Do current therapeutic anti-Aβ antibodies for Alzheimer’s disease engage the target?

Reducing amyloid-β peptide (Aβ) burden at the pre-symptomatic stages of Alzheimer’s disease (AD) is currently the advocated clinical strategy for treating this disease. The most developed method for targeting Aβ is the use of monoclonal antibodies including bapineuzumab, solanezumab and crenezumab. We have synthesized these antibodies and used surface plasmon resonance (SPR) and mass spectrometry to characterize and compare the ability of these antibodies to target Aβ in transgenic mouse tissue as well as human AD tissue. SPR analysis showed that the antibodies were able to bind Aβ with high affinity. All of the antibodies were able to bind Aβ in mouse tissue. However, significant differences were observed in human brain tissue. While bapineuzumab was able to capture a variety of N-terminally truncated Aβ species, the Aβ detected using solanezumab was barely above detection limits while crenezumab did not detect any Aβ. None of the antibodies were able to detect any Aβ species in human blood. Immunoprecipitation experiments using plasma from AD subjects showed that both solanezumab and crenezumab have extensive cross-reactivity with non-Aβ related proteins. Bapineuzumab demonstrated target engagement with brain Aβ, consistent with published clinical data. Solanezumab and crenezumab did not, most likely as a result of a lack of specificity due to cross-reactivity with other proteins containing epitope overlap. This lack of target engagement raises questions as to whether solanezumab and crenezumab are suitable drug candidates for the preventative clinical trials for AD.     

“I Just Have to Stick with It and It’ll Work”: Experiences of Adolescents and Young Adults with Mental Health Concerns

Mental health issues are common among adolescents and young adults but service utilization in this group is low. This study aimed to better understand the experiences of older adolescents and young adults who were experiencing symptoms of depression or anxiety, including the factors that affected their decision to seek treatment and their feelings about their experience of mental health issues. We conducted semi-structured interviews with 37 older adolescents and young adults. Participants tended to have a sophisticated understanding of the causes of mental disorders, but to have been unsure about whether their own experiences of depression or anxiety were the result of a mental disorder, or just “normal” experiences. They reported concerns about taking medication and about keeping information about their condition private. They also felt that it was important to them to be active participants in their own care.     

Antimicrobial treatment options for neurosurgical ventricular shunt infections in children from 1993 to 2012: a systematic review

Purpose

The aim of this systematic review was to review studies that existed from 1993 to 2012 regarding antimicrobial treatment options of paediatric neurosurgical shunt.

Methods

Studies were identified from MEDLINE, Scopus and Cochrane databases using a search strategy that was registered on the PROSPERO database. Studies were included if they had two or more patients, aged less than 18 years, and also specified the organism and antimicrobial treatment that was used.

Results

The search yielded 2,985 articles, and 76 articles were suitable for full review. In the final qualitative analysis, only eight studies were included, involving 86 participants. The most common antimicrobial regimens for Gram-positive infections was intravenous and intrathecal vancomycin (n?=?7), followed by intravenous vancomycin monotherapy.

Conclusion

This systematic review has shown that there are no prospective randomised studies of antimicrobial treatment options for paediatric neurosurgical patients in the last 20 years, and larger prospective studies are urgently required for this serious infection. There is some limited case series showing the benefits of certain antimicrobials such as vancomycin and ceftriaxone, but a larger case series or randomised controlled trial is required, particularly to establish the benefit, if any, of additional intraventricular antimicrobials.     

The cholinergic basal forebrain in the ferret and its inputs to the auditory cortex

Cholinergic inputs to the auditory cortex can modulate sensory processing and regulate stimulus‐specific plasticity according to the behavioural state of the subject. In order to understand how acetylcholine achieves this, it is essential to elucidate the circuitry by which cholinergic inputs influence the cortex. In this study, we described the distribution of cholinergic neurons in the basal forebrain and their inputs to the auditory cortex of the ferret, a species used increasingly in studies of auditory learning and plasticity. Cholinergic neurons in the basal forebrain, visualized by choline acetyltransferase and p75 neurotrophin receptor immunocytochemistry, were distributed through the medial septum, diagonal band of Broca, and nucleus basalis magnocellularis. Epipial tracer deposits and injections of the immunotoxin ME20.4‐SAP (monoclonal antibody specific for the p75 neurotrophin receptor conjugated to saporin) in the auditory cortex showed that cholinergic inputs originate almost exclusively in the ipsilateral nucleus basalis. Moreover, tracer injections in the nucleus basalis revealed a pattern of labelled fibres and terminal fields that resembled acetylcholinesterase fibre staining in the auditory cortex, with the heaviest labelling in layers II/III and in the infragranular layers. Labelled fibres with small en‐passant varicosities and simple terminal swellings were observed throughout all auditory cortical regions. The widespread distribution of cholinergic inputs from the nucleus basalis to both primary and higher level areas of the auditory cortex suggests that acetylcholine is likely to be involved in modulating many aspects of auditory processing.     

Comparing perceived public stigma and personal stigma of mental health treatment seeking in a young adult sample

Perceived public stigma regarding seeking mental health treatment can be a barrier to accessing services for young adults. While factors associating with personal stigma regarding how one would view and treat others have been identified, the discrepancies between perceived and personal stigma have received less research attention. We designed the current study to expand on previous research and examine the discrepancies between perceived public stigma and personal stigma among a sample of 386 primarily White and Asian college students. Participants completed surveys of mental health symptoms, treatment experience and attitudes, perceived public, and personal stigma. Overall, participants generally reported greater perceived public stigma than personal stigma; an effect that was particularly evident for women and those with mental health symptoms. The majority of participants disagreed with items assessing personal stigma. Negative attitudes toward treatment and anxiety symptoms associated with perceived public stigma, while male gender, Asian ethnicity, and negative attitudes toward treatment associated with personal stigma. Findings have implications for interventions and marketing programs to help change perceptions about mental health stigma to encourage utilization of services for those young people who could benefit from care.