PI), and BRAF V600E mutation help better define PMAs. We report 5 patients' clinical and neuroimaging findings, pathology (PI), and outcome. Four of the 5 patients had PET scans. Three patients showed [18F]fluoro-deoxyglucose hypermetabolism. The PI was elevated in all 5 cases and the BRAF V600E mutation was found in 3 of the 3 patients tested. Our data suggest that PMAs are hypermetabolic on PET, have elevated PIs and BRAF V600E mutations, and behave aggressively.

Supraorbital Keyhole Microsurgical Fenestration of Symptomatic Temporal Arachnoid Cysts in Children: Advantages and Limitations.

To investigate the impact of endoscope-assisted microsurgical fenestration on temporal arachnoid cysts, and to determine the advantages and limitations of the technique. Twenty-five children with symptomatic temporal arachnoid cysts were operated via eyebrow supraorbital keyhole microsurgical fenestration targeting the medial cyst wall. Preoperative magnetic resonance imaging (MRI) of the brain was done for all patients. Preoperative clinical presentation of the patients included headache (80%), nausea & vomiting (64%), drug resistant epilepsy (52%), macrocephaly (12%) papilledema (28%), motor weakness in the form of right-sided hemiparesis (12%) and cranial nerve palsy. Postoperative complete subsidence of headache was noted in 50%, while 20% remained unchanged. Drug resistant epilepsy improved in 69% of the patients. Postoperative MRI showed initial decrease in cyst volume as early as 3 months, only in a range of 5-12% volume reduction, and the late follow-up done at 6 and 18 months continued to show further reduction reported to be significant (p < 0.001). Transient subgaleal cerebrospinal fluid (CSF) collection was the most common complication (20%). Only 1 patient experienced CSF leak mandating cysto-peritoneal shunting. Conclusıon: Eyebrow supraorbital keyhole microsurgical fenestration for temporal arachnoid cysts can be performed with a fairly low risk of complications and yields a favorable improvement in clinical and neuroimaging outcomes.

Chapter 24 - Rare glial tumors

This chapter describes the epidemiology, pathology, molecular characteristics, clinical and neuroimaging features, treatment, outcome, and prognostic factors of the rare glial tumors. This category includes subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, astroblastoma, chordoid glioma of the third ventricle, angiocentric glioma, ganglioglioma, desmoplastic infantile astrocytoma and ganglioma, dysembryoplastic neuroepithelial tumor, papillary glioneuronal tumor, and rosette-forming glioneuronal tumor of the fourth ventricle. Many of these tumors, in particular glioneuronal tumors, prevail in children and young adults, are characterized by pharmacoresistant seizures, and have an indolent course, and long survival following surgical resection. Radiotherapy and chemotherapy are reserved for recurrent and/or aggressive forms. New molecular alterations are increasingly recognized.

Human immunodeficiency virus has similar effects on brain volumetrics and cognition in males and females.

Most studies that have examined neuropsychological impairments associated with human immunodeficiency virus (HIV) have focused on males, yet females represent one of the largest groups of newly infected patients. Further, few studies have examined neuropsychological performance and neuroimaging outcomes among females compared to males in the modern era of highly active anti-retroviral therapy (HAART). The present study investigated neuropsychological performance and brain volumetrics among HIV+ males (n = 93) and females (n = 44) on stable HAART compared to HIV seronegative (HIV-) males (n = 42) and females (n = 49). Results revealed a significant effect of HIV on neuropsychological performance and neuroimaging measures. An effect of gender, independent of HIV status, was also observed for neuroimaging measures but not neuropsychological performance. Additionally, no significant differences in neuropsychological performance or brain volumetrics were seen between HIV+ males and females. No significant interaction was observed between HIV and gender on either neuropsychological or neuroimaging indices. Our results suggest that both HIV+ males and females treated with HAART experience similar outcomes in terms of brain integrity.

CLINICAL AND IMAGING ANALYSIS OF HUNTINGTON DISEASE WITH USE OF RESTING-STATE FUNCTIONAL MAGNETIC RESONANCE IMAGING

Huntington’s disease (HD) is an autosomal dominant progressive neurodegenerative disorder, which is caused by a CAG repeat expansion in huntingtin gene. HD is characterized by a triad of symptoms: motor dysfunction, cognitive decline, and psychiatric disturbance. This disease is still incurable; however considerable progress has been achieved in disease management targeted on correction of specific stages of pathogenic mechanism. This fact induces the search of various HD biomarkers in order to study nature course of the disease and evaluate the efficacy of innovatory experimental therapeutic approaches. The article presents the results of clinical and imaging analysis with resting-state functional magnetic resonance imaging of pathological gene carriers and patients with full-scaled symptoms of HD. We found certain clinical and neuroimaging outcomes, which can be considered as potential biomarkers.

Editorial: Radiosurgery and cavernous malformations

The successful obliteration of selected cerebral arteriovenous malformations (AVMs) using the Gamma Knife prompted the treatment of cavernous malformations (CMs) and aneurysms. For CMs, their small volume, lack of intervening normal brain tissue, and relatively low rate of clinically significant hemorrhage made them an appealing target for stereotactic radiosurgery (SRS). Radiosurgery for aneurysms was quickly abandoned as a failure, but radiosurgery for CMs persists despite controversy regarding its therapeutic value.13 Unlike for AVMs, radiosurgery for CMs often appears to have little to no effect evident on follow-up neuroimaging studies. In a previous report, a CM treated with Gamma Knife radiosurgery appeared unchanged on follow-up MRI 5 years afterwards.13 Extirpation of the lesion was undertaken, and histological examination revealed the lesion was partially obliterated with patency to a single persistent capillary channel (Fig. 1). Therefore, the correlation between radiographic and pathological changes may be unreliable following CM radiosurgery. From a series of more than 100 CMs treated at the University of Pittsburgh, Shin and colleagues report on the histopathological responses of 4 patients with CM who underwent resection 4 months to 7 years following radiosurgery.10 The CMs were treated with prescription doses of 14–15 Gy of radiation. In all 4 cases, radiosurgery failed and the patients suffered recurrent hemorrhages. Histopathological analysis revealed partially obliterated vessels and incomplete sclerosis as early as 4 months following radiosurgery. Partial obliteration could be a response to repeated microbleeds, recent hemorrhage, or past radiosurgery. Foci of neovascularization were also observed, as evidenced by staining for vascular endothelial growth factor (VEGF). In the case from our institution as well as the 4 from the University of Pittsburgh, we run the risk of drawing too much significance from a small and undoubtedly biased cohort. Nevertheless, the findings from Shin et al.’s study are some of the best available for elucidating the underlying radiobiological changes from radiosurgery on CMs. Coupling these histopathological findings with the neuroimaging and clinical outcomes published in the literature, it would seem safe to conclude that radiosurgery induces some of the same vessel sclerosis in CMs as it does in AVMs. However, the changes in AVM compared to CM vasculature following radiosurgery are substantially more robust and complete in the majority of patients.1,9,12 The incomplete response seen in CMs after radiosurgery may explain the potentially lower but still tangible risk of recurrent hemorrhage (8.8% annual risk for the first 2 years, then 1.1% annual risk after 2 years based on the group’s prior publication) in patients even years after radiosurgery.6 In contrast, in more than 1400 AVM patients treated using SRS, we have not observed a single hemorrhage in an AVM confirmed to be obliterated on angiography.11 The incomplete histopathological changes in CMs are consistent with the reduced but persistent risk of hemorrhage following radiosurgery. These findings raise 2 potential options for improving CM radiosurgery outcomes. First, the 4 patients in the current series were treated with a radiosurgical dose of 14–15 Gy to the margin of the CM. Prior preclinical and clinical studies have demonstrated more beneficial vascular changes with higher doses.1,5,7 However, such higher doses in patients with CM have also been associated with more complications. For example, in an early cohort of 22 CM patients treated with a mean margin dose of 18 Gy, 6 patients suffered neurological decline due to radiationinduced changes, and 5 (22.7%) had permanent deficits.4 Radiation-induced complications were defined as radionecrosis or transient radiation-induced changes demonstrated on CT or MRI and associated with a neurological decline. The radiation-induced complication rate in CMs was more than 2 times higher than expected for a simi-

Sample size calculations for clinical trials targeting tauopathies: a new potential disease target.

Disease-modifying therapies are being developed to target tau pathology, and should, therefore, be tested in primary tauopathies. We propose that progressive apraxia of speech should be considered one such target group. In this study, we investigate potential neuroimaging and clinical outcome measures for progressive apraxia of speech and determine sample size estimates for clinical trials. We prospectively recruited 24 patients with progressive apraxia of speech who underwent two serial MRI with an interval of approximately 2 years. Detailed speech and language assessments included the Apraxia of Speech Rating Scale and Motor Speech Disorders severity scale. Rates of ventricular expansion and rates of whole brain, striatal and midbrain atrophy were calculated. Atrophy rates across 38 cortical regions were also calculated and the regions that best differentiated patients from controls were selected. Sample size estimates required to power placebo-controlled treatment trials were calculated. The smallest sample size estimates were obtained with rates of atrophy of the precentral gyrus and supplementary motor area, with both measures requiring less than 50 subjects per arm to detect a 25% treatment effect with 80% power. These measures outperformed the other regional and global MRI measures and the clinical scales. Regional rates of cortical atrophy, therefore, provide the best outcome measures in progressive apraxia of speech. The small sample size estimates demonstrate feasibility for including progressive apraxia of speech in future clinical treatment trials targeting tau.

The role of vascular endothelial growth factor in neurodegeneration and cognitive decline: exploring interactions with biomarkers of Alzheimer disease.

A subset of older adults present post mortem with Alzheimer disease (AD) pathologic features but without any significant clinical manifestation of dementia. Vascular endothelial growth factor (VEGF) has been implicated in staving off AD-related neurodegeneration. To evaluate whether VEGF levels are associated with brain aging outcomes (hippocampal volume and cognition) and to further evaluate whether VEGF modifies relations between AD biomarkers and brain aging outcomes. Biomarker analysis using neuroimaging and neuropsychological outcomes from the Alzheimer's Disease Neuroimaging Initiative. This prospective longitudinal study across North America included individuals with normal cognition (n = 90), mild cognitive impairment (n = 130), and AD (n = 59) and began in October 2004, with follow-up ongoing. Cerebrospinal fluid VEGF was cross-sectionally related to brain aging outcomes (hippocampal volume, episodic memory, and executive function) using a general linear model and longitudinally using mixed-effects regression. Alzheimer disease biomarker (cerebrospinal fluid β-amyloid 42 and total tau)-by-VEGF interactions evaluated the effect of VEGF on brain aging outcomes in the presence of enhanced AD biomarkers. Vascular endothelial growth factor was associated with baseline hippocampal volume (t277 = 2.62; P = .009), longitudinal hippocampal atrophy (t858 = 2.48; P = .01), and longitudinal decline in memory (t1629 = 4.09; P < .001) and executive function (t1616 = 3.00; P = .003). Vascular endothelial growth factor interacted with tau in predicting longitudinal hippocampal atrophy (t845 = 4.17; P < .001), memory decline (t1610 = 2.49; P = .01), and executive function decline (t1597 = 3.71; P < .001). Vascular endothelial growth factor interacted with β-amyloid 42 in predicting longitudinal memory decline (t1618 = -2.53; P = .01). Elevated cerebrospinal fluid VEGF was associated with more optimal brain aging in vivo. The neuroprotective effect appeared strongest in the presence of enhanced AD biomarkers, suggesting that VEGF may be particularly beneficial in individuals showing early hallmarks of the AD cascade. Future work should evaluate the interaction between VEGF expression in vitro and pathologic burden to address potential mechanisms.

Neurocognitive and neuroimaging outcome of early treated young adult PKU patients: A longitudinal study.

The aim of the study was to explore the outcome of neurocognitive deficits and neuroimaging correlates in young adult early treated phenylketonuric (PKU) patients. We conducted a longitudinal study of 14 PKU patients that were assessed for IQ and neuropsychological functioning including executive functions (EF) over 14 years of follow-up (age range at 1st and 2nd assessments were 7.8-13.5 and 22.2-27.7 years, respectively). The IQ of all 14 PKU patients was within the normal range. With respect to the 1st assessment, mean IQ at follow-up did not decrease significantly. Compared to control subjects (n = 14), mean IQ of patients was significantly lower (p = .0005). Throughout adolescence and early adulthood there was an improvement of neuropsychological functioning of PKU patients in spite of the relaxation of diet, however some deficits were still detectable when compared to controls. All patients that underwent a second MRI scan showed white matter alterations ranging from mild to severe which was correlated neither with IQ nor with EF scoring. Cognitive, neuropsychological and neuroimaging outcome was influenced from life-long and/or second decade of life metabolic control. Nevertheless patients' developmental trajectories were in some cases independent from metabolic control. Our results support the hypothesis of an individual vulnerability to phenylalanine. However, as long as individual factors that account for the vulnerability to Phe are not recognized, strict dietary control is recommended for all the patients also in the second decade of life.

Mathematical Difficulties and White Matter Abnormalities in Subacute Pediatric Mild Traumatic Brain Injury.

Mathematical difficulties have been documented following pediatric mild traumatic brain injury (mTBI), yet a precise characterization of these impairments and their neural correlates is currently unavailable. We aimed to characterize these impairments by comparing behavioral and neuroimaging (i.e., diffusion tensor imaging [DTI]) outcomes from children with subacute mTBI to typically-developing controls. Twenty subacute pediatric mTBI patients and 20 well-matched controls underwent cognitive assessment and DTI examination. DTI tractography was used to detect white matter abnormalities in the corpus callosum (CC) and superior and inferior longitudinal fasciculi; these tracts are involved in mathematical performance and they are often damaged after mTBI. Behavioral results revealed that children with mTBI performed significantly more poorly on rapid apprehension of small numbers of objects (or "subitizing"), processing of non-symbolic numerosities, and procedural problem solving. These group differences were explained by differences in visuospatial working memory, which suggests that the observed mathematical difficulties may be a consequence of impairments in visuospatial abilities. DTI analysis revealed subtle group differences in the CC genu and splenium (i.e., higher fractional anisotropy and lower mean and radial diffusivity in children with mTBI) but the observed white matter abnormalities of the CC were not significantly associated with the observed mathematical difficulties in the mTBI patients.

The cyclical lower extremity exercise for Parkinson's trial (CYCLE): methodology for a randomized controlled trial.

BackgroundMotor and non-motor impairments affect quality of life in individuals with Parkinson’s disease. Our preliminary research indicates that forced exercise cycling, a mode of exercise in which a participant’s voluntary rate of exercise is augmented on a stationary cycle, results in global improvements in the cardinal symptoms of Parkinson’s disease. The objective of the Cyclical Lower Extremity Exercise (CYCLE) trial for Parkinson’s disease is to determine the effects of forced exercise cycling on motor and non-motor performance when compared to voluntary rate cycling and a non-exercise control group. Additionally, we plan to identify any associated changes in neural activity determined by functional magnetic resonance imaging.Methods/DesignA total of 100 individuals with mild to moderate idiopathic Parkinson’s disease will participate in a single-center, parallel-group, rater-blind study. Participants will be randomized 2:2:1 into a forced exercise, voluntary exercise, or no-exercise control group, respectively. Both exercise groups will cycle 3 times per week for 8 weeks at identical aerobic intensities for 40 minutes, but participants in the forced exercise group will cycle 30% faster than their voluntary rate by means of an augmented motorized bicycle. Neuroimaging, clinical, and biomechanical assessments of motor and non-motor performance will be made at baseline both ‘on’ and ‘off’ medication, after four weeks of exercise (midpoint), end of treatment, 4 weeks after end of treatment, and 8 weeks after end of treatment.DiscussionCYCLE trial will play a critical role in determining the effectiveness of two different types of aerobic exercise, forced and voluntary, on motor and non-motor performance in individuals with Parkinson’s disease. Additionally, the coupling of clinical, biomechanical, and neuroimaging outcomes has the potential to provide insight into mechanisms underlying change in function as a result of exercise.Trial registrationClinicaltrials.gov registration number NCT01636297.

The Effect of Central Nervous System Penetration Effectiveness of Highly Active Antiretroviral Therapy on Neuropsychological Performance and Neuroimaging in HIV Infected Individuals.

The incidence of HIV-associated dementia has been greatly reduced in the era of highly active antiretroviral therapy (HAART); however milder forms of cognitive impairment persist. It remains uncertain whether HAART regimens with a high degree of central nervous system penetration effectiveness (CPE) exert beneficial neurological outcomes in HIV-infected (HIV+) individuals on stable treatment. Sixty-four HIV-infected adults on HAART were assigned a CPE score using a published ranking system and divided into high (≥7; n = 35) and low (<7; n = 29) CPE groups. All participants completed neuropsychological testing in addition to structural neuroimaging. Neuropsychological tests included measures known to be sensitive to HIV with values converted into standardized scores (NPZ-4) based on published normative scores. A semi-automated methodology was utilized to assess brain volumetrics within cortical (grey and white matter) and subcortical (thalamus, caudate, putamen) regions of interest. Analyses assessed NPZ-4 and brain volumetric differences between HIV+ individuals with high and low CPE scores. No significant differences in brain integrity were observed between the two groups. Long-term HAART regimens with a high degree of CPE were not associated with significantly improved neuropsychological or neuroimaging outcomes in HIV+ adults. Results suggest that alternate mechanisms may potentially contribute to better neurological outcomes in the era of HAART.

Hippocampal Metabolites Correlate with Neuroimaging Outcomes in the Piglet

By combining magnetic resonance imaging (MRI) and metabolomic profiling techniques, the objective of this study was to elucidate relationships between brain structure and hippocampal metabolites in the piglet. Two-day-old, vaginally-delivered male piglets (n=24) were artificially reared using standardized procedures and feeding a custom milk replacer formulated to meet piglet nutrient requirements. At 30 d of age, piglets underwent MRI procedures, and brain tissue was collected 24 h post-imaging for metabolomic and lipodomic profiling of hippocampal tissue. Analysis of MRI data in 19 brain regions yielded volumetric estimates as well as microstructural details measured by diffusion tensor fractional anisotropy (FA), and radial (RD), axial (AD), and mean (MD) diffusivities, which provide directional characterization of water movement within axons. Comparison of fatty acids in n-3, n-6, and n-9 categories with MRI measures yielded correlations (P < 0.05) in 150 of 2726, 162 of 3596, and 129 of 2494 possible outcomes, respectively. Neuroimaging outcomes that were highly correlative across fatty acid categories included MD, RD, and AD in the internal capsule and right hippocampus, suggesting ongoing myelination in the piglet brain. Nervonic acid, a fatty acid known to be prevalent at peak myelination, was correlated with 26 of 58 total outcomes, further supporting the link between metabolism and neurodevelopment. In conclusion, significant correlations between metabolic and structural outcomes in the neonatal piglet brain emphasize targets whereby dietary manipulation may alter neurodevelopmental patterns. Supported by Mead Johnson Nutrition.

Clinical correlates of retrograde amnesia in mild traumatic brain injury

Primary objective: The purpose of this study was to examine the clinical significance of retrograde amnesia (RA) in patients with acute mild traumatic brain injuries (MTBI).Methods and procedures: An emergency department sample of patients (n = 75), aged 18–60 years, with no pre-morbid medical or psychiatric conditions, who met the WHO criteria for MTBI were enrolled in this prospective, descriptive, follow-up study. This study examined the presence and duration of RA in relation to socio-demographics, MTBI severity markers including neuroimaging (CT, MRI) and clinical outcomes (Rivermead post-concussion symptoms questionnaire, post-concussion syndrome (PCS) diagnosis and return to work (RTW) status) at 2 weeks, 1 month and 6 months post-injury.Main outcomes and results: GCS scores and duration of post-traumatic amnesia (PTA) were related to RA. Those with GCS scores of 14 vs. 15 were more likely to have RA (χ2(1) = 13.70, p < 0.0001) and a longer duration (Mann-Whitney U = 56.0, p < 0.0001, d = 1.15) of RA. The duration of RA and PTA correlated positively (Spearman ρ(75) = 0.42, p < 0.0001) and those with RA had longer durations of PTA (Mann-Whitney U = 228.5, p = 0.001, d = 1.21). During the follow-up, the presence and duration of RA were not significantly associated with PCS diagnosis or time to RTW.Conclusions: In this study, the presence and duration of RA was not associated with outcome.

Abstract 17: Development of High Risk TCD in Sickle Cell Disease

Background: The Stroke Prevention Trial in Sickle Cell Anemia (STOP) and Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) established routine transcranial Doppler ultrasound (TCD) as standard of care. Some information on conversion from low to high risk was derived from the STOP/2 studies but information is needed from “real world” practice to improve TCD screening guidelines. Subjects and Methods: During STOP and STOP2, 3,837 children, ages 2 to 16 y with SCD-SS or SCD-SBeta-0-thalassemia, underwent screening TCD. The POST-STOP study was designed to follow-up all children who participated in one or both of these trials. 19 of the 26 original study sites participated in POST-STOP, contributing a total of 3,541 (92%) of STOP/STOP2 subjects. Data abstractors visited the clinical sites to extract TCD, neuroimaging and neurological outcome information. Results: Of the 3,541 subjects, follow-up data were available for 2834 (80%). The mean age at the last TCD STOP/2study was 9.5 years, the mean age at last follow-up in POST-STOP was 19.6 years and the mean duration of follow-up after exiting STOP/STOP2 was 9.2 years. STOP TCD risk stratification was used: normal &lt; 170 cm/sec; conditional 170-199 cm/sec; abnormal &gt;200 cm/sec. Subjects were classified by their highest risk TCD in STOP/STOP 2. The population was divided on this basis into normal (1813 --64%), conditional (478 --17%), abnormal (357-- 13%) or inadequate (186 --7%). Among the 478 with conditional TCD studies in STOP/STOP2, the mean age at last follow-up in POST-STOP was 19.2 years (range 4.9-33.1) and follow-up TCD was obtained on 252 (53%) from 11 months to 16 years after STOP/2 (median 10.4) . Forty three of these had an abnormal TCD (mean age at abnormal was 8.5 years from 3 months to 8.4 years after STOP/2 (median 1.97 years). Conclusions: 1) We could find evidence of follow up TCD for about of half of these children indicating that more needs to be done to insure regular and consistent surveillance of these children who have some elevated risk. 2) Conversions to abnormal TCD were documented. Treatment decisions as well as stroke outcomes for all the 479 with conditional TCD will be derived from adjudication of the complete data set (in progress).

Neuroimaging and neurodevelopmental outcome in extremely preterm infants.

Extremely preterm infants are at risk for neurodevelopmental impairment (NDI). Early cranial ultrasound (CUS) is usual practice, but near-term brain MRI has been reported to better predict outcomes. We prospectively evaluated MRI white matter abnormality (WMA) and cerebellar lesions, and serial CUS adverse findings as predictors of outcomes at 18 to 22 months' corrected age. Early and late CUS, and brain MRI were read by masked central readers, in a large cohort (n = 480) of infants <28 weeks' gestation surviving to near term in the Neonatal Research Network. Outcomes included NDI or death after neuroimaging, and significant gross motor impairment or death, with NDI defined as cognitive composite score <70, significant gross motor impairment, and severe hearing or visual impairment. Multivariable models evaluated the relative predictive value of neuroimaging while controlling for other factors. Of 480 infants, 15 died and 20 were lost. Increasing severity of WMA and significant cerebellar lesions on MRI were associated with adverse outcomes. Cerebellar lesions were rarely identified by CUS. In full multivariable models, both late CUS and MRI, but not early CUS, remained independently associated with NDI or death (MRI cerebellar lesions: odds ratio, 3.0 [95% confidence interval: 1.3-6.8]; late CUS: odds ratio, 9.8 [95% confidence interval: 2.8-35]), and significant gross motor impairment or death. In models that did not include late CUS, MRI moderate-severe WMA was independently associated with adverse outcomes. Both late CUS and near-term MRI abnormalities were associated with outcomes, independent of early CUS and other factors, underscoring the relative prognostic value of near-term neuroimaging.

Normative amplitude-integrated EEG measures in preterm infants.

ObjectiveAssessing qualitative patterns of amplitude integrated EEG (aEEG) maturation of preterm infants requires personnel with training in interpretation and an investment of time. Quantitative algorithms provide a method for rapidly and reproducibly assessing an aEEG recording independent of provider skill level. Although there are several qualitative and quantitative normative datasets in the literature, this study provides the broadest array of quantitative aEEG measures in a carefully selected and followed cohort of preterm infants with mild or no visible injury on term equivalent MRI and subsequently normal neurodevelopment at 2 and 7 years of age.Study DesignA two-channel aEEG recording was obtained on days 4,7,14, and 28 of life for infants born ≤30 weeks EGA. Measures of amplitude and continuity, spectral edge frequency, percentage of trace in interburst interval, interburst interval length, and frequency counts of smooth delta waves, delta brushes and theta bursts were obtained. MRI was obtained at term-equivalent age (TEA) and neurodevelopmental testing was conducted at 2 and 7 years of corrected age.ResultCorrelations were found between increasing post-menstrual age (PMA) and decreasing maximum amplitude (R=−0.23, p=0.05), increasing minimum amplitude (R=0.46, p=0.002), and increasing spectral edge frequency (R=0.78, p=4.17x10−14). Negative correlations were noted between increasing PMA and counts of smooth delta waves (R=−0.39, p=0.001), delta brushes (R=−0.37, p=0.003), and theta bursts (R=−0.61, p=5.66x10−8). Increasing PMA was also associated with a decreased amount of time spent in the interburst interval (R=−0.38, p=0.001) and a shorter length of the maximum IBI (R=−0.27, p=0.03).ConclusionThis analysis supports a strong correlation between quantitatively determined aEEG measures and PMA, in a cohort of preterm infants with normal TEA neuroimaging and neurodevelopmental outcomes at 7 years of age, which is both predictable and reproducible. These “normative” quantitative values support the pattern of maturation previously identified by qualitative analysis.

A translational investigation targeting stress-reactivity and prefrontal cognitive control with guanfacine for smoking cessation.

Stress and prefrontal cognitive dysfunction have key roles in driving smoking; however, there are no therapeutics for smoking cessation that attenuate the effects of stress on smoking and enhance cognition. Central noradrenergic pathways are involved in stress-induced reinstatement to nicotine and in the prefrontal executive control of adaptive behaviors. We used a novel translational approach employing a validated laboratory analogue of stress-precipitated smoking, functional magnetic resonance imaging (fMRI), and a proof-of-concept treatment period to evaluate whether the noradrenergic α2a agonist guanfacine (3 mg/day) versus placebo (0 mg/day) reduced stress-precipitated smoking in the laboratory, altered cortico-striatal activation during the Stroop cognitive-control task, and reduced smoking following a quit attempt. In nicotine-deprived smokers (n=33), stress versus a neutral condition significantly decreased the latency to smoke, and increased tobacco craving, ad-libitum smoking, and systolic blood pressure in placebo-treated subjects, and these effects were absent or reduced in guanfacine-treated subjects. Following stress, placebo-treated subjects demonstrated decreased cortisol levels whereas guanfacine-treated subjects demonstrated increased levels. Guanfacine, compared with placebo, altered prefrontal activity during a cognitive-control task, and reduced cigarette use but did not increase complete abstinence during treatment. These preliminary laboratory, neuroimaging, and clinical outcome data were consistent and complementary and support further development of guanfacine for smoking cessation.

Neuroimaging and Neurodevelopmental Outcome in Extremely Preterm Infants

Neuroimaging and Neurodevelopmental Outcome in Extremely Preterm Infants

Follow-up of folinic acid supplementation for patients with cerebral folate deficiency and Kearns-Sayre syndrome.

BackgroundKearns-Sayre syndrome (KSS) is a mitochondrial DNA deletion syndrome that presents with profound cerebral folate deficiency and other features. Preliminary data support the notion that folinic acid therapy might be useful in the treatment of KSS patients. Our aim was to assess the clinical and neuroimaging outcomes of KSS patients receiving folinic acid therapy.MethodsPatients: We recruited eight patients with diagnoses of KSS. Four cases were treated at 12 de Octubre Hospital, and the other two cases were treated at Sant Joan de Déu Hospital. Two patients refused to participate in the treatment protocol.Methods: Clinical, biochemical and neuroimaging data (magnetic resonance imaging or computed tomography scan) were collected in baseline conditions and at different time points after the initiation of therapy. Cerebrospinal fluid 5-methyltetrahydrofolate levels were analysed with HPLC and fluorescence detection. Large-scale mitochondrial DNA deletions were analysed by Southern blot.Treatment protocol: The follow-up periods ranged from one to eight years. Cases 1–4 received oral folinic acid at a dose of 1 mg/kg/day, and cases 6 and 8 received 3 mg/kg/day.ResultsNo adverse effects of folinic acid treatment were observed. Cerebral 5-methyltetrahydrofolate deficiencies were observed in all cases in the baseline conditions. Moreover, all three patients who accepted lumbar puncture after folinic acid therapy exhibited complete recoveries of their decreased basal cerebrospinal fluid 5-methyltetrahydrofolate levels to normal values. Two cases neurologically improved after folinic therapy. Disease worsened in the other patients.Post-treatment neuroimaging was performed for the 6 cases that received folinic acid therapy. One patient exhibited improvements in white matter abnormalities. The remaining patients displayed progressions in subcortical cerebral white matter, the cerebellum and cerebral atrophy.ConclusionsFour patients exhibited clinical and radiological progression of the disease following folinic acid treatment. Only one patient who was treated in an early stage of the disease exhibited both neurological and radiological improvements following elevated doses of folinic acid, and an additional patient experienced neurological improvement. Early treatment with high-dose folinic acid therapy seems to be advisable for the treatment of KSS.Trial registrationEudracT2007-00-6748-23Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-014-0217-2) contains supplementary material, which is available to authorized users.