Examining the relation between bilingualism and age of symptom onset in frontotemporal dementia.

Bilingualism is thought to confer advantages in executive functioning, thereby contributing to cognitive reserve and a later age of dementia symptom onset. While the relation between bilingualism and age of onset has been explored in Alzheimer's dementia, there are few studies examining bilingualism as a contributor to cognitive reserve in frontotemporal dementia (FTD). In line with previous findings, we hypothesized that bilinguals with behavioral variant FTD would be older at symptom onset compared to monolinguals, but that no such effect would be found in patients with nonfluent/agrammatic variant primary progressive aphasia (PPA) or semantic variant PPA. Contrary to our hypothesis, we found no significant difference in age at symptom onset between monolingual and bilingual speakers within any of the FTD variants, and there were no notable differences on neuropsychological measures. Overall, our results do not support a protective effect of bilingualism in patients with FTD-spectrum disease in a U.S. based cohort.

Development of an Abbreviated Adult Reading History Questionnaire (ARHQ-Brief) Using a Machine Learning Approach.

Several crucial reasons exist to determine whether an adult has had a reading disorder (RD) and to predict a child's likelihood of developing RD. The Adult Reading History Questionnaire (ARHQ) is among the most commonly used self-reported questionnaires. High ARHQ scores indicate an increased likelihood that an adult had RD as a child and that their children may develop RD. This study focused on whether a subset of ARHQ items (ARHQ-Brief) could be equally effective in assessing adults' reading history as the full ARHQ. We used a machine learning approach, lasso (known as L1 regularization), and identified 6 of 23 items that resulted in the ARHQ-Brief. Data from 97 adults and 47 children were included. With the ARHQ-Brief, we report a threshold of 0.323 as suitable to identify past likelihood of RD in adults with a sensitivity of 72.4% and a specificity of 81.5%. Comparison of predictive performances between ARHQ-Brief and the full ARHQ showed that ARHQ-Brief explained an additional 10%-35.2% of the variance in adult and child reading. Furthermore, we validated ARHQ-Brief's superior ability to predict reading ability using an independent sample of 28 children. We close by discussing limitations and future directions.

Children with developmental dyslexia show elevated parasympathetic nervous system activity at rest and greater cardiac deceleration during an empathy task.

Reading difficulties are the hallmark feature of dyslexia, but less is known about other areas of functioning. Previously, we found children with dyslexia exhibited heightened emotional reactivity, which correlated with better social skills. Whether emotional differences in dyslexia extend to the parasympathetic nervous system-an autonomic branch critical for attention, social engagement, and empathy-is unknown. Here, we measured autonomic nervous system activity in 24 children with dyslexia and 24 children without dyslexia, aged 7 - 12, at rest and during a film-based empathy task. At rest, children with dyslexia had higher respiratory sinus arrhythmia (RSA) than those without dyslexia. Cardiac deceleration during the empathy task was greater in dyslexia and correlated with higher resting RSA across the sample. Children with dyslexia produced more facial expressions of concentration during film-viewing, suggesting greater engagement. These results suggest elevated resting parasympathetic activity and accentuated autonomic and behavioral responding to others' emotions in dyslexia.

Functional and morphological correlates of developmental dyslexia: A multimodal investigation of the ventral occipitotemporal cortex.

BACKGROUND AND PURPOSE: The ventral occipitotemporal cortex (vOT) is a region crucial for reading acquisition through selective tuning to printed words. Developmental dyslexia is a disorder of reading with underlying neurobiological bases often associated with atypical neural responses to printed words. Previous studies have discovered anomalous structural development and function of the vOT in individuals with dyslexia. However, it remains unclear if or how structural abnormalities relate to functional alterations. METHODS: In this study, we acquired structural, functional (words and faces processing), and diffusion MRI data from 26 children with dyslexia (average age = 10.4 ± 2.0 years) and 14 age-matched typically developing readers (average age = 10.4 ± 1.6 years). Morphological indices of local gyrification, neurite density (i.e., dendritic arborization structure), and orientation dispersion (i.e., dendritic arborization orientation) were analyzed within the vOT region that showed preferential activation in typically developing readers for words (as compared to face stimuli). RESULTS: The two cohorts diverged significantly in both functional and structural measures. Compared to typically developing controls, children with dyslexia did not show selectivity for words in the left vOT (contrast: words > false fonts). This lack of tuning to printed words was associated with greater neurite dispersion heterogeneity in the dyslexia cohort, but similar neurite density. These group differences were not present in the homologous contralateral area, the right vOT. CONCLUSIONS: Our findings provide new insight into the neurobiology of the lack of vOT word tuning in dyslexia by linking behavior, alterations in functional activation, and neurite organization.

Cortically constrained shape recognition: Automated white matter tract segmentation validated in the pediatric brain.

BACKGROUND AND PURPOSE: Manual segmentation of white matter (WM) bundles requires extensive training and is prohibitively labor-intensive for large-scale studies. Automated segmentation methods are necessary in order to eliminate operator dependency and to enable reproducible studies. Significant changes in the WM landscape throughout childhood require flexible methods to capture the variance across the span of brain development. METHODS: Here, we describe a novel automated segmentation tool called Cortically Constrained Shape Recognition (CCSR), which combines two complementary approaches: (1) anatomical connectivity priors based on FreeSurfer-derived regions of interest and (2) shape priors based on 3-dimensional streamline bundle atlases applied using RecoBundles. We tested the performance and repeatability of this approach by comparing volume and diffusion metrics of the main language WM tracts that were both manually and automatically segmented in a pediatric cohort acquired at the UCSF Dyslexia Center (n = 59; 25 females; average age: 11 ± 2; range: 7-14). RESULTS: The CCSR approach showed high agreement with the expert manual segmentations: across all tracts, the spatial overlap between tract volumes showed an average Dice Similarity Coefficient (DSC) of 0.76, and the fractional anisotropy (FA) on average had a Lin's Concordance Correlation Coefficient (CCC) of 0.81. The CCSR's repeatability in a subset of this cohort achieved a DSC of 0.92 on average across all tracts. CONCLUSION: This novel automated segmentation approach is a promising tool for reproducible large-scale tractography analyses in pediatric populations and particularly for the quantitative assessment of structural connections underlying various clinical presentations in neurodevelopmental disorders.

Enhanced visceromotor emotional reactivity in dyslexia and its relation to salience network connectivity.

Dyslexia is a neurodevelopmental disorder mainly defined by reading difficulties. During reading, individuals with dyslexia exhibit hypoactivity in left-lateralized language systems. Lower activity in one brain circuit can be accompanied by greater activity in another, and, here, we examined whether right-hemisphere-based emotional reactivity may be elevated in dyslexia. We measured emotional reactivity (i.e., facial behavior, physiological activity, and subjective experience) in 54 children ages 7-12 with (n = 32) and without (n = 22) dyslexia while they viewed emotion-inducing film clips. Participants also underwent task-free functional magnetic resonance imaging. Parents of children with dyslexia completed the Behavior Assessment System for Children, which assesses real-world behavior. During film viewing, children with dyslexia exhibited significantly greater reactivity in emotional facial behavior, skin conductance level, and respiration rate than those without dyslexia. Across the sample, greater emotional facial behavior correlated with stronger connectivity between right ventral anterior insula and right pregenual anterior cingulate cortex (pFWE<.05), key salience network hubs. In children with dyslexia, greater emotional facial behavior related to better real-world social skills and higher anxiety and depression. Our findings suggest there is heightened visceromotor emotional reactivity in dyslexia, which may lead to interpersonal strengths as well as affective vulnerabilities.

Mapping abnormal subcortical neurodevelopment in a cohort of Thai children with HIV.

Alterations in subcortical brain structures have been reported in adults with HIV and, to a lesser extent, pediatric cohorts. The extent of longitudinal structural abnormalities in children with perinatal HIV infection (PaHIV) remains unclear. We modeled subcortical morphometry from whole brain structural magnetic resonance imaging (1.5 T) scans of 43 Thai children with PaHIV (baseline age = 11.09±2.36 years) and 50 HIV- children (11.26±2.80 years) using volumetric and surface-based shape analyses. The PaHIV sample were randomized to initiate combination antiretroviral treatment (cART) when CD4 counts were 15-24% (immediate: n = 22) or when CD4 < 15% (deferred: n = 21). Follow-up scans were acquired approximately 52 weeks after baseline. Volumetric and shape descriptors capturing local thickness and surface area dilation were defined for the bilateral accumbens, amygdala, putamen, pallidum, thalamus, caudate, and hippocampus. Regression models adjusting for clinical and demographic variables examined between and within group differences in morphometry associated with HIV. We assessed whether baseline CD4 count and cART status or timing associated with brain maturation within the PaHIV group. All models were adjusted for multiple comparisons using the false discovery rate. A pallidal subregion was significantly thinner in children with PaHIV. Regional thickness, surface area, and volume of the pallidum was associated with CD4 count in children with PaHIV. Longitudinal morphometry was not associated with HIV or cART status or timing, however, the trajectory of the left pallidum volume was positively associated with baseline CD4 count. Our findings corroborate reports in adult cohorts demonstrating a high predilection for HIV-mediated abnormalities in the basal ganglia, but suggest the effect of stable PaHIV infection on morphological aspects of brain development may be subtle.

Atypical clinical features associated with mixed pathology in a case of non-fluent variant primary progressive aphasia.

A 66-year-old woman presented with agrammatism and apraxia of speech, meeting criteria for non-fluent/agrammatic variant primary progressive aphasia (nfvPPA). However, three years later, she developed frontal/executive, short-term phonological memory, visuospatial, and visual memory deficits suggesting involvement of multiple brain networks. Multimodal neuroimaging showed damage of both fronto-striatal and posterior brain regions. She was found to have multiple pathological processes: corticobasal degeneration (CBD), Alzheimer's disease (AD), and TAR DNA-binding protein (TDP)-43 type A. We hypothesize that cognitive and neuroimaging findings consistent with damage to multiple brain networks, each associated with vulnerability to certain molecular disease subtypes, could indicate mixed pathology.

"Looks familiar, but I do not know who she is": The role of the anterior right temporal lobe in famous face recognition.

Processing a famous face involves a cascade of steps including detecting the presence of a face, recognizing it as familiar, accessing semantic/biographical information about the person, and finally, if required, production of the proper name. Decades of neuropsychological and neuroimaging studies have identified a network of occipital and temporal brain regions ostensibly comprising the 'core' system for face processing. Recent research has also begun to elucidate upon an 'extended' network, including anterior temporal and frontal regions. However, there is disagreement about which brain areas are involved in each step, as many aspects of face processing occur automatically in healthy individuals and rarely dissociate in patients. Moreover, some common phenomena are not easily induced in an experimental setting, such as having a sense of familiarity without being able to recall who the person is. Patients with the semantic variant of Primary Progressive Aphasia (svPPA) often recognize a famous face as familiar, even when they cannot specifically recall the proper name or biographical details. In this study, we analyzed data from a large sample of 105 patients with neurodegenerative disorders, including 43 svPPA, to identify the neuroanatomical substrates of three different steps of famous face processing. Using voxel-based morphometry, we correlated whole-brain grey matter volumes with scores on three experimental tasks that targeted familiarity judgment, semantic/biographical information retrieval, and naming. Performance in naming and semantic association significantly correlates with grey matter volume in the left anterior temporal lobe, whereas familiarity judgment with integrity of the right anterior middle temporal gyrus. These findings shed light on the neuroanatomical substrates of key components of overt face processing, addressing issues of functional lateralization, and deepening our understanding of neural substrates of semantic knowledge.

Primary progressive aphasia and the FTD-MND spectrum disorders: clinical, pathological, and neuroimaging correlates.

Objective: Behavioral variant frontotemporal dementia (bvFTD), is commonly considered the cognitive presentation of the frontotemporal dementia-motor neuron disease (FTD-MND) spectrum disorder. We evaluated the prevalence of primary progressive aphasia in a series of pathologically confirmed cases of FTD-MND spectrum. Methods: Pathologically confirmed cases of frontotemporal lobar degeneration-motor neuron disease (FTLD-MND) were obtained from the UCSF brain bank. Cases were analyzed for presence of language impairment via retrospective chart review of research visits that include neurologic exam, in-depth cognitive testing and magnetic resonance imaging (MRI) imaging. Forty one cases were included. Thirty two were diagnosed with FTD-MND, while nine cases were diagnosed as MND-only from clinical evaluation. Results: Ten FTLD-MND cases (31%) presented with prominent or isolated language involvement consistent with a diagnosis of primary progressive aphasia (PPA), which we called progressive aphasia with motor neuron disease (PA-MND). Of these, three cases that mirrored the non-fluent variant of PPA (nfvPPA) were named nfvPA-MND. The imaging pattern of these nfvPA-MND showed atrophy strictly confined to the frontal and anterior temporal language cortical areas. Another group of seven cases that resembled patients with the semantic variant PPA (svPPA) were named svPA-MND. The group of svPPA-MND on imaging analysis showed selective atrophy of the temporal lobe and orbitofrontal cortex. Conclusions: Language impairment was a frequent phenotype of FTD-MND associated with focal atrophy patterns within the language networks. This data suggest patients with FTD-MND can present quite often with language phenotype of nfvPPA and svPPA, as opposed to exclusive bvFTD symptoms.

Cortical developmental abnormalities in logopenic variant primary progressive aphasia with dyslexia.

An increased prevalence of dyslexia has been observed in individuals diagnosed with primary progressive aphasia, most notably the logopenic variant primary progressive aphasia. The underlying pathology most commonly associated with logopenic variant primary progressive aphasia is Alzheimer's disease. In this clinical case report series, we describe the neuropathological findings of three patients with logopenic variant primary progressive aphasia and developmental dyslexia, each demonstrating a pattern of cerebrocortical microdysgenesis, reminiscent of findings first reported in dyslexic individuals, alongside expected Alzheimer's disease pathology. Neurodevelopmental and most severe Alzheimer's disease pathological changes overlapped within perisylvian brain regions, areas associated with phonological deficits in both logopenic variant primary progressive aphasia and dyslexia. These three cases with pathological findings support the hypothesis that early-life neurodevelopmental changes might influence later-life susceptibility to neurodegenerative disease and could contribute to non-amnestic, early age-of-onset presentations of Alzheimer's disease. Larger studies investigating neurobiological vulnerability across the lifespan are needed.

Altered topology of the functional speech production network in non-fluent/agrammatic variant of PPA.

Non-fluent/agrammatic primary progressive aphasia (nfvPPA) is caused by neurodegeneration within the left fronto-insular speech and language production network (SPN). Graph theory is a branch of mathematics that studies network architecture (topology) by quantifying features based on its elements (nodes and connections). This approach has been recently applied to neuroimaging data to explore the complex architecture of the brain connectome, though few studies have exploited this technique in PPA. Here, we used graph theory on functional MRI resting state data from a group of 20 nfvPPA patients and 20 matched controls to investigate topological changes in response to focal neurodegeneration. We hypothesized that changes in the network architecture would be specific to the affected SPN in nfvPPA, while preserved in the spared default mode network (DMN). Topological configuration was quantified by hub location and global network metrics. Our findings showed a less efficiently wired and less optimally clustered SPN, while no changes were detected in the DMN. The SPN in the nfvPPA group showed a loss of hubs in the left fronto-parietal-temporal area and new critical nodes in the anterior left inferior-frontal and right frontal regions. Behaviorally, speech production score and rule violation errors correlated with the strength of functional connectivity of the left (lost) and right (new) regions respectively. This study shows that focal neurodegeneration within the SPN in nfvPPA is associated with network-specific topological alterations, with the loss and gain of crucial hubs and decreased global efficiency that were better accounted for through functional rather than structural changes. These findings support the hypothesis of selective network vulnerability in nfvPPA and may offer biomarkers for future behavioral intervention.

Abnormal age-related cortical folding and neurite morphology in children with developmental dyslexia.

There is increasing recognition of a relationship between regional variability in cerebral gyrification and neurodevelopment. Recent work in morphometric MRI has shown that the local gyrification index (lGI), a measure of regional brain folding, may be altered in certain neurodevelopmental disorders. Other studies report that the lGI generally decreases with age in adolescence and young adulthood; however, little is known about how these age-dependent differences in brain maturation occur in atypical neurodevelopment and mechanisms underlying gyrification, such as synaptic pruning. Organization and optimization of dendrites and axons connections across the brain might be driving gyrification and folding processes. In this study, we first assessed lGI differences in the left hemisphere in a cohort of 39 children with developmental dyslexia (DD) between the ages of 7 and 15 years in comparison to 56 typically developing controls (TDC). To better understand the microstructural basis of these changes, we next explored the relationship between lGI differences and cortical thickness and neurite morphology by applying neurite orientation dispersion and density imaging (NODDI). We identified significant differences in lGI between children with DD and TDC in left lateral temporal and middle frontal regions. Further, DD failed to show the expected age-related decreases in lGI in the same regions. Age-related differences in lGI in DD were not explained by differences in cortical thickness, but did correlate with NODDI neurite density and orientation dispersion index. Our findings suggest that gyrification changes in DD are related to abnormal neurite morphology, and are possibly an expression of differences in synaptic pruning.

Rates of Amyloid Imaging Positivity in Patients With Primary Progressive Aphasia.

Importance: The ability to predict the pathology underlying different neurodegenerative syndromes is of critical importance owing to the advent of molecule-specific therapies. Objective: To determine the rates of positron emission tomography (PET) amyloid positivity in the main clinical variants of primary progressive aphasia (PPA). Design, Setting, and Participants: This prospective clinical-pathologic case series was conducted at a tertiary research clinic specialized in cognitive disorders. Patients were evaluated as part of a prospective, longitudinal research study between January 2002 and December 2015. Inclusion criteria included clinical diagnosis of PPA; availability of complete speech, language, and cognitive testing; magnetic resonance imaging performed within 6 months of the cognitive evaluation; and PET carbon 11-labeled Pittsburgh Compound-B or florbetapir F 18 brain scan results. Of 109 patients referred for evaluation of language symptoms who underwent amyloid brain imaging, 3 were excluded because of incomplete language evaluations, 5 for absence of significant aphasia, and 12 for presenting with significant initial symptoms outside of the language domain, leaving a cohort of 89 patients with PPA. Main Outcomes and Measures: Clinical, cognitive, neuroimaging, and pathology results. Results: Twenty-eight cases were classified as imaging-supported semantic variant PPA (11 women [39.3%]; mean [SD] age, 64 [7] years), 31 nonfluent/agrammatic variant PPA (22 women [71.0%]; mean [SD] age, 68 [7] years), 26 logopenic variant PPA (17 women [65.4%]; mean [SD] age, 63 [8] years), and 4 mixed PPA cases. Twenty-four of 28 patients with semantic variant PPA (86%) and 28 of 31 patients with nonfluent/agrammatic variant PPA (90%) had negative amyloid PET scan results, while 25 of 26 patients with logopenic variant PPA (96%) and 3 of 4 mixed PPA cases (75%) had positive scan results. The amyloid positive semantic variant PPA and nonfluent/agrammatic variant PPA cases with available autopsy data (2 of 4 and 2 of 3, respectively) all had a primary frontotemporal lobar degeneration and secondary Alzheimer disease pathologic diagnoses, whereas autopsy of 2 patients with amyloid PET-positive logopenic variant PPA confirmed Alzheimer disease. One mixed PPA patient with a negative amyloid PET scan had Pick disease at autopsy. Conclusions and Relevance: Primary progressive aphasia variant diagnosis according to the current classification scheme is associated with Alzheimer disease biomarker status, with the logopenic variant being associated with carbon 11-labeled Pittsburgh Compound-B positivity in more than 95% of cases. Furthermore, in the presence of a clinical syndrome highly predictive of frontotemporal lobar degeneration pathology, biomarker positivity for Alzheimer disease may be associated more with mixed pathology rather than primary Alzheimer disease.

Visuospatial Functioning in the Primary Progressive Aphasias.

OBJECTIVES: The aim of this study was to identify whether the three main primary progressive aphasia (PPA) variants would show differential profiles on measures of visuospatial cognition. We hypothesized that the logopenic variant would have the most difficulty across tasks requiring visuospatial and visual memory abilities. METHODS: PPA patients (n=156), diagnosed using current criteria, and controls were tested on a battery of tests tapping different aspects of visuospatial cognition. We compared the groups on an overall visuospatial factor; construction, immediate recall, delayed recall, and executive functioning composites; and on individual tests. Cross-sectional and longitudinal comparisons were made, adjusted for disease severity, age, and education. RESULTS: The logopenic variant had significantly lower scores on the visuospatial factor and the most impaired scores on all composites. The nonfluent variant had significant difficulty on all visuospatial composites except the delayed recall, which differentiated them from the logopenic variant. In contrast, the semantic variants performed poorly only on delayed recall of visual information. The logopenic and nonfluent variants showed decline in figure copying performance over time, whereas in the semantic variant, this skill was remarkably preserved. CONCLUSIONS: This extensive examination of performance on visuospatial tasks in the PPA variants solidifies some previous findings, for example, delayed recall of visual stimuli adds value in differential diagnosis between logopenic variant PPA and nonfluent variant PPA variants, and illuminates the possibility of common mechanisms that underlie both linguistic and non-linguistic deficits in the variants. Furthermore, this is the first study that has investigated visuospatial functioning over time in the PPA variants. (JINS, 2018, 24, 259-268).

White matter hyperintensities correlate to cognition and fiber tract integrity in older adults with HIV.

Our aim was to examine the clinical relevance of white matter hyperintensities (WMH) in HIV. We used an automated approach to quantify WMH volume in HIV seropositive (HIV+; n = 65) and HIV seronegative (HIV-; n = 29) adults over age 60. We compared WMH volumes between HIV+ and HIV- groups in cross-sectional and multiple time-point analyses. We also assessed correlations between WMH volumes and cardiovascular, HIV severity, cognitive scores, and diffusion tensor imaging variables. Serostatus groups did not differ in WMH volume, but HIV+ participants had less cerebral white matter (mean: 470.95 [43.24] vs. 497.63 [49.42] mL, p = 0.010). The distribution of WMH volume was skewed in HIV+ with a high proportion (23%) falling above the 95th percentile of WMH volume defined by the HIV- group. Serostatus groups had similar amount of WMH volume growth over time. Total WMH volume directly correlated with measures of hypertension and inversely correlated with measures of global cognition, particularly in executive functioning, and psychomotor speed. Greater WMH volume was associated with poorer brain integrity measured from diffusion tensor imaging (DTI) in the corpus callosum and sagittal stratum. In this group of HIV+ individuals over 60, WMH burden was associated with cardiovascular risk and both worse diffusion MRI and cognition. The median total burden did not differ by serostatus; however, a subset of HIV+ individuals had high WMH burden.

Neuroanatomical substrates of executive functions: Beyond prefrontal structures.

Executive functions are often considered lynchpin "frontal lobe tasks", despite accumulating evidence that a broad network of anterior and posterior brain structures supports them. Using a latent variable modelling approach, we assessed whether prefrontal grey matter volumes independently predict executive function performance when statistically differentiated from global atrophy and individual non-frontal lobar volume contributions. We further examined whether fronto-parietal white matter microstructure underlies and independently contributes to executive functions. We developed a latent variable model to decompose lobar grey matter volumes into a global grey matter factor and specific lobar volumes (i.e. prefrontal, parietal, temporal, occipital) that were independent of global grey matter. We then added mean fractional anisotropy (FA) for the superior longitudinal fasciculus (dorsal portion), corpus callosum, and cingulum bundle (dorsal portion) to models that included grey matter volumes related to cognitive variables in previous analyses. Results suggested that the 2-factor model (shifting/inhibition, updating/working memory) plus an information processing speed factor best explained our executive function data in a sample of 202 community dwelling older adults, and was selected as the base measurement model for further analyses. Global grey matter was related to the executive function and speed variables in all four lobar models, but independent contributions of the frontal lobes were not significant. In contrast, when assessing the effect of white matter microstructure, cingulum FA made significant independent contributions to all three executive function and speed variables and corpus callosum FA was independently related to shifting/inhibition and speed. Findings from the current study indicate that while prefrontal grey matter volumes are significantly associated with cognitive neuroscience measures of shifting/inhibition and working memory in healthy older adults, they do not independently predict executive function when statistically isolated from global atrophy and individual non-frontal lobar volume contributions. In contrast, better microstructure of fronto-parietal white matter, namely the corpus callosum and cingulum, continued to predict executive functions after accounting for global grey matter atrophy. These findings contribute to a growing literature suggesting that prefrontal contributions to executive functions cannot be viewed in isolation from more distributed grey and white matter effects in a healthy older adult cohort.

Atypical Structural Connectome Organization and Cognitive Impairment in Young Survivors of Acute Lymphoblastic Leukemia.

Survivors of pediatric acute lymphoblastic leukemia (ALL) are at increased risk for cognitive impairments that disrupt everyday functioning and decrease quality of life. The specific biological mechanisms underlying cognitive impairment following ALL remain largely unclear, but previous studies consistently demonstrate significant white matter pathology. We aimed to extend this literature by examining the organization of the white matter connectome in young patients with a history of ALL treated with chemotherapy only. We applied graph theoretical analysis to diffusion tensor imaging obtained from 31 survivors of ALL age 5-19 years and 39 matched healthy controls. Results indicated significantly lower small-worldness (p = 0.007) and network clustering coefficient (p = 0.019), as well as greater cognitive impairment (p = 0.027) in the ALL group. Regional analysis indicated that clustered connectivity in parietal, frontal, hippocampal, amygdalar, thalamic, and occipital regions was altered in the ALL group. Random forest analysis revealed a model of connectome and demographic variables that could automatically classify survivors of ALL as having cognitive impairment or not (accuracy = 0.89, p < 0.0001). These findings provide further evidence of brain injury in young survivors of ALL, even those without a history of central nervous system (CNS) disease or cranial radiation. Efficiency of local information processing, reorganization of hub connectivity, and cognitive reserve may contribute to cognitive outcome in these children. Certain connectome properties showed U-shaped relationships with cognitive impairment suggesting an optimal range of regional connectivity.

Screening for Chemical Toxicity Using Cryopreserved Precision Cut Lung Slices.

To assess chemical toxicity, current high throughput screening (HTS) assays rely primarily on in vitro measurements using cultured cells. Responses frequently differ from in vivo results due to the lack of physical and humoral interactions provided by the extracellular matrix, cell-cell interactions, and other molecular components of the native organ. To more accurately reproduce organ complexity in HTS, we developed an organotypic assay using the cryopreserved precision cut lung slice (PCLS) from rats and mice. Compared to the never-frozen PCLS, their frozen-thawed counterpart slices showed viability or metabolic activity that is decreased to an extent comparable to that observed in other cryopreserved cells and tissues, but shows no differences in further changes in cell viability, mitochondrial integrity, and glutathione activity in response to the model toxin zinc chloride (ZnCl2). Notably, these measurements were successfully miniaturized so as to establish HTS capacity in a 96-well plate format. Finally, PCLS responses correlated with common markers of lung injury measured in lavage fluid from rats intratracheally instilled with ZnCl2. In summary, we establish that the cryopreserved PCLS is a feasible approach for HTS investigations in predictive toxicology.

Effects of zinc oxide nanoparticles on Kupffer cell phagosomal motility, bacterial clearance, and liver function.

BACKGROUND: Zinc oxide engineered nanoparticles (ZnO ENPs) have potential as nanomedicines due to their inherent properties. Studies have described their pulmonary impact, but less is known about the consequences of ZnO ENP interactions with the liver. This study was designed to describe the effects of ZnO ENPs on the liver and Kupffer cells after intravenous (IV) administration. MATERIALS AND METHODS: First, pharmacokinetic studies were conducted to determine the tissue distribution of neutron-activated (65)ZnO ENPs post-IV injection in Wistar Han rats. Then, a noninvasive in vivo method to assess Kupffer cell phagosomal motility was employed using ferromagnetic iron particles and magnetometry. We also examined whether prior IV injection of ZnO ENPs altered Kupffer cell bactericidal activity on circulating Pseudomonas aeruginosa. Serum and liver tissues were collected to assess liver-injury biomarkers and histological changes, respectively. RESULTS: We found that the liver was the major site of initial uptake of (65)ZnO ENPs. There was a time-dependent decrease in tissue levels of (65)Zn in all organs examined, refecting particle dissolution. In vivo magnetometry showed a time-dependent and transient reduction in Kupffer cell phagosomal motility. Animals challenged with P. aeruginosa 24 hours post-ZnO ENP injection showed an initial (30 minutes) delay in vascular bacterial clearance. However, by 4 hours, IV-injected bacteria were cleared from the blood, liver, spleen, lungs, and kidneys. Seven days post-ZnO ENP injection, creatine phosphokinase and aspartate aminotransferase levels in serum were significantly increased. Histological evidence of hepatocyte damage and marginated neutrophils were observed in the liver. CONCLUSION: Administration of ZnO ENPs transiently inhibited Kupffer cell phagosomal motility and later induced hepatocyte injury, but did not alter bacterial clearance from the blood or killing in the liver, spleen, lungs, or kidneys. Our data show that diminished Kupffer cell organelle motion correlated with ZnO ENP-induced liver injury.