Distinct spatiotemporal atrophy patterns in corticobasal syndrome are associated with different underlying pathologies.

Objective: To identify imaging subtypes of the cortico-basal syndrome (CBS) based solely on a data-driven assessment of MRI atrophy patterns, and investigate whether these subtypes provide information on the underlying pathology. Methods: We applied Subtype and Stage Inference (SuStaIn), a machine learning algorithm that identifies groups of individuals with distinct biomarker progression patterns, to a large cohort of 135 CBS cases (52 had a pathological or biomarker defined diagnosis) and 252 controls. The model was fit using volumetric features extracted from baseline T1-weighted MRI scans and validated using follow-up MRI. We compared the clinical phenotypes of each subtype and investigated whether there were differences in associated pathology between the subtypes. Results: SuStaIn identified two subtypes with distinct sequences of atrophy progression; four-repeat-tauopathy confirmed cases were most commonly assigned to the Subcortical subtype (83% of CBS-PSP and 75% of CBS-CBD), while CBS-AD was most commonly assigned to the Fronto-parieto-occipital subtype (81% of CBS-AD). Subtype assignment was stable at follow-up (98% of cases), and individuals consistently progressed to higher stages (100% stayed at the same stage or progressed), supporting the model's ability to stage progression. Interpretation: By jointly modelling disease stage and subtype, we provide data-driven evidence for at least two distinct and longitudinally stable spatiotemporal subtypes of atrophy in CBS that are associated with different underlying pathologies. In the absence of sensitive and specific biomarkers, accurately subtyping and staging individuals with CBS at baseline has important implications for screening on entry into clinical trials, as well as for tracking disease progression.

Axonal damage and astrocytosis are biological correlates of grey matter network integrity loss: a cohort study in autosomal dominant Alzheimer disease.

Brain development and maturation leads to grey matter networks that can be measured using magnetic resonance imaging. Network integrity is an indicator of information processing capacity which declines in neurodegenerative disorders such as Alzheimer disease (AD). The biological mechanisms causing this loss of network integrity remain unknown. Cerebrospinal fluid (CSF) protein biomarkers are available for studying diverse pathological mechanisms in humans and can provide insight into decline. We investigated the relationships between 10 CSF proteins and network integrity in mutation carriers (N=219) and noncarriers (N=136) of the Dominantly Inherited Alzheimer Network Observational study. Abnormalities in Aß, Tau, synaptic (SNAP-25, neurogranin) and neuronal calcium-sensor protein (VILIP-1) preceded grey matter network disruptions by several years, while inflammation related (YKL-40) and axonal injury (NfL) abnormalities co-occurred and correlated with network integrity. This suggests that axonal loss and inflammation play a role in structural grey matter network changes. Key points: Abnormal levels of fluid markers for neuronal damage and inflammatory processes in CSF are associated with grey matter network disruptions.The strongest association was with NfL, suggesting that axonal loss may contribute to disrupted network organization as observed in AD.Tracking biomarker trajectories over the disease course, changes in CSF biomarkers generally precede changes in brain networks by several years.

A data-driven model of brain volume changes in progressive supranuclear palsy.

The most common clinical phenotype of progressive supranuclear palsy is Richardson syndrome, characterized by levodopa unresponsive symmetric parkinsonism, with a vertical supranuclear gaze palsy, early falls and cognitive impairment. There is currently no detailed understanding of the full sequence of disease pathophysiology in progressive supranuclear palsy. Determining the sequence of brain atrophy in progressive supranuclear palsy could provide important insights into the mechanisms of disease progression, as well as guide patient stratification and monitoring for clinical trials. We used a probabilistic event-based model applied to cross-sectional structural MRI scans in a large international cohort, to determine the sequence of brain atrophy in clinically diagnosed progressive supranuclear palsy Richardson syndrome. A total of 341 people with Richardson syndrome (of whom 255 had 12-month follow-up imaging) and 260 controls were included in the study. We used a combination of 12-month follow-up MRI scans, and a validated clinical rating score (progressive supranuclear palsy rating scale) to demonstrate the longitudinal consistency and utility of the event-based model's staging system. The event-based model estimated that the earliest atrophy occurs in the brainstem and subcortical regions followed by progression caudally into the superior cerebellar peduncle and deep cerebellar nuclei, and rostrally to the cortex. The sequence of cortical atrophy progresses in an anterior to posterior direction, beginning in the insula and then the frontal lobe before spreading to the temporal, parietal and finally the occipital lobe. This in vivo ordering accords with the post-mortem neuropathological staging of progressive supranuclear palsy and was robust under cross-validation. Using longitudinal information from 12-month follow-up scans, we demonstrate that subjects consistently move to later stages over this time interval, supporting the validity of the model. In addition, both clinical severity (progressive supranuclear palsy rating scale) and disease duration were significantly correlated with the predicted subject event-based model stage (P < 0.01). Our results provide new insights into the sequence of atrophy progression in progressive supranuclear palsy and offer potential utility to stratify people with this disease on entry into clinical trials based on disease stage, as well as track disease progression.

Not all voxels are created equal: Reducing estimation bias in regional NODDI metrics using tissue-weighted means.

Neurite orientation dispersion and density imaging (NODDI) estimates microstructural properties of brain tissue relating to the organisation and processing capacity of neurites, which are essential elements for neuronal communication. Descriptive statistics of NODDI tissue metrics are commonly analyzed in regions-of-interest (ROI) to identify brain-phenotype associations. Here, the conventional method to calculate the ROI mean weights all voxels equally. However, this produces biased estimates in the presence of CSF partial volume. This study introduces the tissue-weighted mean, which calculates the mean NODDI metric across the tissue within an ROI, utilising the tissue fraction estimate from NODDI to reduce estimation bias. We demonstrate the proposed mean in a study of white matter abnormalities in young onset Alzheimer's disease (YOAD). Results show the conventional mean induces significant bias that correlates with CSF partial volume, primarily affecting periventricular regions and more so in YOAD subjects than in healthy controls. Due to the differential extent of bias between healthy controls and YOAD subjects, the conventional mean under- or over-estimated the effect size for group differences in many ROIs. This demonstrates the importance of using the correct estimation procedure when inferring group differences in studies where the extent of CSF partial volume differs between groups. These findings are robust across different acquisition and processing conditions. Bias persists in ROIs at higher image resolution, as demonstrated using data obtained from the third phase of the Alzheimer's disease neuroimaging initiative (ADNI); and when performing ROI analysis in template space. This suggests that conventional ROI means of NODDI metrics are biased estimates under most contemporary experimental conditions, the correction of which requires the proposed tissue-weighted mean. The tissue-weighted mean produces accurate estimates of ROI means and group differences when ROIs contain voxels with CSF partial volume. In addition to NODDI, the technique can be applied to other multi-compartment models that account for CSF partial volume, such as the free water elimination method. We expect the technique to help generate new insights into normal and abnormal variation in tissue microstructure of regions typically confounded by CSF partial volume, such as those in individuals with larger ventricles due to atrophy associated with neurodegenerative disease.

Obstructive sleep apnoea and Alzheimer's disease: In search of shared pathomechanisms.

Alzheimer's disease (AD) is a significant public health concern. The incidence continues to rise, and it is set to be over one million in the UK by 2025. The processes involved in the pathogenesis of AD have been shown to overlap with those found in cognitive decline in patients with Obstructive Sleep Apnoea (OSA). Currently, the standard treatment for OSA is Continuous Positive Airway Pressure. Adherence to treatment can, however, be an issue, especially in patients with dementia. Also, not all patients respond adequately, necessitating the use of additional treatments. Based on the body of data, we here suggest that excessive and prolonged neuronal activity might contribute to genesis and acceleration of both AD and OSA in the absence of appropriately structured sleep. Further, we argue that external factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain, and further promote disease progression. If this hypothesis is proven in future studies, it could have far-reaching clinical translational implications, as well as implications for future treatment strategies in OSA.

Probabilistic non-linear registration with spatially adaptive regularisation.

This paper introduces a novel method for inferring spatially varying regularisation in non-linear registration. This is achieved through full Bayesian inference on a probabilistic registration model, where the prior on the transformation parameters is parameterised as a weighted mixture of spatially localised components. Such an approach has the advantage of allowing the registration to be more flexibly driven by the data than a traditional globally defined regularisation penalty, such as bending energy. The proposed method adaptively determines the influence of the prior in a local region. The strength of the prior may be reduced in areas where the data better support deformations, or can enforce a stronger constraint in less informative areas. Consequently, the use of such a spatially adaptive prior may reduce unwanted impacts of regularisation on the inferred transformation. This is especially important for applications where the deformation field itself is of interest, such as tensor based morphometry. The proposed approach is demonstrated using synthetic images, and with application to tensor based morphometry analysis of subjects with Alzheimer's disease and healthy controls. The results indicate that using the proposed spatially adaptive prior leads to sparser deformations, which provide better localisation of regional volume change. Additionally, the proposed regularisation model leads to more data driven and localised maps of registration uncertainty. This paper also demonstrates for the first time the use of Bayesian model comparison for selecting different types of regularisation.

Time to surgery and 30-day morbidity and mortality of periprosthetic hip fractures.

BACKGROUND AND AIM: The management of femoral periprosthetic fractures following hip replacement surgery is a complex and challenging situation. Whilst the early complications for both primary hip arthroplasty and proximal femoral fracture surgery have been widely documented, there is a paucity of published data regarding early outcomes following periprosthetic fracture surgery. Delay to surgery for native proximal femoral fractures has been clearly documented as a predictor towards adverse outcome. This study therefore aims to correlate the timing of operative intervention with the complication rate following periprosthetic fracture surgery. In addition, the study aims to identify further factors in the perioperative period that positively predict a poor postoperative outcome. METHODS: Sixty patients who were operatively managed for a femoral implant periprosthetic fracture were identified and each case assessed retrospectively. RESULTS AND CONCLUSION: There was an overall complication rate of 45% including a 30-day mortality of 10%. An abbreviated mental test score of 8 out of 10 or less and a delay to surgery of >72h were found to be significant risk factors for adverse outcome. Both the patient cohort in this study and the predictors for poor postoperative outcome were comparable to those for native proximal femoral fractures.

Molecular analysis of imipenem-resistant Acinetobacter baumannii isolated from US service members wounded in Iraq, 2003-2008.

Global dissemination of imipenem-resistant (IR) clones of Acinetobacter baumannii - A. calcoaceticus complex (ABC) have been frequently reported but the molecular epidemiological features of IR-ABC in military treatment facilities (MTFs) have not been described. We characterized 46 IR-ABC strains from a dataset of 298 ABC isolates collected from US service members hospitalized in different US MTFs domestically and overseas during 2003-2008. All IR strains carried the bla(OXA-51) gene and 40 also carried bla(OXA-23) on plasmids and/or chromosome; one carried bla(OXA-58) and four contained ISAbal located upstream of bla(OXA-51). Strains tended to cluster by pulsed-field gel electrophoresis profiles in time and location. Strains from two major clusters were identified as international clone I by multilocus sequence typing.

The role of tenodesis in surgery of the upper limb.

This paper describes the presence of tenodesis effects in normal physiology and explores the uses of operative tenodesis in surgery of the upper limb.

Methicillin-resistant Staphylococcus aureus infection in combat support hospitals in three regions of Iraq.

SUMMARYStaphylococcus aureus is a leading cause of infections in deployed service members. Based on a molecular epidemiological study of 182 MRSA isolates from patients in three U.S. Army combat support hospitals in separate regions in Iraq, USA300 clone was the most predominant (80%) pulsotype. This finding suggested that strain carriage from the home country by military personnel is epidemiologically more important than local acquisition.

Subthalamic nucleus neurones in slices from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mice show irregular, dopamine-reversible firing pattern changes, but without synchronous activity.

The loss of dopamine in idiopathic or animal models of Parkinson's disease induces synchronized low-frequency oscillatory burst-firing in subthalamic nucleus neurones. We sought to establish whether these firing patterns observed in vivo were preserved in slices taken from dopamine-depleted animals, thus establishing a role for the isolated subthalamic-globus pallidus complex in generating the pathological activity. Mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) showed significant reductions of over 90% in levels of dopamine as measured in striatum by high pressure liquid chromatography. Likewise, significant reductions in tyrosine hydroxylase immunostaining within the striatum (>90%) and tyrosine hydroxylase positive cell numbers (65%) in substantia nigra were observed. Compared with slices from intact mice, neurones in slices from MPTP-lesioned mice fired significantly more slowly (mean rate of 4.2 Hz, cf. 7.2 Hz in control) and more irregularly (mean coefficient of variation of inter-spike interval of 94.4%, cf. 37.9% in control). Application of ionotropic glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 2-amino-5-phosphonopentanoic acid (AP5) and the GABA(A) receptor antagonist picrotoxin caused no change in firing pattern. Bath application of dopamine significantly increased cell firing rate and regularized the pattern of activity in cells from slices from both MPTP-treated and control animals. Although the absolute change was more modest in control slices, the maximum dopamine effect in the two groups was comparable. Indeed, when taking into account the basal firing rate, no differences in the sensitivity to dopamine were observed between these two cohorts. Furthermore, pairs of subthalamic nucleus cells showed no correlated activity in slices from either control (21 pairs) or MPTP-treated animals (20 pairs). These results indicate that the isolated but interconnected subthalamic-globus pallidus network is not itself sufficient to generate the aberrant firing patterns in dopamine-depleted animals. More likely, inputs from other regions, such as the cortex, are needed to generate pathological oscillatory activity.

Sensitivity to urea fertilization in three amphibian species.

Forest fertilization with granular urea is a well-established management practice in many forested regions of the world. We hypothesize that chemical forest fertilizers may be affecting forest-dwelling wildlife. In the laboratory, we studied the effects of fertilization doses of granular urea on three species of forest-dwelling amphibians (Plethodon vehiculum, Rhyacotriton variegatus, and Taricha granulosa). In avoidance experiments, the three species avoided a substrate treated with a dose of 225 kg N/ha urea. In toxicity experiments, we exposed amphibians to urea at doses of 225 kg N/ha and 450 kg N/ha for 4 days. The observed effects increased with time and dose, and there were significant differences in sensitivity among the species. Both treatment levels had an acute effect on survival of P. vehiculum and R. variegatus. At 24 h, mortality at the highest dose was 67% for P. vehiculum, and 47% for R. variegatus. In contrast, there was no mortality for T. granulosa at these concentrations. We suggest that environmental levels of urea could be affecting behavior and survival of some amphibians species in fertilized forests.

Neuroprotective effect of aminoguanidine on transient focal ischaemia in the rat brain.

Using serial magnetic resonance imaging we have evaluated the effectiveness of aminoguanidine (AG) as a neuroprotective agent in a rat model of transient middle cerebral artery occlusion (MCAO). Because aminoguanidine's neuroprotective properties have primarily been ascribed to its action as iNOS inhibitor, we also performed a biochemical analysis of nitric oxide metabolites and NOS isoforms in our model of ischaemia. Daily injections of AG (100 mg/kg) or saline, were started at 6 h after the occlusion and the effects of this treatment on lesion progression monitored by T(2)-weighted MRI at 6 (pre-treatment scan), 24 and 72 h. Measurements of lesion volumes showed that between 6 and 72 h post-MCAO, lesion growth was slower in AG-treated rats than in control rats. This difference was most pronounced between 24 and 72 h post-MCAO when AG halted the lesion volume expansion observed in control rats. Measurements of plasma NOx (nitrite plus nitrate) at 0, 24, 48 and 72 h after MCAO, showed that NO levels did not differ significantly between the AG- and saline-treated groups at any time-point. Moreover, NOS activity assays revealed that no iNOS activity was present in any of the brains tested and that constitutive neuronal NOS activity was similar across the two hemispheres between both groups. The absence of iNOS protein in the ischaemic and contralateral hemispheres at 48 and 72 h after MCAO (control group only) was confirmed by Western blot analysis. These results suggest that AG treatment reduces the rate of growth of ischaemic lesions, perhaps preserving the functioning of perifocal neurons. Our observations contradict suggestions that high levels of NO generated by iNOS are partially responsible for exacerbating the neuronal damage in the postischaemic phase of MCAO. Although this does not rule out a role for AG as a neuroprotective agent via its ability to inhibit iNOS, these findings indicate that neuroprotective actions of AG may also be mediated via other cellular targets.

A CAT-derived one to three session intervention for repeated deliberate self-harm: a description of the model and initial experience of trainee psychiatrists in using it.

We describe a new Cognitive Analytic Therapy (CAT)-based intervention for those who repeatedly self-harm. It is specifically designed to be deliverable by staff with no training in psychotherapy. The intervention is simply manualized into sequential tasks that are mediated by new CAT-style standardized tools. A particular feature of this intervention is the deliberate use of feelings elicited in the therapist ('counter-transference') as (a) a guide to how professional poise is being threatened or lost and (b) an indicator of the appropriate focus for this very brief therapy. The psychiatrists' reflection on their elicited feelings is mediated by a new CAT tool, the 'Assessor's Response File' developed in this project. Audiotape analysis suggested that following a very brief learning period, trainee psychiatrists were able to adhere to the structure of the model and arrive at an appropriate reformulation in the first session but tended to be collusive in reciprocating the patients' dysfunctional coping styles.

Identification of newt connective tissue growth factor as a target of retinoid regulation in limb blastemal cells.

In order to analyse target genes regulated by retinoic acid in urodele limb regeneration, we have used pseudotyped retroviruses to obtain stably transfected newt limb blastemal (progenitor) cells in culture which express chimeric retinoic acid/thyroid hormone receptors delta1 or delta2. After treatment with thyroid hormone to activate the chimeric receptors, we used a polymerase chain reaction (PCR)-based subtraction method to identify target genes which are retinoid regulated. Newt connective tissue growth factor, a secreted protein recognised in several vertebrates, has been identified in this way and found to be expressed in the limb blastema and regulated by retinoic acid. This approach should permit a systematic analysis of retinoid target genes in limb regeneration.

Inhibition of gamma-aminobutyric acid uptake by bicuculline analogues.

Enantiomers of norbicuculline, (+)[1S,9R] and (-)[1R,9S]erythro-1-[1'-(4',5'-methylenedioxyphthalidyl)]-6,7-meth ylenedioxy-1,2,3,4-tetrahydroisoquinoline and of the N-methyl derivatives {(+)[1S,9R] and (-)[1R,9S]bicuculline} were found to inhibit the progress of the gamma-aminobutyric acid transporter-mediated uptake of 40 microM [14C]gamma-aminobutyric acid into native plasma membrane vesicles from the rat cerebral cortex at 30 degrees C. The values for the dissociation constants of the reversible inhibition, relative to (+)[1S,9R]bicuculline, in order of increasing inhibition, were: (-)[1R,9S]bicuculline, 3.3; (+)[1S,9R]-bicuculline, 1.0; (-)[1R,9S]norbicuculline, 0.4 approximately (+)[1S,9R]norbicuculline; guvacine, 0.02. The norbicucullines have higher potencies than (+)[1S,9R]bicuculline for the gamma-aminobutyric acid transporter, in contrast to the relative potencies of these inhibitors for the inhibition of function and gamma-aminobutyric acid binding of the gamma-aminobutyric acid type A receptor.

Desensitization of a gamma-aminobutyric acid type A receptor in rat is increased by chronic treatment with chlordiazepoxide: a molecular mechanism of dependence.

When rats were made tolerant to the benzodiazepine tranquilizer chlordiazepoxide (CDPX) by its steady administration, a particular gamma-aminobutyric acid type A (GABAA) receptor in cerebral cortex was modified. Its rate of desensitization in the absence of CDPX was enhanced (3-fold with 10 microM GABA) below saturation with GABA, and the dependence of this rate on GABA concentration was changed from sigmoid to hyperbolic. This mimicked the effect of the presence of CDPX on desensitization of the naive receptor. This receptor has been characterized by its rapid desensitization (t1/2 = 30 msec at saturation). In contrast, a different, slower desensitizing GABAA receptor, on the same membrane, was unaffected, and the initial transmembrane halide exchange rate of the faster desensitizing receptor was unaltered. In the presence of CDPX, the initial halide exchange rate of the modified receptor was enhanced, but the already enhanced desensitization rate was not altered. During chronic presence of CDPX and the development of tolerance, the total signal due to this receptor remained constant at the value before exposure. After discontinuation, the total signal decreased but could be restored to the original value by the presence of CDPX. It was postulated that dependence and withdrawal syndromes result from a decreased ratio of initial chloride flux rate to desensitization rate, caused by an increase in desensitization. The contribution of this effect in vivo would depend on desensitization making a contribution to signal termination [or the fraction of receptors that are inactive (desensitized)]. In the quench flow experiments, the total signal due to this receptor from naive rat did not depend much on GABA concentration or the presence of CDPX because the result of increased channel opening was counterbalanced by increased desensitization. In contrast, the total signal of this receptor from tolerant rat was significantly increased by CDPX or increased GABA concentration. Differences between these experiments and measurements reported with other drugs could be explained if, in those experiments, the halide exchange rate, as well as its desensitization rate, retained an enhanced value in the absence of the drug.

Retinoic acid receptor alpha function in vertebrate limb skeletogenesis: a modulator of chondrogenesis.

Retinoic acid is a signaling molecule involved in the regulation of growth and morphogenesis during development. There are three types of nuclear receptors for all-trans retinoic acid in mammals, RAR alpha, RAR beta, and RAR gamma, which transduce the retinoic acid signal by inducing or repressing the transcription of target genes (Leid, M., P. Kastner, and P. Chambon. 1992. Trends Biochem. Sci. 17:427-433). While RAR alpha, RAR beta, and RAR gamma are expressed in distinct but overlapping patterns in the developing mouse limb, their exact role in limb development remains unclear. To better understand the role of retinoic acid receptors in mammalian limb development, we have ectopically expressed a modified RAR alpha with constitutive activity (Balkan, W., G.K. Klintworth, C.B. Bock, and E. Linney. 1992. Dev. Biol. 151:622-625) in the limbs of transgenic mice. Overexpression of the transgene was associated with marked pre- and postaxial limb defects, particularly in the hind limb, where expression of the transgene was consistently seen across the whole anteroposterior axis. The defects displayed in these mice recapitulate, to a large degree, many of the congenital limb malformations observed in the fetuses of dams administered high doses of retinoic acid (Kochhar, D.M. 1973. Teratology. 7:289-295). Further analysis of these transgenic animals showed that the defect in skeletogenesis resided at the level of chondrogenesis. Comparison of the expression of the transgene relative to that of endogenous RAR alpha revealed that downregulation of RAR alpha is important in allowing the chondrogenic phenotype to be expressed. These results demonstrate a specific function for RARalpha in limb development and the regulation of chondroblast differentiation.