Degree Of Neurocognitive Impairment Research Articles

Long-Term Follow-Up of Apert Syndrome Following Mid-Face Advancement: More Than 3 Decades Later.

Apert syndrome is characterized by craniosynostosis, a hypoplastic mid-face, skeletal abnormalities, symmetric syndactyly of the hands and feet, and a degree of neurocognitive impairment. Long-term outcomes of patients who have undergone surgical correction of Apert syndrome are limited. The authors present the case of a 73-year-old female with Apert syndrome, with follow-up of more than 3 decades following a fronto-orbital advancement and Le Fort III advancement. Clinical and radiologic images demonstrate a degree of skeletal resorption and relapse that is likely unavoidable. This provides insight into the long-term skeletal stability and esthetic outcomes for patients with Apert syndrome.

Extracellular vesicles produced by HIV-1 Nef-expressing cells induce myelin impairment and oligodendrocyte damage in the mouse central nervous system

HIV-associated neurocognitive disorders (HAND) are a spectrum of cognitive impairments that continue to affect approximately half of all HIV-positive individuals despite effective viral suppression through antiretroviral therapy (ART). White matter pathologies have persisted in the ART era, and the degree of white matter damage correlates with the degree of neurocognitive impairment in patients with HAND. The HIV protein Nef has been implicated in HAND pathogenesis, but its effect on white matter damage has not been well characterized. Here, utilizing in vivo, ex vivo, and in vitro methods, we demonstrate that Nef-containing extracellular vesicles (Nef EVs) disrupt myelin sheaths and inflict damage upon oligodendrocytes within the murine central nervous system. Intracranial injection of Nef EVs leads to reduced myelin basic protein (MBP) staining and a decreased number of CC1 + oligodendrocytes in the corpus callosum. Moreover, cerebellar slice cultures treated with Nef EVs exhibit diminished MBP expression and increased presence of unmyelinated axons. Primary mixed brain cultures and enriched oligodendrocyte precursor cell cultures exposed to Nef EVs display a decreased number of O4 + cells, indicative of oligodendrocyte impairment. These findings underscore the potential contribution of Nef EV-mediated damage to oligodendrocytes and myelin maintenance in the pathogenesis of HAND.

Prevalence of Neurocognitive Impairment for NPC Survivors after Definitive Intensity-Modulated Radiotherapy: A Cross-Sectional Study

<h3>Purpose/Objective(s)</h3> High-dose intensity-modulated radiotherapy (IMRT) has led to excellent prognosis in patients with localized nasopharyngeal carcinoma (NPC). Given the relatively young age of onset and the close anatomic relationship between the nasopharynx and the central nervous system, post-radiation neurocognitive impairment among long-term survivors represents an under-recognized late complication. This study aims to determine the prevalence and the affected cognitive domains in post-IMRT NPC survivors. <h3>Materials/Methods</h3> We undertook a cross-sectional study in a high-volume tertiary oncology center in Hong Kong. NPC survivors who underwent IMRT with a minimal post-radiotherapy interval of 1 year were eligible. All patients underwent an initial screening using the Montreal Cognitive Assessment-Hong Kong (MoCA-HK) test, followed by a 2-hour comprehensive battery of neurocognitive assessments covering 8 distinct domains: intellectual capacity (WAIS-IV), attention span (WAIS-IV digit span, WMS-III Visual Spatial Span), visual memory (WMS-III Visual reproduction span), verbal memory (Auditory Verbal Learning Test), processing speed (Color Trail Test), executive function (Stroop Test), motor dexterity (Grooved Pegboard Test) and language ability (Verbal Fluency Test). Mean percentiles and Z-scores of all neurocognitive assessments were compared with age- and/or education-matched population normative data using one-sample t-tests. Correlation of cognitive outcomes with clinical factors were analyzed using multivariable linear regression. <h3>Results</h3> A total of 182 NPC survivors were enrolled. The median post-radiotherapy interval was 6.9 years, 129 (70.9%) were long-term survivors at least 5 years beyond radiotherapy. The median age was 56 years old, 89% of the enrolled patients had stage III-IVA NPC by AJCC/UICC 8^th Edition, and 87% of patients received chemotherapy. The mean MoCA score was 23.6, 25.8% of patients were considered cognitively impaired. NPC survivors demonstrated significant cognitive impairment in verbal memory (p<0.001), processing speed (p<0.001), executive function (p<0.001), motor dexterity (p<0.001) and language ability (p=0.001). Most significant impairment was observed in executive function, mean z-scores of which were -1.76 to -1.38 below normative data. Post-IMRT interval, disease stage and chemotherapy usage showed no significant association with the degree of neurocognitive impairment. <h3>Conclusion</h3> Post-IMRT neurocognitive impairment was prevalent in NPC survivors. Neurocognitive function was not impaired globally but occurred predominantly in selected domains, particularly executive function. Cognitive assessment and training should be considered a part of survivorship care for NPC patients. Future research on the correlation between neurocognitive function and radiation dosimetry of various brain subsites would be informative.

Abstract 3032: A pilot study of epigenetic age acceleration and neurocognitive outcomes among survivors of pediatric medulloblastoma

Abstract Background: Medulloblastoma is the most common malignant brain tumor diagnosed in children. Treatments for medulloblastoma are associated with neurocognitive impairment; however, there is little known about the biological factors which influence variability in neurocognitive outcomes. There is emerging evidence that epigenetic age acceleration (EAA) – the difference between DNA methylation-based predicted age and chronological age – is associated with chronic health conditions among pediatric cancer survivors. Therefore, we sought to evaluate the association between EAA and neurocognitive outcomes in pediatric medulloblastoma survivors. Methods: Neurocognitive tests were obtained between 2003 and 2012 from &amp;gt;1-year survivors of pediatric medulloblastoma (n=49). Assessments included the following: Full Scale Intelligence Quotient (FSIQ), Working Memory Index (WMI), and Processing Speed Index (PSI). Whole blood samples were obtained, and DNA was extracted for genome-wide DNA methylation using the Illumina HumanMethylation450K chip. DNA methylation age was calculated using the Horvath DNA Methylation Age Calculator. Associations were assessed using linear regression models with statistical significance defined at p&amp;lt;0.05. Results: Patients were predominantly male (n=36, 73.5%), non-Hispanic White (n=34, 69%) and diagnosed at a mean age of 7.5 years. Patients received intensity-modulated radiation (n=39, 80%) or proton beam radiation (n=10, 20%). The mean FSIQ was 82.2 (95% CI: 76.9-87.6), WMI was 82.2 (95% CI: 76.2-88.2), and PSI was 79.5 (95% CI: 73.5-85.6) a median of 3.03 years (range: 1.0 – 15.2 years) post-radiotherapy. On average, the DNA methylation age of participants was significantly higher than their chronologic age at the time of sample collection (mean difference = 2.4 years; 95% CI: 1.2-3.5; p &amp;lt;0.01). Time from diagnosis to sample collection was significantly (p &amp;lt;0.01) associated with a larger deviation between DNA methylation and chronologic age. While not significantly associated with poorer neurocognitive performance on FSIQ or PSI in unadjusted models, EAA was associated with poorer WMI (beta coefficient = -1.99, p = 0.03), which was slightly attenuated after accounting for age at radiation therapy, radiation modality, dose, and time post-radiation (beta coefficient = -1.24, p = 0.15). Conclusions: In this pilot study of pediatric medulloblastoma survivors, we report that the biologic age assessed by DNA methylation profiles often exceeds the chronologic age of survivors. We also identified suggestive associations between EAA and the degree of neurocognitive impairment in survivors of medulloblastoma. These findings highlight the potential utility of evaluating measures of biological aging to better understand variability in neurocognitive performance in larger, longitudinal cohorts of patients with pediatric medulloblastoma. Citation Format: Kevin O. Wilhelm, Philip J. Lupo, Kimberly P. Raghubar, Lisa S. Kahalley, Murali Chintagumpala, Mehmet F. Ocku, Michael E. Scheurer, Austin L. Brown. A pilot study of epigenetic age acceleration and neurocognitive outcomes among survivors of pediatric medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3032.

T2 Relaxometry Evidence of Microstructural Changes in Diffusely Abnormal White Matter in Relapsing–Remitting Multiple Sclerosis and Clinically Isolated Syndrome: Impact on Visuomotor Performance

BackgroundAlthough diffusely abnormal white matter (DAWM) is commonly seen in multiple sclerosis (MS), it is rarely considered in clinical/imaging studies.PurposeTo evaluate quantitative markers of microstructural changes in DAWM of patients with clinically isolated syndrome (CIS) and relapsing–remitting MS (RR‐MS) in relation to MS lesions and degree of neurocognitive impairment, by using a multi‐echo spin echo (MESE) Proton Density PD‐to‐T2 sequence.Study TypeProspective, cross‐sectional.PopulationThirty‐seven RR‐MS patients, 33 CIS patients, and 52 healthy controls.Field Strength/Sequence1.5 T/T1‐, T2‐weighted, fluid‐attenuated inversion recovery, and MESE sequences.AssessmentLong T2, short T2, and myelin water fraction (MWF) values were estimated as indices of intra/extracellular water content and myelin content, respectively, in DAWM, posterior periventricular normal appearing white matter (NAWM), and focal MS lesions, classified according to their signal intensity on T1 sequences. Patients were, also, administered a battery of neuropsychological tests.Statistical TestsComparisons of T2 and MWF values in DAWM, NAWM, and MS lesions were examined, using two‐way mixed analyses of variance. Associations of Grooved Pegboard performance with T2 and MWF values in DAWM and NAWM were assessed using Pearson correlation coefficients.ResultsT2 and MWF values of DAWM were intermediate between the respective values of NAWM and T1 hypointense focal lesions, while there was no difference between the respective values of DAWM and T1‐isointense lesions. T2 values in DAWM were strongly associated with visuomotor performance in CIS patients.Data ConclusionIntra/extracellular water and myelin water content of DAWM are similar to those of T1‐isointense lesions and predict visuomotor performance in CIS patients.Level of Evidence2Technical EfficacyStage 2

Clinical assessment of upper airway and its complications in Hunter syndrome.

Hunter syndrome (HS) is an X-linked, recessive, lysosomal storage disease caused by a deficiency of the lysosomal enzyme, iduronate sulfatase (IDS). It is characterized by multisystem accumulations of glycosaminoglycans and upper airway obstruction is one of the major causes of death. While the current disease severity classifications for HS are mainly based on the degree of neurocognitive impairment, its association with the level of upper airway obstruction has not been assessed. A retrospective chart review of HS patients who were followed at the Jikei University School of Medicine was performed. Association between the degree of airway obstruction and the currently used disease severity scores was evaluated. We identified eight HS patients and they were enrolled in the study. The Modified Mallampati classification (MMC) score, used to predict difficulties for oropharyngeal procedures, was significantly correlated with the HS severity. It was also correlated with the Apnea-Hypopnea Index (AHI). No significant correlation between IDS enzymatic activity and the severity of HS disease was identified. Variable clinical expressivities exist in HS, but the risk of respiratory complications is likely to be associated with disease severity, assessed by the previously recognized neurocognitive function-based severity scoring systems. MMC can be a simple supplementary tool to evaluate disease severity as well as predict difficulties for oropharyngeal procedures and respiratory function complications in HS, such as sleep apnea.

When Epilepsy Grows Up….

Neurocognition in Childhood Epilepsy: Impact on Mortality and Complete Seizure Remission 50 Years Later Sillanpää M, Saarinen MM, Karrasch M, Schmidt D, Hermann BP. Epilepsia. 2019;60(1):131-138. doi:10.1111/epi.14606. Epub 2018 Nov 22.Objective:To study associations of the severity of impairment in childhood neurocognition (NC) with long-term mortality and complete seizure remission.Methods:A population-based cohort of 245 subjects with childhood-onset epilepsy was followed up for 50 years (median = 45, range = 2-50). Childhood NC before age 18 years was assessed as a combination of formal intelligence quotient scores and functional criteria (school achievement, working history, and psychoneurological development). Impaired NC was categorized with respect to definitions of intellectual functioning in International Classification of Diseases, Tenth Revision (R41.83, F70-F73). The outcome variables, defined as all-cause mortality and 10-year terminal remission with the 5 past years off medication (10YTR), were analyzed with Cox regression models.Results:Of the 245 subjects, 119 (49%) had normal childhood NC, whereas 126 (51%) had various degrees of neurocognitive impairment. During the 50-year observation period, 71 (29%) of the subjects died, 13% of those with normal and 44% of those with impaired NC. The hazard of death increased gradually in line with more impaired cognition, reaching significance in moderate, severe, and profound impairment versus normal NC (hazard ratio [Bonferroni corrected 95% confidence interval] = 3.3 [1.2-9.2], 4.2 [1.2-14.2], and 5.5 [2.4-12.3], respectively). The chance for 10YTR was highest among subjects with normal NC (61%), whereas none of those with profound impairment reached 10YTR. In the intermediate categories, the chance was, however, not directly related to the increasing severity of impairment.Significance:The severity of neurocognitive impairment during childhood shows a parallel increase in the risk of death. In comparison with normal NC, subjects with lower childhood NC are less likely to enter seizure remission. However, normal NC does not guarantee complete remission or prevent premature death in some individuals with childhood-onset epilepsy.

Neurocognition in childhood epilepsy: Impact on mortality and complete seizure remission 50 years later.

To study associations of the severity of impairment in childhood neurocognition (NC) with long-term mortality and complete seizure remission. A population-based cohort of 245 subjects with childhood onset epilepsy was followed up for 50 years (median = 45, range = 2-50). Childhood NC before age 18 years was assessed as a combination of formal intelligence quotient scores and functional criteria (school achievement, working history, and psychoneurological development). Impaired NC was categorized with respect to definitions of intellectual functioning in International Classification of Diseases, 10th revision (R41.83, F70-F73). The outcome variables, defined as all-cause mortality and 10-year terminal remission with the 5 past years off medication (10YTR), were analyzed with Cox regression models. Of the 245 subjects, 119 (49%) had normal childhood NC, whereas 126 (51%) had various degrees of neurocognitive impairment. During the 50-year observation period, 71 (29%) of the subjects died, 13% of those with normal and 44% of those with impaired NC. The hazard of death increased gradually in line with more impaired cognition, reaching significance in moderate, severe, and profound impairment versus normal NC (hazard ratio [Bonferroni corrected 95% confidence interval] = 3.3 [1.2-9.2], 4.2 [1.2-14.2], and 5.5 [2.4-12.3], respectively). The chance for 10YTR was highest among subjects with normal NC (61%), whereas none of those with profound impairment reached 10YTR. In the intermediate categories, the chance was, however, not directly related to the increasing severity of impairment. The severity of neurocognitive impairment during childhood shows a parallel increase in the risk of death. In comparison with normal NC, subjects with lower childhood NC are less likely to enter seizure remission. However, normal NC does not guarantee complete remission or prevent premature death in some individuals with childhood onset epilepsy.

Shaping pathological cortical dynamics with high-frequency neurostimulation

Disrupted neural synchrony is a hallmark pattern observed in numerous pathological states, such as dementia, depression, Parkinson's disease, epilepsy, and schizophrenia. Patients with brain lesions and conditions involving brain damage commonly display abnormal slow-wave EEG/MEG oscillatory activity that further shapes responses at rest and in response to stimuli [1]. Such pathological dysrhythmia usually takes the form of a gradual shift between fast cyclic activity in favor of slower frequency bands and strongly correlates with the degree of neurocognitive impairment [2]. Despite the diversity in the underlying pathology, dysrhythmia is a robust, consistent observation across many of these conditions, suggesting that synchrony disruption might alone be responsible of some of the symptoms. Can these defective oscillations be fixed? In parallel and despite the surge of interest in neurostimulation techniques (e.g. DBS, TMS, tDCS) to treat brain disorders and/or manipulate brain activity, little computational insight has been gathered about the influence of electromagnetic drive on the dynamics of neural populations. Notably, the interference patterns between stimulation signals and ongoing oscillatory states are a highly debated yet still poorly understood problem [3]. How does neurostimulation interact with synchronous dynamics in the presence of pathological dysrhythmia? Can one actively tune ongoing oscillatory neural activity in order to treat neurophysiological disorders and alleviate symptoms of brain-related dysfunctions? In this work, we analyze the influence of high-frequency stimulation on synchronous dynamics in heterogeneous networks. Using a non-linear and sparsely connected network of cortical neurons with finite conduction velocity, we examine the functional impact of local damage on network oscillatory dynamics, using both spiking and mean-field descriptions, and thus assess the influence of local neural density depletion on the genesis of pathological dysrhythmia. Our model reveals that deceleration of rhythmic activity scales with damage size, and further pairs with a concomitant decrease in spectral power. Then, building on recent findings about input-mediated tuning of synchronous oscillations and state of the art non-linear analysis tools [4], we provide insights about how weak, high-frequency neurostimulation can be used to accelerate and potentially restore oscillatory activity to healthy levels. By doing so, we propose a framework in which peculiar neurostimulation patterns, such as those accessible via TMS or tDCS used in conjunction with EEG, could bi-directionally regulate the frequency and power expressed by synchronous cortical networks. These novel findings are further shown to be distinct from the more common resonance and entrainment phenomena in which periodic stimuli enhance or even replace ongoing neural dynamics. By addressing the implications of structural heterogeneity on synchronous dynamics and providing novel ways of compensating for them, our work outlines the key role played by axonal delays on healthy neural activity. These developments further provide key analytical and numerical insights about how pulsatile stimulation can be used to shape ongoing cyclic activity in the healthy and damaged brain. Financial support for this work has been provided by: National Science and Engineering Council of Canada, Swiss National Science Foundation.

Cell-free mitochondrial DNA in CSF is associated with early viral rebound, inflammation, and severity of neurocognitive deficits in HIV infection.

Cell-free mitochondiral DNA (mtDNA) is an immunogenic molecule associated with many inflammatory conditions. We evaluated the relationship between cell-free mtDNA in cerebrospinal fluid (CSF) and neurocognitive performance and inflammation during HIV infection. In a cross-sectional analysis, we evaluated the association of mtDNA levels with clinical assessments, inflammatory markers, and neurocognitive performance in 28 HIV-infected individuals. In CSF, we measured mtDNA levels by droplet digital PCR, and soluble CD14 and CD163, neurofilament light, and neopterin by ELISA. In blood and CSF, we measured soluble IP-10, MCP-1, TNF-α, and IL-6 by ELISA, and intracellular expression of IL-2, IFN-γ, and TNF-α in CD4(+) and CD8(+) T cells by flow cytometry. We also evaluated the relationship between CSF pleocytosis and mtDNA longitudinally in another set of five individuals participating in an antiretroviral treatment (ART) interruption study. Cell-free CSF mtDNA levels strongly correlated with neurocognitive performance among individuals with neurocognitive impairment (NCI) (r = 0.77, p = 0.001). CSF mtDNA also correlated with levels of IP-10 in CSF (r = 0.70, p = 0.007) and MCP-1 in blood plasma (r = 0.66, p = 0.01) in individuals with NCI. There were no significant associations between inflammatory markers and mtDNA in subjects without NCI, and levels of mtDNA did not differ between subjects with and without NCI. MtDNA levels preceded pleocytosis and HIV RNA following ART interruption. Cell-free mtDNA in CSF was strongly associated with the severity of neurocognitive dysfunction and inflammation only in individuals with NCI. Our findings suggest that within a subset of subjects cell-free CSF mtDNA is associated with inflammation and degree of NCI.

MDMA is certainly damaging after 25 years of empirical research: a reply and refutation of Doblinet al. (2014)

Human Psychopharmacology recently published my review into the increase in empirical knowledge about the human psychobiology of MDMA over the past 25 years (Parrott, 2013a). Deficits have been demonstrated in retrospective memory, prospective memory, higher cognition, complex visual processing, sleep architecture, sleep apnoea, pain, neurohormonal activity, and psychiatric status. Neuroimaging studies have shown serotonergic deficits, which are associated with lifetime Ecstasy/MDMA usage, and degree of neurocognitive impairment. Basic psychological skills remain intact. Ecstasy/MDMA use by pregnant mothers leads to psychomotor impairments in the children. Hence, the damaging effects of Ecstasy/MDMA were far more widespread than was realized a few years ago. In their critique of my review, Doblin et al. (2014) argued that my review contained misstatements, omitted contrary findings, and recited dated misconceptions. In this reply, I have answered all the points they raised. I have been able to refute each of their criticisms by citing the relevant empirical data, since many of their points were based on inaccurate summaries of the actual research findings. Doblin and colleagues are proponents of the use of MDMA for drug-assisted psychotherapy, and their strongest criticisms were focused on my concerns about this proposal. However, again all the issues I raised were based on sound empirical evidence or theoretical understanding. Indeed I would recommend potentially far safer co-drugs such as D-cycloserine or oxytocin. In summary, MDMA can induce a wide range of neuropsychobiological changes, many of which are damaging to humans.

EPA-1457 – Cognitive functioning in major psychoses: delineating diagnostic continuity and discontinuity

The Kraepelinian dichotomy posits that patients with schizophrenia (SCZ) and bipolar disorder (BD) present as two separate psychotic entities such that they differ in terms of clinical severity including neurocognitive functioning. Based on clinical impression within a tertiary psychiatric hospital context and extant data, we hypothesized that patients with SCZ had a similar level of neurcognitive impairment compared with BD. Forty-nine healthy controls (HC), 72 SCZ and 42 BD patients who were matched for age, gender, and premorbid IQ were administered the Brief Assessment of Cognition battery (BAC), the Positive and Negative Syndrome Scale for SCZ patients, the Young Mania Rating Scale (YMRS) for BD patients, and Global Assessment of Functioning (GAF) for both patients groups. Both BD and SCZ groups demonstrated similar patterns of neurocognitive deficits across several domains (verbal memory, working memory, semantic fluency, processing speed) compared with HC subjects. However, no significant difference was found in neurocognitive functioning between BD and SCZ patients, suggesting that both patient groups suffer the same degree of neurocognitive impairment. Moreover, patients with lower level of psychosocial functioning as indicated by lower GAF score (F(1,112) = 2.661, p = 0.009) and older age (F(1,112) = −2.625, p = 0.010), not diagnosis or doses of psychotropic medications, predicted were associated with poorer overall neurocognitive functioning as measured by the(lower BAC composite score). Our findings of comparable neurocognitive impairments between SCZ and BD affirm our hypothesis and support less the Kraepelinian concept of dichotomy but more of a continuum of psychotic spectrum conditions.

Identification of an atypical variant of logopenic progressive aphasia

The purpose of this study was to examine the association between aphasia severity and neurocognitive function, disease duration and temporoparietal atrophy in 21 individuals with the logopenic variant of primary progressive aphasia (lvPPA). We found significant correlations between aphasia severity and degree of neurocognitive impairment as well as temporoparietal atrophy; but not disease duration. Cluster analysis identified three variants of lvPPA: (1) subjects with mild aphasia and short disease duration (mild typical lvPPA); (2) subjects with mild aphasia and long disease duration (mild atypical lvPPA); and, (3) subjects with severe aphasia and relatively long disease duration (severe typical lvPPA). All three variants showed temporoparietal atrophy, with the mild atypical group showing the least atrophy despite the longest disease duration. The mild atypical group also showed mild neuropsychological impairment. The subjects with mild aphasia and neuropsychological impairment despite long disease duration may represent a slowly progressive variant of lvPPA.

Neurocognitive Functioning in Schizophrenia and Bipolar Disorder: Clarifying Concepts of Diagnostic Dichotomy vs. Continuum

The Kraepelinian dichotomy posits that patients with schizophrenia (SCZ) and bipolar disorder (BD) present as two separate psychotic entities such that they differ in terms of clinical severity including neurocognitive functioning. Our study aimed to specifically compare and contrast the level of neurocognitive functioning between SCZ and BD patients and identify predictors of their poor neurocognitive functioning. We hypothesized that patients with SCZ had a similar level of neurocognitive impairment compared with BD. About 49 healthy controls (HC), 72 SCZ, and 42 BD patients who were matched for age, gender, and premorbid IQ were administered the Brief Assessment of Cognition battery (BAC). Severity of psychopathology and socio-occupational functioning were assessed for both patients groups. Both BD and SCZ groups demonstrated similar patterns of neurocognitive deficits across several domains (verbal memory, working memory, semantic fluency, processing speed) compared with HC subjects. However, no significant difference was found in neurocognitive functioning between BD and SCZ patients, suggesting that both patient groups suffer the same degree of neurocognitive impairment. Patients with lower level of psychosocial functioning [F(1,112) = 2.661, p = 0.009] and older age [F(1,112) = −2.625, p = 0.010], not diagnosis or doses of psychotropic medications, predicted poorer overall neurocognitive functioning as measured by the lower BAC composite score. Our findings of comparable neurocognitive impairments between SCZ and BD affirm our hypothesis and support less the Kraepelinian concept of dichotomy but more of a continuum of psychotic spectrum conditions. This should urge clinicians to investigate further the underlying neural basis of these neurocognitive deficits, and be attentive to the associated socio-demographic and clinical profile in order to recognize and optimize early the management of the widespread neurocognitive deficits in patients with SCZ and BD.

Activated Kras Alters Epidermal Homeostasis of Mouse Skin, Resulting in Redundant Skin and Defective Hair Cycling

Germline mutations in the RAS-mitogen-activated protein kinase (RAS/MAPK) pathway are associated with genodermatoses, characterized by cutaneous, cardiac, and craniofacial defects, and cancer predisposition. Whereas activating mutations in HRAS are associated with the vast majority of patients with Costello syndrome, mutations in its paralog, KRAS, are rare. To better understand the disparity among RAS paralogs in human syndromes, we generated mice that activate a gain-of-function Kras allele (Lox-Stop-Lox (LSL)-Kras(G12D)) in ectodermal tissue using two different Cre transgenic lines. Using Msx2-Cre or ligand-inducible keratin 15 (K15)-CrePR, the embryonic effects of activated Kras were bypassed and the effects of Kras(G12D) expression from its endogenous promoter were determined. We found that Kras(G12D) induced redundant skin, papillomas, shortened nails, and hair loss. Redundant skin was associated with basal keratinocyte hyperplasia and an increase in body surface area. Paradoxically, Kras(G12D) also prevented hair cycle activation. We find that Kras(G12D) blocks proliferation in the bulge region of the hair follicle, when activated through Msx2-Cre but not through K15-CrePR. These studies reveal that KRAS, although infrequently involved in RAS/MAPK syndromes, is capable of inducing multiple cutaneous features that grossly resemble human RAS/MAPK syndromes.

Detection of Human Immunodeficiency Virus–Induced Inflammation and Oxidative Stress in Lenticular Nuclei With Magnetic Resonance Spectroscopy Despite Antiretroviral Therapy

Single-voxel magnetic resonance spectroscopy measurements of N-acetyl aspartate, choline, and creatine (Cr) are affected in patients with human immunodeficiency virus (HIV) and neurocognitive impairment. However, these metabolic markers are often normalized in affected central nervous system regions, such as the lenticular nuclei, after initiation of highly active antiretroviral therapy (HAART). To examine whether lactate (Lac), a marker of inflammation and anaerobic glycolysis, and lipid, an indicator of cell membrane turnover resulting from oxidative stress, could serve as surrogate biomarkers within the lenticular nuclei of HIV-positive patients with different degrees of neurocognitive impairment. Three-tesla 2-dimensional-chemical shift imaging magnetic resonance spectroscopy at echo times of 30 milliseconds and 135 milliseconds was performed in voxels overlapping the lenticular nuclei of seronegative controls and a spectrum of HIV-positive patients (neurocognitively normal, mildly impaired, or moderately to severely impaired). University of Pennsylvania, Philadelphia. Ten seronegative controls and 45 HIV-positive patients with different degrees of neurocognitive impairment (15 neurocognitively normal patients, 12 mildly impaired patients, and 18 moderately to severely impaired patients). In vivo 2-dimensional-chemical shift imaging magnetic resonance spectroscopy analysis of N-acetyl aspartate:Cr, choline:Cr, Lac:Cr, and (lipid + Lac):Cr ratios among the various groups. In addition, the effect of the degree of HAART central nervous system penetration (high vs low) on these ratios was studied. No significant lenticular nuclei atrophy was detected with volumes similar across all of the groups. Both N-acetyl aspartate:Cr and choline:Cr ratios were similar across all of the groups at either echo time. In contrast, the Lac:Cr ratio was significantly greater in HIV-positive patients with moderate to severe impairment compared with seronegative controls. The (lipid + Lac):Cr ratio was significantly elevated within each HIV-positive subgroup compared with seronegative controls. Within HIV-positive patients receiving HAART, the degree of central nervous system penetration (high vs low) did not affect metabolic ratios. As seen with 2-dimensional-chemical shift imaging magnetic resonance spectroscopy, HIV induces inflammation and oxidative stress in HIV-positive patients despite HAART. Lipid and Lac are more sensitive inflammatory biomarkers that may be used to differentiate HIV-positive subgroups. However, no significant difference in efficacy, as measured by metabolic ratios, exists for high- vs low-central nervous system-penetrating HAART.

Dendritic injury is a pathological substrate for human immunodeficiency virus-related cognitive disorders. HNRC Group. The HIV Neurobehavioral Research Center.

To determine the neuropathological substrate of human immunodeficiency virus (HIV)-associated neurocognitive disorders, we examined persons with acquired immunodeficiency syndrome before their death and related their antemortem neuropsychological performance to postmortem indicators of HIV encephalitis, viral burden, and presynaptic and postsynaptic neuronal injury. Of 20 prospectively examined cases, 9 were neurocognitively normal, 5 showed neuropsychological impairment, 5 had minor cognitive/motor disorder, and 1 was demented. Degree of neurocognitive impairment was strongly related to the amount of dendritic simplification based on microtubule-associated protein 2 immunohistochemical staining, somewhat less so to a semiquantitative viral burden score based on numbers of HIV gp41-immunoreactive cells, and much less so to the presence of multinucleated giant cells or microglial nodules. It appears that even milder neurocognitive impairment reflects microneuroanatomical injury to synaptic structures.

Neuroanatomic and neuropsychological predictors of unawareness of cognitive deficit in the vascular population

Unawareness of cognitive deficit following brain damage was investigated in a sample of 108 cerebrovascular accident patients and 30 orthopaedic controls. The purpose of this study was to: 1. investigate the incidence of unawareness, 2. test if neurocognitive factors were predictive of unawareness, and 3. determine which specific neuroanatomic lesion sites were predictive of the phenomenon. Neuroanatomic lesion site was identified by CT/MRI. Unawareness of cognitive deficit was assessed using a structured unawareness interview, while neurocognitive status was quantified on several indices. Results showed unawareness was associated with brain injury (p <.0001), occurred in varying degrees of severity in about 40% of the cerebrovascular group, was significantly correlated with various neurocognitive indices, and was more frequently associated with cortical verses subcortical lesion sites (p <.0001). The results could partially be explained by existing theoretical models, but showed that both degree of neurocognitive impairment and neuroanatomic lesion site are predictive variables of the unawareness phenomenon. The potential clinical use of unawareness screening as a part of routine neuropsychological evaluation was discussed.