The stress granule response in wild-type and ALS-mutant neurons

Stress granules (SGs) are cytoplasmic ribonucleoprotein aggregates which form in response to cellular stress and disassemble following stress cessation. Mutations in human SG proteins cause the neurodegenerative disease amyotrophic lateral sclerosis (ALS) and have been demonstrated to alter granule dynamics. Further, SGs have a compositional protein overlap with the post-mortem cytoplasmic inclusions that characterise ALS, suggesting that SGs may act as a precursor to, or seed, these inclusions. For this thesis, I first optimised the use of different SG inducers in mouse primary fibroblast and neuronal cultures. Following this, I cultured primary neurons in compartmentalised devices, applying the oxidative stressor sodium arsenite to either the somal or axonal compartment, to investigate the kinetics of SG formation. I observed a delayed SG assembly response in neuronal somas when arsenite was applied axonally, for both cortical and sensory neurons. This response is decreased by inhibition of dynein or protein translation in the axonal compartment. Further, I investigated the effect of ALS-causing mutations on the SG response, using a novel FUS-mutant mouse model. This model expresses a humanised Cterminal disease-causing mutation that results in a frameshifted amino acid sequence downstream of the mutation, eradicating the nuclear localisation signal of the FUS protein. This frameshift sequence allowed for the generation of antibodies able to distinguish between wild-type and mutant FUS. Using these antibodies, I observed that the normally predominately nuclear FUS protein mislocalised to the cytoplasm in neurons heterozygous and homozygous for the mutation. Additionally, I demonstrated that the mutant protein is present in SGs at a higher level than the wild-type protein. Finally, I optimised a method for sorting neuronal somas following labelling with fluorescently-tagged retrograde toxin subunits. These results demonstrate the ability of neuronal axons to respond to exogeneous oxidative stressors and highlight the importance of the SG response in ALS-mutant cell

Learning to predict is spared in mild cognitive impairment due to Alzheimer's disease.

Learning the statistics of the environment is critical for predicting upcoming events. However, little is known about how we translate previous knowledge about scene regularities to sensory predictions. Here, we ask whether patients with mild cognitive impairment due to Alzheimer's disease (MCI-AD) that are known to have spared implicit but impaired explicit recognition memory are able to learn temporal regularities and predict upcoming events. We tested the ability of MCI-AD patients and age-matched controls to predict the orientation of a test stimulus following exposure to sequences of leftwards or rightwards oriented gratings. Our results demonstrate that exposure to temporal sequences without feedback facilitates the ability to predict an upcoming stimulus in both MCI-AD patients and controls. Further, we show that executive cognitive control may account for individual variability in predictive learning. That is, we observed significant positive correlations of performance in attentional and working memory tasks with post-training performance in the prediction task. Taken together, these results suggest a mediating role of circuits involved in cognitive control (i.e. frontal circuits) that may support the ability for predictive learning in MCI-AD.This work was supported by grants to PB from Birmingham and Solihull Mental Health Foundation Trust Research and Development, and to ZK from the Leverhulme Trust [RF-2011-378] and the [European Community's] Seventh Framework Programme [FP7/2007-2013] under agreement PITN-GA-2011-290011.This is the author accepted manuscript. The final version is available at http://link.springer.com/article/10.1007%2Fs00221-015-4356-z

Learning temporal statistics for sensory predictions in mild cognitive impairment.

Training is known to improve performance in a variety of perceptual and cognitive skills. However, there is accumulating evidence that mere exposure (i.e. without supervised training) to regularities (i.e. patterns that co-occur in the environment) facilitates our ability to learn contingencies that allow us to interpret the current scene and make predictions about future events. Recent neuroimaging studies have implicated fronto-striatal and medial temporal lobe brain regions in the learning of spatial and temporal statistics. Here, we ask whether patients with mild cognitive impairment due to Alzheimer's disease (MCI-AD) that are characterized by hippocampal dysfunction are able to learn temporal regularities and predict upcoming events. We tested the ability of MCI-AD patients and age-matched controls to predict the orientation of a test stimulus following exposure to sequences of leftwards or rightwards orientated gratings. Our results demonstrate that exposure to temporal sequences without feedback facilitates the ability to predict an upcoming stimulus in both MCI-AD patients and controls. However, our fMRI results demonstrate that MCI-AD patients recruit an alternate circuit to hippocampus to succeed in learning of predictive structures. In particular, we observed stronger learning-dependent activations for structured sequences in frontal, subcortical and cerebellar regions for patients compared to age-matched controls. Thus, our findings suggest a cortico-striatal-cerebellar network that may mediate the ability for predictive learning despite hippocampal dysfunction in MCI-AD.This work was supported by grants to PB from Birmingham and Solihull Mental Health Foundation Trust Research and Development, and to ZK from the Leverhulme Trust [RF-2011-378] and the [European Community's] Seventh Framework Programme [FP7/2007-2013] under agreement PITN-GA-2011-290011.This is the accepted manuscript. The final version is available at http://www.sciencedirect.com/science/article/pii/S0028393215300506

Tau Aggregation Inhibitor Therapy : An Exploratory Phase 2 Study in Mild or Moderate Alzheimer's Disease

ACKNOWLEDGMENTS We thank patients and their caregivers for their participation in the study and are indebted to all the investigators involved in the study, particularly Drs. Douglas Fowlie and Donald Mowat for their helpful contributions to the clinical execution of the study in Scotland. We thank Sharon Eastwood, Parexel, for assistance in preparing initial drafts of the manuscript. We acknowledge constructive comments provided by Professors G. Wilcock and S. Gauthier on drafts of the article. CMW, CRH, and JMDS are officers of, and hold beneficial interests in, TauRx Therapeutics. RTS, PB, KK, and DJW are paid consultants to TauRx Therapeutics. The study was financed entirely by TauRx TherapeuticsPeer reviewedPublisher PD

Long-term hydromethylthionine treatment is associated with delayed clinical onset and slowing of cerebral atrophy in a pre-symptomatic P301S MAPT mutation carrier

ACKNOWLEDGMENTS We thank the patient for permitting publication of the present report. Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/21-0390r1).Peer reviewedPublisher PD

Minocycline 200 mg or 400 mg versus placebo for mild Alzheimer's disease: the MADE Phase II, three-arm RCT

Background: Minocycline is an anti-inflammatory drug and protects against the toxic effects of β-amyloid in vitro and in animal models of Alzheimer’s disease. To the best of our knowledge, no randomised placebo-controlled clinical trials in patients with Alzheimer’s disease looking at the efficacy and tolerability of minocycline have been carried out. Objectives: The trial investigated whether or not minocycline was superior to placebo in slowing down the rate of decline in cognitive and functional ability over 2 years. The safety and tolerability of minocycline were also assessed. Design: A Phase II, three-arm, randomised, double-blind, multicentre trial with a semifactorial design. Participants continued on trial treatment for up to 24 months. Setting: Patients were identified from memory services, both within the 32 participating NHS trusts and within the network of memory services supported by the Dementias and Neurodegenerative Diseases Research Network (also known as DeNDRoN). Participants: Patients with standardised Mini Mental State Examination scores of > 23 points and with Alzheimer’s disease assessed by the National Institute on Aging–Alzheimer’s Association’s criteria were identified from memory services. Intervention: Patients with mild Alzheimer’s disease were randomly allocated 1 : 1 : 1 to receive one of three treatments: arm 1 – 400 mg per day of minocycline; arm 2 – 200 mg per day of minocycline; or arm 3 – placebo. Patients continued treatment for 24 months. Participants, investigators and outcome assessors were blind to treatment allocation. Main outcome measures: Primary outcome measures were decline in standardised Mini Mental State Examination and Bristol Activities of Daily Living Scale scores of combined minocycline treatment arms versus placebo, as analysed by intention-to-treat repeated measures regression. Results: Between 23 May 2014 and 14 April 2016, 554 participants were randomised. Of the 544 eligible participants, the mean age was 74.3 years and the average standardised Mini Mental State Examination score was 26.4 points. A total of 252 serious adverse events were reported, with the most common categories being neuropsychiatric and cardiocirculatory. Significantly fewer participants completed treatment with 400 mg of minocycline [29% (53/184)] than 200 mg [62% (112/181)] or placebo [64% (114/179)] (p < 0.0001), mainly because of gastrointestinal symptoms (p = 0.0008), dermatological side effects (p = 0.02) and dizziness (p = 0.01). Assessment rates were also lower in the 400-mg treatment arm: 68% (119 of 174 expected) for standardised Mini Mental State Examination scores at 24 months, compared with 82% (144/176) for the 200-mg treatment arm and 84% (140/167) for the placebo arm. Decline in standardised Mini Mental State Examination scores over the 24-month study period in the combined minocycline arms was similar to that in the placebo arm (4.1- vs. 4.3-point reduction; p = 0.9), as was the decline in the 400- and 200-mg treatment arms (3.3 vs. 4.7 points; p = 0.08). Likewise, worsening of Bristol Activities of Daily Living Scale scores over 24 months was similar in all trial arms (5.7, 6.6 and 6.2 points in the 400-mg treatment arm, 200-mg treatment arm and placebo arm, respectively; a p-value of 0.57 for minocycline vs. placebo and a p-value of 0.77 for 400 vs. 200 mg of minocycline). Results were similar in different patient subgroups and in sensitivity analyses adjusting for missing data. Limitations: Potential limitations of the study include that biomarkers were not used to confirm the diagnosis of Alzheimer’s disease, as these and apolipoprotein E (APOE) genotyping are not routinely available within the NHS. Compliance was also worse than expected and differential follow-up rates were observed, with fewer assessments obtained for the 400-mg treatment arm than for the 200-mg treatment and placebo arms. Conclusions: Minocycline does not delay the progress of cognitive or functional impairment in people with mild Alzheimer’s disease over a 2-year period. Minocycline at a dose of 400 mg is poorly tolerated in this population. Future work: The Minocycline in mild Alzheimer’s DiseasE (MADE) study provides a framework for a streamlined trial design that can be usefully applied to test other disease-modifying therapies

Degeneration of basal and limbic networks is a core feature of behavioural variant frontotemporal dementia

Acknowledgment We would like to acknowledge the support of the Maxwell Computer Cluster funded by the University of Aberdeen. We also gratefully acknowledge study investigators and the generosity of study participants. Funding This study was sponsored entirely by TauRx Therapeutics Ltd (PAR1577). The Maxwell Computer Cluster is funded by the University of Aberdeen.Peer reviewedPublisher PD

A qualitative study investigating training requirements of nurses working with people with dementia in nursing homes

Background: The care home workforce (over half a million people in the UK) has a pivotal role in the quality of care provided to the residents. Much care in this setting is inadequate, lacks a person-centred focus and neglects the dignity of residents. A combination of factors leads to burnout in nurses working in nursing homes, contributing to poor quality care. Recent reports have indicated that cultures of care need to be addressed through training, improved workforce support and supervision and that improving the quality of care for people with dementia can be achieved by the development of leadership in nursing and clarifying professional values. Addressing burnout through an educational intervention should improve quality of care and nurses’ experiences. Objectives: The study aimed to explore the training needs of nurses working with people with dementia in nursing homes with a view to developing an educational intervention to reduce nurses’ burnout and improve person-centred care. Design: Four focus groups were conducted with 11 qualified nurses working in nursing homes; data was analysed using thematic analysis. Results: Four themes emerged through the analysis of the transcripts. Participants reported that their work responsibilities revolved mainly around directing others, day to day care, paper work and supporting family carers. Nurses identified the importance of person-centred ways of being, communication and clinical skills when working in nursing home setting. They expressed their frustrations associated with managing staff levels, responding to behaviour that challenges and lack of time. Conclusions: The barriers to learning, experience of previous training and gaps in knowledge identified could inform the design of future training and support programmes

Cost-effectiveness analyses for mirtazapine and sertraline in dementia: randomised controlled trial

BACKGROUND Depression is a common and costly comorbidity in dementia. There are very few data on the cost-effectiveness of antidepressants for depression in dementia and their effects on carer outcomes. AIMS To evaluate the cost-effectiveness of sertraline and mirtazapine compared with placebo for depression in dementia. METHOD A pragmatic, multicentre, randomised placebo-controlled trial with a parallel cost-effectiveness analysis (trial registration: ISRCTN88882979 and EudraCT 2006-000105-38). The primary cost-effectiveness analysis compared differences in treatment costs for patients receiving sertraline, mirtazapine or placebo with differences in effectiveness measured by the primary outcome, total Cornell Scale for Depression in Dementia (CSDD) score, over two time periods: 0-13 weeks and 0-39 weeks. The secondary evaluation was a cost-utility analysis using quality-adjusted life years (QALYs) computed from the Euro-Qual (EQ-5D) and societal weights over those same periods. RESULTS There were 339 participants randomised and 326 with costs data (111 placebo, 107 sertraline, 108 mirtazapine). For the primary outcome, decrease in depression, mirtazapine and sertraline were not cost-effective compared with placebo. However, examining secondary outcomes, the time spent by unpaid carers caring for participants in the mirtazapine group was almost half that for patients receiving placebo (6.74 v. 12.27 hours per week) or sertraline (6.74 v. 12.32 hours per week). Informal care costs over 39 weeks were £1510 and £1522 less for the mirtazapine group compared with placebo and sertraline respectively. CONCLUSIONS In terms of reducing depression, mirtazapine and sertraline were not cost-effective for treating depression in dementia. However, mirtazapine does appear likely to have been cost-effective if costing includes the impact on unpaid carers and with quality of life included in the outcome. Unpaid (family) carer costs were lower with mirtazapine than sertraline or placebo. This may have been mediated via the putative ability of mirtazapine to ameliorate sleep disturbances and anxiety. Given the priority and the potential value of supporting family carers of people with dementia, further research is warranted to investigate the potential of mirtazapine to help with behavioural and psychological symptoms in dementia and in supporting carers