Carboplatin and ototoxicity: hearing loss rates among survivors of childhood medulloblastoma

Purpose  

Patients with medulloblastoma are exposed to ototoxic treatments including radiation therapy and platinum chemotherapy. The favorable toxicity profile of carboplatin led us to substitute this chemotherapeutic agent for cisplatin in the HIT-1991, HIT-MED-1999, and HIT-2000 chemotherapy protocols. We retrospectively investigated its consequences in terms of overall survival and ototoxicity rates.     

Early dynamics of white matter deficits in children developing dyslexia

Neural anomalies have been demonstrated in dyslexia. Recent studies in pre-readers at risk for dyslexia and in pre-readers developing poor reading suggest that these anomalies might be a cause of their reading impairment. Our study goes one step further by exploring the neurodevelopmental trajectory of white matter anomalies in pre-readers with and without a familial risk for dyslexia (n = 61) of whom a strictly selected sample develops dyslexia later on (n = 15). We collected longitudinal diffusion MRI and behavioural data until grade 3. The results provide evidence that children with dyslexia exhibit pre-reading white matter anomalies in left and right long segment of the arcuate fasciculus (AF), with predictive power of the left segment above traditional cognitive measures and familial risk. Whereas white matter differences in the left AF seem most strongly related to the development of dyslexia, differences in the left IFOF and in the right AF seem driven by both familial risk and later reading ability. Moreover, differences in the left AF appeared to be dynamic. This study supports and expands recent insights into the neural basis of dyslexia, pointing towards pre-reading anomalies related to dyslexia, as well as underpinning the dynamic character of white matter.     

Multiple biochemical deficits in both gray and white matter of Alzheimer brains

A biochemical investigation of 21 brains from patients with dementia of Alzheimer type (AD/SDAT) and 22 brains from controls was made. In the normal brains 5-hydroxytryptamine (5-HT), noradrenaline (NA) and dopamine (DA) were reduced with age while their metabolites were not reduced. In the brains from the Alzheimer patients the examination of gray matter (caudate nucleus and hippocampus) showed a significant reduced activity of choline-acetyl transferase (CAT) and a reduction of acetylcholinesterase (AChE) that bordered significance in the hippocampus. In the brains from the Alzheimer patients a disturbance was found in the 5-HT system in the form of reduced levels of 5-HT and 5-hydroxyindolacetic acid (5-HIAA). The catecholamine systems were also disturbed but to a less extent. In the 5-HT and DA systems the active amines as well as the metabolites were reduced in the brains from patients with AD/SDAT indicating not only a possible neuronal loss but also an incapacity of the remaining neurons to compensate for the loss by an increased turnover. The lipid content was slightly reduced in gray matter of the demented brains. In white matter there was a more severe reduction of the lipids and in this tissue also the cerebrosides and sulfatides were reduced. It is concluded that in brains from patients with AD/SDAT there are multiple biochemical deficits in gray as well as in white matter. The changes in white matter may be of pathogenetic importance in subgroups of AD/SDAT.     

Disrupted white matter tract integrity of anterior cingulate in trauma survivors

The objective of this study was to examine the integrity of whole-brain white matter in posttraumatic stress disorder patients. Twenty posttraumatic stress disorder patients who survived the Taegu subway fire incident and 20 healthy volunteers participated in this study. Statistical parametric mapping was used to evaluate the global differences in fractional anisotropy values between the two groups. The results show that posttraumatic stress disorder patients had significantly lower fractional anisotropy values in the left anterior cingulate regions. Posttraumatic stress disorder symptom severity negatively correlated to the level of decrease in anterior cingulate fractional anisotropy values. The outcome of the current study suggests that the disruption of the left anterior cingulate white matter tract integrity may play an important role in the pathophysiology of posttraumatic stress disorder.     

Neurocognitive deficits and disability in major depressive disorder

Disability in life functioning is an important and poorly understood consequence of major depressive disorder (MDD). Mood symptoms do not account for the magnitude of disability resulting from MDD. Impairments in several domains of neurocognitive (NC) functioning have been shown to interfere with functionality in other psychiatric populations. These deficits, also present in MDD, may play a significant role in disability experienced by many with this disorder. The aim of this study was to examine the degree to which NC deficits, independent of affective and psychotic symptoms, explain functional outcome 6 months following hospitalization for a major depressive episode. Participants with an MDD diagnosis (N=48) received NC testing and symptom ratings while in the hospital. These procedures were repeated, along with functionality ratings, 6 months later. Six-month NC performance was strongly associated with functionality ratings after covariation for residual depression. Selected NC domains tested at baseline were predictive of functionality at 6 months. These data indicate that NC deficits, at least for some MDD sufferers, play an important role in functional recovery. New treatments, whether pharmacologic or rehabilitative, may be required to help affected patients accommodate neurocognitively based performance deficits at work, at home and in the community.     

Chronic neurological deficits in mice after perinatal hypoxia and ischemia correlate with hemispheric tissue loss and white matter injury detected by MRI

We investigated the effects of perinatal hypoxia-ischemia (HI) on brain injury and neurological functional outcome at postnatal day (P)30 through P90. HI was induced by exposing P9 mice to 8% O(2) for 55 min using the Vannucci HI model. Following HI, mice were treated with either vehicle control or Na(+)/H(+) exchanger isoform 1 (NHE1) inhibitor HOE 642. The animals were examined by the accelerating rotarod test at P30 and the Morris water maze (MWM) test at P60. T(2)-weighted MRI was conducted at P90. Diffusion tensor imaging (DTI) was subsequently performed in ex vivo brains, followed by immunohistochemical staining for changes in myelin basic protein (MBP) and neurofilament protein expression in the corpus callosum (CC). Animals at P30 after HI showed deficits in motor and spatial learning. T(2) MRI detected a wide spectrum of brain injury in these animals. A positive linear correlation was observed between learning deficits and the degree of tissue loss in the ipsilateral hemisphere and hippocampus. Additionally, CC DTI fractional anisotropy (FA) values correlated with MBP expression. Both FA and MBP values correlated with performance on the MWM test. HOE 642-treated mice exhibited improved spatial learning and memory, and less white matter injury in the CC. These findings suggest that HI-induced cerebral atrophy and CC injury contribute to the development of deficits in learning and memory, and that inhibition of NHE1 is neuroprotective in part by reducing white matter injury. T(2)-weighted MRI and DTI are useful indicators of functional outcome after perinatal HI.     

Memory loss from a subcortical white matter infarct.

Clinical disorders of memory are believed to occur from the dysfunction of either the mesial temporal lobe, the mesial thalamus, or the basal forebrain. Fibre tract damage at the level of the fornix has only inconsistently produced amnesia. A patient is reported who suffered a cerebrovascular accident involving the posterior limb of the left internal capsule that resulted in a persistent and severe disorder of verbal memory. The inferior extent of the lesion effectively disconnected the mesial thalamus from the amygdala and the frontal cortex by disrupting the ventral amygdalofugal and thalamic-frontal pathways as they course through the diencephalon. This case demonstrates that an isolated lesion may cause memory loss without involvement of traditional structures associated with memory and may explain memory disturbances in other white matter disease such as multiple sclerosis and lacunar state.     

Neurocognitive dysfunction in survivors of childhood brain tumors

Newer treatments have resulted in increasing numbers of survivors of childhood cancer, for whom neurological and neurocognitive toxicity directly impacts overall functioning and quality of life. There are multiple disease- and host-related factors that influence the development of cancer-related neurocognitive dysfunction, which can progress over time and lead to significant functional impairments. This article provides an overview of the types of neurocognitive deficits seen in survivors of childhood brain tumors, the tools used to assess neurocognitive function, and the factors that impact its severity. This provides a framework for consideration of potential areas for primary prevention by reducing treatment-related toxicity as well as interventions, using behavioral and pharmacologic treatments.     

Neurocognitive deficits associated with shoplifting in young adults

Objectives

Shoplifting is a relatively common behavior in young adults, but the demographic and neuropsychological correlates of shoplifting remain poorly characterized in this context.

Method

Non–treatment-seeking young adults (18-29 years) were recruited from the general community on the basis of having no Axis I disorders, no history of illicit substance use, and no history of conduct disorder or antisocial personality disorder. Participants were grouped according to presence or absence of shoplifting (at least 1 time over the past 12 months). Measures relating to impulsivity along with objective computerized neuropsychological measures were collected.

Results

Shoplifters (n = 14) and controls (n = 95) did not differ significantly in terms of salient demographic characteristics. Compared with controls, shoplifters endorsed higher impulsivity on the Barratt Impulsiveness Scale and Eysenck Impulsivity Questionnaire, gambled significantly more points on the Cambridge Gambling Task, and showed deficits on the hardest level of difficulty on the Spatial Working Memory task. Performance on executive planning, set-shifting, and response inhibition did not differ significantly between shoplifters and controls.

Conclusions

This study identified significant cognitive deficits in those with past-year shoplifting behavior even in the absence of Axis I disorders and a history of illicit drugs or alcohol. These preliminary findings inform our understanding of the neurocognitive sequelae of shoplifting and its relationship with other impulse control problems, subclinical and clinical. Future work should use longitudinal designs to examine the temporal relationship between these deficits, shoplifting behavior, other impulsive behavior, and functional impairment.     

Executive control deficits correlate with reduced frontal white matter volume in multiple sclerosis

Introduction: Executive control deficits are frequently reported in patients with multiple sclerosis (MS). We have previously proposed that in the context of competing automatic and volitional processes, such deficits may in part reflect poor resolution of response conflict. This study aimed to investigate the neuropathological underpinnings of executive control deficits in MS, focusing on the frontostriatal system proposed to mediate executive control.

Method: Forty-one MS patients and 25 healthy controls completed measures of executive control that have previously been used to characterize deficit in MS: antisaccade and endogenously cued saccade paradigms, and the Stroop color and word test. Relationships between task performance and volumetric measures of frontal white matter, frontal gray matter, striatum, and pallidum were investigated.

Results: MS participants performed significantly more poorly on the Stroop and antisaccade tasks than controls. For MS patients, higher erroneous responding on the antisaccade task was related to reduced frontal white matter volume.

Conclusion: These findings suggest that loss of frontal white matter may underlie executive control deficits in MS, and provides information that may inform the development of targeted cognitive training strategies in MS.     

Association between white matter hyperintensity volume and social functioning limitations among stroke survivors

ObjectiveExisting literature on white matter hyperintensity volume (WMHV) in stroke patients has rarely focused on post-stroke outcomes related to social functioning limitations, such as transportation, social interaction, food preparation, grocery shopping, and housekeeping. Using prospective data from the VITamin D and OmegA-3 TriaL (VITAL) study, we evaluated the association between WMHV and social functioning limitations among 151 ischemic stroke patients.Materials and methodsWMHV was ascertained from magnetic resonance imaging (MRI) collected at the time of the stroke event using a validated semiautomated method, and social functioning limitations were assessed using a stroke outcomes questionnaire administered a median of 1.25 years after the date of the MRI scan. Logistic regression was used to explore the association between WMHV and social functioning limitations.ResultsAfter adjusting for age and sex, a statistically significant association was found between WMHV and limitations in social interaction (OR=2.82; 95% CI: 1.21-7.55). Increased risks were seen for limitations related to food preparation (OR=2.06; 95% CI: 0.99-4.54), transportation (OR=1.39; 95% CI: 0.85-2.27), and housekeeping (OR=1.37; 95% CI: 0.91-2.11); however, the associations did not reach statistical significance. We observed no association between WMHV and limitations in grocery shopping (OR=1.08; 95% CI: 0.61-1.89).ConclusionsFuture studies are needed to further explore the biological mechanisms underlying the relationship with limitations in social interaction and to replicate our findings using a larger and more diverse study sample.     

Neurocognitive deficits and prefrontal cortical atrophy in patients with schizophrenia

RATIONALE: Cognitive deficits are of particular importance in schizophrenia since they are strongly associated with poor prognosis. We investigated the relationship between prefrontal cortical atrophy as measured by MRI and the neuropsychological performance of participants diagnosed with DSM-IV-TR schizophrenia. METHODS: Fourteen unmedicated adult patients and thirteen matched controls were studied. Subjects underwent MRI yielding 1 mm isotropic T1-weighted images. Voxel based morphometry was applied to all images using SPM5. The mean gray level of Brodmann area (BA) 9 was also extracted and evaluated using simple regression along with relative score differences on patients neuropsychological tests compared to controls. RESULTS: Patients exhibited a poorer performance on the Controlled Word Association Task (COWAT), Wisconsin Card Sorting Test (WCST) and Trail Making Test (TMT). Patients also presented a greater level of apathy as indexed by the Apathy Evaluation Scale (AES). There was a significant decrease in gray matter volume in patients with schizophrenia in left supplementary motor area, bilateral superior frontal gyrus, left middle frontal gyrus, right opercular area, left angular gyrus, left superior temporal gyrus and left cerebellar hemisphere. Within the schizophrenia group, decreased BA9 gray matter volume was correlated with poorer performance on the WCST and TMT-B. CONCLUSION: Prefrontal gray matter abnormalities in schizophrenia patients may be associated with some symptoms including difficulties with set-shifting and decreased mental flexibility. Further studies evaluating prefrontal connectivity may clarify if such impairment results from abnormalities of the frontal area alone, or are a result of altered networks involving the frontal and extra-frontal areas.     

A1 adenosine receptor activation induces ventriculomegaly and white matter loss

A1 adenosine receptors (A1ARs) are widely expressed in the brain during development. To examine whether A1AR activation can alter postnatal brain formation, neonatal rats from postnatal days 3 to 14 were treated with the A1AR agonist N6-cyclopentyladenosine (CPA) in the presence or absence of the peripheral A1AR antagonist 8-(p-sulfophenyl)-theophylline (8SPT). CPA or CPA + 8SPT treatment resulted in reductions in white matter volume, ventriculomegaly, and neuronal loss. Quantitative electron microscopy revealed reductions in total axon volume following A1AR agonist treatment. We also observed reduced expression of myelin basic protein in treated animals. Showing that functional A1ARs were present over the ranges of ages studies, high levels of specific [3H]CCPA binding were observed at PD 4, 7 and 14, and receptor-G protein coupling was present at each age. These observations show that activation of A1ARs with doses of CPA that mimic the effects of high adenosine levels results in damage to the developing brain.     

Executive testing predicts functional loss in subjects with white matter lesions

In order to assess ecological validity of executive function (EF) tests and the impact of EF dysfunction on functional status in elderly subjects with moderate and severe subcortical white matter hyperintensities (WMHs), we made a correlation analysis between EF scores and two measures of Instrumental Activities of Daily Living (IADL). Trail-making test and CLOX correlated with the ability to perform IADL in subjects with severe WMH. EF tests might present low ecological validity for those with WMH below severe stage.     

Chronic hydrocephalus in rats and humans: white matter loss and behavior changes

Chronic hydrocephalus that begins in childhood and progresses only very gradually is sometimes called "arrested" hydrocephalus. Data suggest that this state eventually can become symptomatic and may be treatable by shunting. However, the pathological substrate of the disorder is not entirely understood. We studied chronic hydrocephalus in rats, 9 months after induction by kaolin injection into the cisterna magna, and in humans. In both circumstances, destruction of periventricular white matter structures was worst in those with the largest ventricles. Structures damaged include the corpus callosum, corticospinal tract, and fimbria/fornix projections from the hippocampus. Myelin turnover was increased. These changes were associated with deficits of motor and cognitive function. The cerebral cortex was largely spared. There appears to be a threshold of ventricle size beyond which functional changes manifest, but this undoubtedly is modified by factors such as age of onset and rate of enlargement. These data support the need for persistent follow-up of patients with chronic, apparently stable hydrocephalus. A slight increase in size of already enlarged ventricles might cause significant axonal damage.     

Neurocognitive deficits and quality of life in outpatients with schizophrenia

The purpose of this cross-sectional study was to examine the relationships between neurocognitive deficits and quality of life for patient with schizophrenia. Fifty-seven schizophrenic outpatients (38 men and 19 women) were assessed for neurocognitive deficits using the Wisconsin Card Sorting Test (WCST) and all patients completed the PCASEE (P=physical, C=cognitive, A=affective, S=social, E=economic-social, and E=ego functions) questionnaire to assess their quality of life. We assessed psychiatric symptoms using the Schedule for the Assessment of Positive Symptoms (SAPS) and the Schedule for the Assessment of Negative Symptoms (SANS). We rated the Abnormal Involuntary Movement Scale (AIMS) for extrapyramidal side effects. Pearson correlational analyses were conducted to assess the relationships among measures of quality of life, neurocognitive functioning, symptoms, and extrapyramidal side effects. There were significant relationships among the total score of the PCASEE questionnaire and the SANS total score and the AIMS total score (P<.001). Small but significant associations were found among the total score of the PCASEE questionnaire and the SAPS total score and a number of nonperseverative errors (P<.05). Negative symptoms and extrapyramidal side effects in schizophrenia appear to have direct impact on the patient's perceived quality of life.