Synthesis, characterization and 11C radiolabeling of aminophenyl benzothiazoles:structural effects on the alkylation of amino group

Several aminophenyl benzothiazoles were prepared with a view to using them as amyloid binding agents for imaging β-amyloid in Alzheimer's disease. These precursors were radiolabeled with 11C-positron-emitting radioisotope using an automated synthesizer and selected radiolabeled compounds were further purified by HPLC. Our results demonstrate that changes in structure have a major influence on the radioactive yield and the ease with which the radiolabel can be introduced. Aminophenyl benzothiazoles with an attached isopropyl group resisted dialkylation perhaps due to steric hindrance caused by this group. Straight chain attachment of methyl, ethyl, butyl, and crotyl groups in the structure decreased the radiochemical yield. Notably, the o-aminophenyl benzothiazole derivatives were difficult to alkylate despite stringent experimental conditions. This reactivity difference is attributed to the hydrogen bonding characteristics of the o-amino group with the nitrogen atom of the thiazole ring

Altered functional connectivity in mesial temporal lobe epilepsy.

Growing evidence of altered functional connectivity suggests that mesial temporal lobe epilepsy (mTLE) alters not only hippocampal networks, but also a number of resting state networks. These highly coherent, yet functionally distinct brain circuits interact dynamically with each other in order to mediate consciousness, memory, and attention. However, little is currently known about the modulation of these networks by epileptiform activity, such as interictal spikes and seizures. The objective of the study was to use simultaneous EEG-fMRI to investigate functional connectivity in three resting state networks: default mode network (DMN), salience network (SN), and dorsal attentional network (DAN) in patients with mTLE compared to a healthy cohort, and in relation to the onset of interictal spikes and the period immediately prior to the spikes. Compared to the healthy participants, mTLE patients showed significant alterations in functional connectivity of all three resting state networks, generally characterized by a lack of functional connectivity to prefrontal areas and increased connectivity to subcortical and posterior areas. Critically, prior to the onset of interictal spikes, compared to resting state, mTLE patients showed a lack of functional connectivity to the DMN and decreased synchronization within the SN and DAN, demonstrating alterations in functional coherence that may be responsible for the generation of epileptiform activity. Our findings demonstrate mTLE-related alterations of connectivity during the resting state as well as in relation to the onset of interictal spikes. These functional changes may underlie epilepsy-related cognitive abnormalities, because higher cognitive functions, such as memory or attention, rely heavily on the coordinated activity of all three resting state networks

The relation of structural integrity and task-related functional connectivity in the aging brain.

The relations among structural integrity, functional connectivity (FC), and cognitive performance in the aging brain are still understudied. Here, we used multimodal and multivariate approaches to specifically examine age-related changes in task-related FC, gray-matter volumetrics, white-matter integrity, and performance. Our results are two-fold, showing (i) age-related differences in FC of the working memory network and (ii) age-related recruitment of a compensatory network associated with better accuracy on the task. Increased connectivity in the compensatory network correlates positively with preserved white-matter integrity in bilateral frontoparietal tracks and with larger gray-matter volume of right inferior parietal lobule. These findings demonstrate the importance of structural integrity and FC in working memory performance associated with healthy aging

The Neurocognitive Components of Pitch Processing: Insights from Absolute Pitch

The natural variability of pitch naming ability in the population (known as absolute pitch or AP) provides an ideal method for investigating individual differences in pitch processing and auditory knowledge formation and representation. We have demonstrated the involvement of different cognitive processes in AP ability that reflects varying skill expertise in the presence of similar early age of onset of music tuition. These processes were related to different regions of brain activity, including those involved in pitch working memory (right prefrontal cortex) and the long-term representation of pitch (superior temporal gyrus). They reflected expertise through the use of context dependent pitch cues and the level of automaticity of pitch naming. They impart functional significance to structural asymmetry differences in the planum temporale of musicians and establish a neurobiological basis for an AP template. More generally, they indicate variability of knowledge representation in the presence of environmental fostering of early cognitive development that translates to differences in cognitive ability

The Neurocognitive Components of Pitch Processing: Insights from Absolute Pitch

The natural variability of pitch naming ability in the population (known as absolute pitch or AP) provides an ideal method for investigating individual differences in pitch processing and auditory knowledge formation and representation. We have demonstrated the involvement of different cognitive processes in AP ability that reflects varying skill expertise in the presence of similar early age of onset of music tuition. These processes were related to different regions of brain activity, including those involved in pitch working memory (right prefrontal cortex) and the long-term representation of pitch (superior temporal gyrus). They reflected expertise through the use of context dependent pitch cues and the level of automaticity of pitch naming. They impart functional significance to structural asymmetry differences in the planum temporale of musicians and establish a neurobiological basis for an AP template. More generally, they indicate variability of knowledge representation in the presence of environmental fostering of early cognitive development that translates to differences in cognitive ability

Presurgical language fMRI: Clinical practices and patient outcomes in epilepsy surgical planning

The goal of this study was to document current clinical practice and report patient outcomes in presurgical language functional MRI (fMRI) for epilepsy surgery. Epilepsy surgical programs worldwide were surveyed as to the utility, implementation, and efficacy of language fMRI in the clinic; 82 programs responded. Respondents were predominantly US (61%) academic programs (85%), and evaluated adults (44%), adults and children (40%), or children only (16%). Nearly all (96%) reported using language fMRI. Surprisingly, fMRI is used to guide surgical margins (44% of programs) as well as lateralize language (100%). Sites using fMRI for localization most often use a distance margin around activation of 10mm. While considered useful, 56% of programs reported at least one instance of disagreement with other measures. Direct brain stimulation typically confirmed fMRI findings (74%) when guiding margins, but instances of unpredicted decline were reported by 17% of programs and 54% reported unexpected preservation of function. Programs reporting unexpected decline did not clearly differ from those which did not. Clinicians using fMRI to guide surgical margins do not typically map known language-critical areas beyond Broca's and Wernicke's. This initial data shows many clinical teams are confident using fMRI not only for language lateralization but also to guide surgical margins. Reported cases of unexpected language preservation when fMRI activation is resected, and cases of language decline when it is not, emphasize a critical need for further validation. Comprehensive studies comparing commonly-used fMRI paradigms to predict stimulation mapping and post-surgical language decline remain of high importance

Segmentation of the C57BL/6J mouse cerebellum in magnetic resonance images

The C57BL mouse is the centerpiece of efforts to use gene-targeting technology to understand cerebellar pathology, thus creating a need for a detailed magnetic resonance imaging (MRI) atlas of the cerebellum of this strain. In this study we present a methodology for systematic delineation of the vermal and hemispheric lobules of the C57BL/6J mouse cerebellum in magnetic resonance images. We have successfully delineated 38 cerebellar and cerebellar-related structures. The higher signal-to-noise ratio achieved by group averaging facilitated the identification of anatomical structures. In addition, we have calculated average region volumes and created probabilistic maps for each structure. The segmentation method and the probabilistic maps we have created will provide a foundation for future studies of cerebellar disorders using transgenic mouse models

Elemental spatial and temporal association formation in left temporal lobe epilepsy

The mesial temporal lobe (MTL) is typically understood as a memory structure in clinical settings, with the sine qua non of MTL damage in epilepsy being memory impairment. Recent models, however, understand memory as one of a number of higher cognitive functions that recruit the MTL through their reliance on more fundamental processes, such as “self-projection” or “association formation”. We examined how damage to the left MTL influences these fundamental processes through the encoding of elemental spatial and temporal associations. We used a novel fMRI task to image the encoding of simple visual stimuli, either rich or impoverished, in spatial or spatial plus temporal information. Participants included 14 typical adults (36.4 years, sd. 10.5 years) and 14 patients with left mesial temporal lobe damage as evidenced by a clinical diagnosis of left temporal lobe epilepsy (TLE) and left MTL impairment on imaging (34.3 years, sd. 6.6 years). In-scanner behavioral performance was equivalent across groups. In the typical group whole-brain analysis revealed highly significant bilateral parahippocampal activation (right > left) during spatial associative processing and left hippocampal/parahippocampal deactivation in joint spatial-temporal associative processing. In the left TLE group identical analyses indicated patients used MTL structures contralateral to the seizure focus differently and relied on extra-MTL regions to a greater extent. These results are consistent with the notion that epileptogenic MTL damage is followed by reorganization of networks underlying elemental associative processes. In addition, they provide further evidence that task-related fMRI deactivation can meaningfully index brain function. The implications of these findings for clinical and cognitive neuropsychological models of MTL function in TLE are discussed

Aromatase expression is increased in BRCA1 mutation carriers

<p>Abstract</p> <p>Background</p> <p>Until recently, the molecular mechanisms explaining increased incidence of ovarian and breast cancers in carriers of <it>BRCA1 </it>gene mutations had not been clearly understood. Of significance is the finding that BRCA1 negatively regulates aromatase expression <it>in vitro</it>. Our objective was to characterise aromatase gene <it>(CYP19A1) </it>and its promoter expression in breast adipose and ovarian tissue in <it>BRCA1 </it>mutation carriers and unaffected controls.</p> <p>Methods</p> <p>We measured aromatase transcripts, total and promoter-specific (PII, PI.3, PI.4) in prophylactic oophorectomy or mastectomy, therapeutic mastectomy, ovarian and breast tissue from unaffected women.</p> <p>Results</p> <p>We demonstrate that the lack of functional BRCA1 protein correlates to higher aromatase levels in 85% of <it>BRCA1 </it>mutation carriers. This increase is mediated by aberrant transcriptional regulation of aromatase; in breast adipose by increases in promoter II/I.3 and I.4-specific transcripts; and in the ovary with elevation in promoter I.3 and II-specific transcripts.</p> <p>Conclusion</p> <p>Understanding the link between BRCA1 and aromatase is significant in terms of understanding why carcinogenesis is restricted to estrogen-producing tissues in <it>BRCA1 </it>mutation carriers.</p