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The term “Primary age-related tauopathy” (PART) was coined in 2014 to describe the common neuropathological observation of neurofibrillary tangles without associated beta-amyloid (Aβ) pathology. It is possible for PART pathology to be present in both cognitively normal and cognitively impaired individuals. Genetically, Apolipoprotein E (APOE) ε4 has been shown to occur less commonly in PART than in Alzheimer’s disease (AD). Here, we investigate the relationships between PART, AD and those pathologically normal for age, with an emphasis on APOE and cognition, using 152 selected participants from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age and the Manchester arm of the Brains for Dementia Research cohort. APOE genotype differed between PART and AD with APOE ε2 more common in the former and APOE ε4 more common in the latter. Individuals with definite PART were less likely to be cognitively impaired than those with AD and those with pathology considered pathologically normal for age. We postulate that the lack of Aβ in definite PART cases may be due either to an increased frequency of APOE ε2 or decreased frequency of APOE ε4 as their resulting protein isoforms have differing binding properties in relation to Aβ. Similarly, an increased frequency of APOE ε2 or decreased frequency of APOE ε4 may lead to decreased levels of cognitive impairment, which raises questions regarding the impact of Aβ pathology on overall cognition in elderly subjects. We suggest that it may be possible to use the increased frequency of APOE ε2 in definite PART to assist neuropathological diagnosis.

Fragile X‐associated tremor ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a CGG trinucleotide expansion from 55 to 200 repeats in the non‐coding region of the fragile X mental retardation 1 (FMR1) gene (FMR1). Clinical features include cognitive decline, progressive tremor, and gait ataxia. Neuropathologically, FXTAS shows white matter changes, hippocampal and cerebellar involvement, and p62‐positive eosinophilic intranuclear inclusions in astrocytes and neurons. Here, we document the neuropathological findings from a subject who developed cognitive impairment but not tremor and was proved to have genetically confirmed FMR1 premutation. Microscopically, typical p62‐postive intranuclear inclusions were present in all the regions examined. Neocortical regions demonstrated gliosis of layer I and mild degree of neuronal loss and atrophy across the other layers. The molecular, Purkinje's cell, and granule cell layers of the cerebellar folia demonstrated mild gliosis, and cerebellar white matter was mildly affected. Aside from p62‐positive inclusions, the hippocampus was spared. Arteries in the deep white matter often showed changes consistent with moderate small vessel disease (SVD). Reactive gliosis and severe SVD were features of basal ganglia. Florid reactive astrocytosis was found in the white matter of all regions. Axonal loss and features of axonal damage were found in the white matter of the centrum semiovale. Microglial activation was widespread and evenly seen in both the white matter and grey matter, although the grey matter appeared more severely affected. Pathology associated with Alzheimer's disease was limited. Similarly, no abnormal accumulations of α‐synuclein were present. We postulate that age at death and disease duration may play a role in the extent of the pathological features associated with FXTAS. The present results suggest that immunohistochemical staining for p62 can help with the diagnosis of cases with atypical phenotype. In addition, it is likely that the cognitive impairment observed was a result of white matter changes.

Background: Early diagnosis of Alzheimer’s disease (AD) provides an opportunity for early intervention. Cognitive testing has proven to be a reliable way to identify individuals who may be at risk of AD. The Telephone Assessment for Cognitive Screening (TICS) is proficient in screening for cognitive impairment. However, its ability to identify those at risk of developing AD pathology is unknown. Objective: We aim to investigate associations between TICS scores, collected over a period of 13 years, and the cognitive status of participants at death. We also examine relationships between TICS scores and neuropathological indices of AD (CERAD score, Thal phase, and Braak stage). Methods: Between 2004 and 2017, participants from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age underwent cognitive assessment using TICS. Scores from four time points were available for analysis. Cognitive impairment and AD pathology at death was evaluated in 101 participants. Results: TICS scores at time points 2, 3, and 4 were significantly lower in those cognitively impaired at death compared to those considered cognitively normal. There were significant negative correlations between TICS scores and CERAD score and Braak stage at time points 2 and 4. No correlations between Thal phase and TICS were found. Conclusion: Findings indicate that TICS could be used not only to screen for cognitive impairment, but also to identify individuals at risk of developing AD pathology, many years before any overt symptoms occur. Once identified, ‘at risk’ individuals could be targeted for early interventions which could attenuate the progression of the disease.

The observation of neurofibrillary tangles (NFTs) without associated amyloid-beta (Aβ) in the brains of cognitively normal and cognitively impaired elderly individuals has, for many years, been a source of discussion and controversy. The term "primary age-related tauopathy" (PART) was introduced in 2014 and consensus guidelines for the condition were published [1]. The clinical manifestations of PART have been described (see [2] for review). A recent molecular imaging study suggested that mesial temporal tau load is associated with a decline in cognitive performance in those with no Aβ pathology [3].

Blockade of PD-1/PD-L1 interactions is proving an exciting, durable therapeutic modality in a range of cancers whereby T cells are released from checkpoint inhibition to revive their inherent anti-tumour activity. Here we have studied various ways to model ex vivo T cell function in order to compare the impact of the clinically utilised anti-PD-1 antibody, pembrolizumab (Keytruda) on the activation of human T cells: focussing on the release of pro-inflammatory IFNγ and anti-inflammatory IL-10 to assess functionality. Firstly, we investigated the actions of pembrolizumab in an acute model of T-cell activation with either immature or mature allogeneic dendritic cells (DCs); pembrolizumab enhanced IFNγ and IL-10 release from purified CD4+ T-cells in the majority of donors with a bias towards pro-inflammatory cytokine release. Next, we modelled the impact of pembrolizumab in settings of more chronic T-cell activation. In a 7-day antigen-specific response to EBV peptides, the presence of pembrolizumab resulted in a relatively modest increase in both IFNγ and IL-10 release. Where pembrolizumab was assessed against long-term stimulated CD4+ cells that had up-regulated the exhaustion markers TIM-3 and PD-1, there was a highly effective enhancement of the otherwise exhausted response to allogeneic DCs with respect to IFNγ production. By contrast, the restoration of IL-10 production was considerably more limited. Finally, to assess a direct clinical relevance we investigated the consequence of PD-1/PD-L1 blockade in the disease setting of dissociated cells from lung and colon carcinomas responding to allogeneic DCs: here, pembrolizumab once more enhanced IFNγ production from the majority of tumour preparations whereas, again, the increase in IL-10 release was modest at best. In conclusion, we have shown that the contribution of PD-1—revealed by using a canonical blocking antibody to interrupt its interaction with PD-L1—to the production of an exemplar pro- and anti-inflammatory cytokine, respectively, depends in magnitude and ratio on the particular stimulation setting and activation status of the target T cell. We have identified a number of in vitro assays with response profiles that mimic features of dissociated cell populations from primary tumours thereby indicating these represent disease-relevant functional assays for the screening of immune checkpoint inhibitors in current and future development. Such in vitro assays may also support patient stratification of those likely to respond to immuno-oncology therapies in the wider population.

Objectives: Early diagnosis of Alzheimer's disease (AD) is essential for early interventions. Symptoms of depression could represent a prodromal stage of AD. Very early mood alterations may help stratify those at highest risk of late-life AD. We aim to investigate associations between baseline/longitudinal scores for depression, presence of cognitive impairment and/or AD pathology at death.Methods/Design: Between 1991 and 2015, participants from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age underwent 10 waves of assessment using the Geriatric Depression Scale (GDS). AD pathology at death was evaluated in 106 eligible cases. Analyses aimed to examine associations between GDS scores, cognitive status and AD pathology (as measured by Braak stage, Thal phase and CERAD).Results: Baseline GDS scores were significantly higher for those cognitively impaired at death than those cognitively normal. Significantly higher baseline GDS scores were found for those with greater CERAD scores than those with lower CERAD scores. Similarly, significantly higher baseline GDS scores were found for those with a greater Braak stage than those with lower tau burden. These correlations remained after controlling for age at death, education and APOE ε4, but were less robust. Mean longitudinal GDS scores associated with cognition but not pathology.Conclusions: GDS scores collected approximately 20 years before death were associated with cognitive status and AD pathology at death. We postulate that early AD-related pathological change produces raised GDS scores due to an overlapping neural basis with depression, and that this may be considered as an early diagnostic marker for AD. This article is protected by copyright. All rights reserved.

Background:An early symptom of Alzheimer’s disease (AD) is a disturbance of the circadian rhythm that is associated with disrupted sleep/wake cycles.Objective:To investigate if BMAL1, a key gene that drives the circadian cycle, is epigenetically regulated in brains in relation to longitudinal changes in cognition, sleep quality, and AD neuropathology.Methods:Frontal cortex tissues were acquired from the Manchester Brain Bank (N = 96). DNA methylation at six CpG sites at the promoter of BMAL1, determined using bisulfite pyrosequencing, was tested for associations with Braak stage, CERAD score, and Thal phase, longitudinal changes in cognition, sleep measurements, and cross-section measures of depressive symptoms (BDI score).Results:Methylation across all the CpGs strongly correlated with each other. We found increased CpG2 methylation with higher Braak (t(92) = 2.47, p = 0.015) and CERAD (t(94) = 2.04, p = 0.044) stages. No significance was found between longitudinal fluid intelligence, processing speed, and memory tests, but methylation at CpG1 (r = 0.20, p = 0.05) and CpG4 (r = 0.20, p = 0.05) positively correlated with vocabulary. CpG2 positively correlated with cross-sectional fluid intelligence (r = 0.20 p = 0.05) and vocabulary (r = 0.22 p = 0.03). Though longitudinal analysis revealed no significance between sleep duration, midsleep, and efficiency for any of the CpG sites, CpG3 (B = 0.03, 95% CI = 0.00/0.06, p = 0.03) and CpG5 (B = 0.04, 95% CI = 0.01,0.07, p = 0.01) significantly correlated with night wake. CpG4 correlated with depressive symptoms (B = –0.27, 95% CI=0.49/–0.05, p = 0.02).Conclusion:Methylation of BMAL1 associated with tau pathology, changes in cognitive measures, a measure of sleep and depressive symptoms, suggesting an involvement of the circadian cycle.

BACKGROUND: The pathological features of Alzheimer's disease (AD) are well described but little is known as to how both neurodegeneration and vascular changes might interact in causing cognitive impairment.OBJECTIVE: The present study aims to investigate relationships between vascular and AD pathology in cognitively healthy and cognitively impaired individuals with a particular emphasis on those at intermediate Braak tau stages.METHODS: We investigated the interplay between Braak tau stage and measures of vascular pathology as described by the vascular cognitive impairment neuropathology guidelines (VCING) in 185 brains from the Brains for Dementia Research programme and The University of Manchester Longitudinal Study of Cognition in Healthy Old Age. VCING asserts that at least one large (>10 mm) infarct, moderate/severe occipital leptomeningeal cerebral amyloid angiopathy, and moderate/severe arteriosclerosis in occipital white matter accurately predicts the contribution of cerebrovascular pathology to cognitive impairment.RESULTS: We found that the extent of arteriosclerosis in the occipital white matter did not differ between cognitive groups at intermediate (III-IV) Braak stages whereas moderate/severe leptomeningeal occipital cerebral amyloid angiopathy was greater in cognitively impaired than normal individuals at Braak stage III-IV. This finding remained significant after controlling for effects of age, sex, CERAD score, Thal phase, presence/severity of primary age-related tauopathy, presence/severity of limbic-predominant age-related TDP43 encephalopathy and small vessel disease in basal ganglia.CONCLUSION: Interventions targeting cerebral amyloid angiopathy may contribute to delay the onset of cognitive impairment in individuals with intermediate Alzheimer's type pathology.

While many studies have examined the associations between APOE genotype and mortality, findings have oftenbeen conflicting and it remains unclear whether APOE genotype affects longevity. Using selected individuals from theManchester arm of the Brains for Dementia Research programme and University of Manchester Longitudinal Study ofCognition in Normal Healthy Old Age, we investigated relationships between APOE genotype and age at death in bothcognitively normal and cognitively impaired individuals. Results indicated that carrying the APOE 4 allele led to a reducedchance in an individual reaching 80+ years and remaining cognitively healthy. Conversely, APOE 2 carriers tended to livelonger and remain cognitively normal. These findings add to the evidence that APOE genotype influences longevity, especiallyin cognitively impaired individuals who carry the APOE 4 allele.

In the present study we have characterised and compared individuals whose brains were donated as part of The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age (UoM) with those donated through the Manchester arm of the UK Brains for Dementia Research (BDR) programme. The aim of this study was to investigate how differences in study recruitment may affect final pathological composition of cohort studies.UoM cohort was established as a longitudinal study of ageing and cognition whereas the BDR programme was established, prima facie, to collect brains from both demented and non-demented individuals for the purpose of building a tissue research resource. Consequently, the differences in recruitment patterns generated differences in demographic, clinical and neuropathological characteristics. There was a higher proportion of recruits with dementia (mostly Alzheimer’s disease (AD)) within the BDR cohort than in UoM cohort. In pathological terms, the BDR cohort was more ‘polarised’, being more composed of demented cases with high Braak pathology scores and non-demented cases with low Braak scores, and fewer non-AD pathology cases, than UoM cohort. In both cohorts, cerebral amyloid angiopathy (CAA) tended to be greater in demented than non-demented individuals. Such observations partly reflect the recruitment of demented and non-demented individuals into the BDR cohort, and also that insufficient study time may have elapsed for disease onset and development in non-demented individuals to take place. Conversely, in UoM cohort, where there had been nearly 30 years of study time, a broader spread of AD-type pathological changes had ‘naturally’ evolved in the brains of both demented and non-demented participants.

Background The glucocorticoid receptor (NR3C1, GR) is frequently downregulated in breast tumors, and evidence suggests it acts as a tumor suppressor in estrogen receptor-positive (ER+) breast cancer. We previously found that methylation of the GR promoter CpG island represses gene expression and occurs in ER+ breast tumors. In this study, the prognostic and predictive value of GR methylation was examined in ER+ patients from the CCTG MA.12 clinical trial of tamoxifen versus placebo in women with early breast cancer. Methods We developed a targeted multiplex bisulfite next-generation sequencing assay to detect methylation at multiple GR promoter regions in DNA from formalin-fixed paraffin-embedded (FFPE) samples. Following validation in a small cohort of breast tumors, ER+ FFPE tumor samples from MA.12 (n = 208) were tested. Survival analyses evaluated the impact of GR promoter methylation on patient overall survival (OS) and disease-free survival (DFS). Results An analysis of TCGA data found that GR methylation is prevalent in ER+ tumors and is associated with decreased gene expression and analysis of public microarray data (KM Plotter) linked decreased GR expression to a poor outcome. In MA.12, two GR promoter regions (U and C) each had prognostic value, but with opposite effects on the outcome. U methylation was associated with poor OS (HR = 1.79, P = 0.041) whereas C methylation was associated with better OS (HR = 0.40, P = 0.040) and DFS (HR = 0.49, P = 0.037). The classification of patients based on the methylation status of the two regions was prognostic for OS (P = 0.006) and DFS (P = 0.041) and revealed a group of patients (U methylated, C unmethylated) with very poor outcomes. Placebo-treated patients in this high-risk group had worse OS (HR = 2.86, P = 0.002) and DFS (HR = 2.09, P = 0.014) compared to the rest of the cohort. Conclusion Region-specific GR promoter methylation was an independent prognostic marker for patient survival and identified a subset of patients with poor prognosis, particularly without tamoxifen treatment. These findings provide a foundation for future studies into GR methylation as a promising prognostic biomarker in ER+ breast cancer.

ObjectivesHead injury with loss of consciousness (HI-LOC) is a common occurrence. Some studies have linked such injuries with an increased risk of Alzheimer’s disease (AD). However, recent large clinicopathologic studies have failed to find a clear relationship between HI-LOC and the pathological changes associated with AD. The present study aims to further investigate the relationship between HI-LOC and AD pathology in the elderly.Methods/DesignHistory of HI-LOC in participants in The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age was ascertained. The donated brains of 110 of these individuals were assessed for AD pathology using consensus guidelines. Analyses aimed to elucidate relationships between HI-LOC and AD pathology.ResultsNo associations were found between incidence of HI-LOC and regional AD pathology or any of the three established measures of the neuropathology associated with AD: CERAD score, Thal phase or Braak stage.ConclusionsSingle incidences of HI-LOC may not be sufficient to cause the pathology associated with late-stage AD. Other routes of damage, such as diffuse axonal injury or Lewy body pathology, may play a greater role in causing cognitive impairment associated with head injury.

While post mortem studies have identified the major cell types and functional systems affected in Alzheimer’s disease (AD) the initial sites and molecular characteristics of pathology are still unclear. Because individuals with Down syndrome (DS) (trisomy 21) develop the full pathological changes of AD in a predictable way by the time they reach middle to late age, a study of the brains of such persons at different ages makes an ideal ‘model system’ in which the sites of earliest onset of pathology can be detected and the subsequent progression of changes be monitored. In the present study we have examined the brains of 56 individuals with DS ranging from new-born to 76 years for the presence of amyloid and tau pathology in key cortical and subcortical regions. Amyloid pathology was found to commence in the late teens to twenties as a deposition of diffuse plaques initially within the temporal neocortex, quickly involving other neocortical regions but only reaching subcortical regions and cerebellum by the late forties. Cerebral amyloid angiopathy did not regularly commence until after 45–50 years of age. Tau pathology usually commenced after 35 years of age, initially involving not only entorhinal areas and hippocampus but also subcortical regions such as locus caeruleus (LC) and dorsal raphe nucleus (DRN). Later, tau pathology spread throughout the neocortex reaching occipital lobes in most instances by mid-50 years of age. Such a pattern of spread is consistent with that seen in typical AD. We found no evidence that tau pathology might commence within the brain in DS before amyloid deposition had occurred, but there was limited data that suggests tau pathology in LC or DRN might predate that in entorhinal areas and hippocampus or at least be coincident.

Huntington's disease (HD) is a devastating, progressive neurodegenerative disease with a distinct phenotype characterized by chorea and dystonia, incoordination, cognitive decline and behavioral difficulties. The precise mechanisms of HD progression are poorly understood; however, it is known that there is an expansion of the trinucleotide cytosine-adenine-guanine (CAG) repeat in the Huntingtin gene. Herein DI/LC-MS/MS was used to accurately identify and quantify 185 metabolites in post mortem frontal lobe and striatum from HD patients and healthy control cases. The findings link changes in energy metabolism and phospholipid metabolism to HD pathology and also demonstrate significant reductions in neurotransmitters. Further investigation into the oxidation of fatty acids and phospholipid metabolism in pre-clinical models of HD are clearly warranted for the identification of potential therapies. Additionally, panels of 5 metabolite biomarkers were identified in both the frontal lobe (AUC = 0.962 (95% CI: 0.85–1.00) and striatum (AUC = 0.988 (95% CI: 0.899–1.00). This could have clinical utility in more accessible biomatrices such as blood serum for the early detection of those entering the prodromal phase of the disease, when treatment is believed to be most effective. Further evaluation of these biomarker panels in human cohorts is justified to determine their clinical efficacy.

The neuropathological changes responsible for cognitive impairment and dementia remain incompletely understood. Longitudinal studies with a brain donation end point allow the opportunity to examine relationships between cognitive status and neuropathology. We report on the first 97 participants coming to autopsy with sufficient clinical information from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age. This study began in 1983 and recruited 6,542 healthy individuals between 1983 and 1994, 312 of whom consented to brain donation. Alzheimer-type pathology was common throughout the cohort and generally correlated well with cognitive status. However, there was some overlap between cognitive status and measures of Alzheimer pathology with 26% of cognitively intact participants reaching either CERAD B or C, 11% reaching Thal phase 4 or 5, and 29% reaching Braak stage III- VI. Cerebral amyloid angiopathy(CAA), α-synuclein, and TDP-43 pathology was less common, but when present correlated well with cognitive status. Possession of APOEɛ4 allele(s) was associated with more severe Alzheimer-type and CAA pathology and earlier death, whereas possession of APOEɛ2 allele(s) had no effect on pathology but was more common in cognitively intact individuals. The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age cohort is pathologically representative when compared with similar studies. Cognitive impairment in life correlates strongly with all pathologies examined and the APOE status of an individual can affect pathology severity and longevity.

In this study, we have compared the severity of amyloid plaque formation and cerebral amyloid angiopathy (CAA), and the subtype pattern of CAA pathology itself, between APP genetic causes of AD (APPdup, APP mutations), older individuals with Down syndrome (DS) showing the pathology of Alzheimer’s disease (AD) and individuals with sporadic (early and late onset) AD (sEOAD and sLOAD, respectively). The aim of this was to elucidate important group differences and to provide mechanistic insights related to clinical and neuropathological phenotypes. Since lipid and cholesterol metabolism is implicated in AD as well as vascular disease, we additionally aimed to explore the role of APOE genotype in CAA severity and subtypes. Plaque formation was greater in DS and missense APP mutations than in APPdup, sEOAD and sLOAD cases. Conversely, CAA was more severe in APPdup and missense APP mutations, and in DS, compared to sEOAD and sLOAD. When stratified by CAA subtype from 1 to 4, there were no differences in plaque scores between the groups, though in patients with APPdup, APP mutations and sEOAD, types 2 and 3 CAA were more common than type 1. Conversely, in DS, sLOAD and controls, type 1 CAA was more common than types 2 and 3. APOE ε4 allele frequency was greater in sEOAD and sLOAD compared to APPdup, missense APP mutations, DS and controls, and varied between each of the CAA phenotypes with APOE ε4 homozygosity being more commonly associated with type 3 CAA than types 1 and 2 CAA in sLOAD and sEOAD. The differing patterns in CAA within individuals of each group could be a reflection of variations in the efficiency of perivascular drainage, this being less effective in types 2 and 3 CAA leading to a greater burden of CAA in parenchymal arteries and capillaries. Alternatively, as suggested by immunostaining using carboxy-terminal specific antibodies, it may relate to the relative tissue burdens of the two major forms of Aβ, with higher levels of Aβ40 promoting a more ‘aggressive’ form of CAA, and higher levels of Aβ42(3) favouring a greater plaque burden. Possession of APOE ε4 allele, especially ε4 homozygosity, favours development of CAA generally, and as type 3 particularly, in sEOAD and sLOAD. Electronic supplementary material The online version of this article (10.1007/s00401-018-1866-3) contains supplementary material, which is available to authorized users.

Background: Community- or population-based longitudinal studies of cognitive ability with a brain donation end point offer an opportunity to examine relationships between pathology and cognitive state prior to death. Discriminating the earliest signs of dementing disorders, such as Alzheimer disease (AD), is necessary to undertake early interventions and treatments. Methods: The neuropathological profile of brains donated from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age, including CERAD (Consortium to Establish a Registry for Alzheimer’s Disease) and Braak stage, was assessed by immunohistochemistry. Cognitive test scores collected 20 years prior to death were correlated with the extent of AD pathology present at death. Results: Baseline scores from the Memory Circle test had the ability to distinguish between individuals who developed substantial AD pathology and those with no, or low, AD pathology. Predicted test scores at the age of 65 years also discriminated between these pathology groups. The addition of APOE genotype further improved the discriminatory ability of the model. Conclusions: The results raise the possibility of identifying individuals at future risk of the neuropathological changes associated with AD over 20 years before death using a simple cognitive test. This work may facilitate early interventions, therapeutics and treatments for AD by identifying at-risk and minimally affected (in pathological terms) individuals.

The association between the pathological features of AD and dementia is stronger in younger old persons than in older old persons suggesting that additional factors are involved in the clinical expression of dementia in the oldest old. Cumulative data suggests that neuroinflammation plays a prominent role in Alzheimer's disease (AD) and different studies reported an age-associated dysregulation of the neuroimmune system. Consequently, we sought to characterize the pattern of microglial cell activation and astrogliosis in brain post mortem tissue of pathologically confirmed cases of early and late onset AD (EOAD and LOAD) and determine their relation to age., ‘Bolsa para Investigação’ of Centro Hospitalar do Porto. The work at ICVS/3B's has been developed under the scope of the project NORTE‐01‐0145‐FEDER‐000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER), and funded by FEDER funds through the Competitiveness Factors Operational Programme (COMPETE), and the Foundation for Science and Technology (FCT), under the scope of the project POCI‐01‐0145‐FEDER‐007038. We acknowledge The Manchester Brain Bank, The Queen Square Brain Bank and the Oxford Brain Bank [supported by the Medical Research Council (MRC), the NIHR Oxford Biomedical Research Centre and the Brains for Dementia Research programme, jointly funded by Alzheimer′s Research UK and Alzheimer′s Society] for tissue samples supply, info:eu-repo/semantics/publishedVersion

INTRODUCTION: Frontotemporal lobar degeneration (FTLD) is classified mainly into FTLD-tau and FTLD-TDP according to the protein present within inclusion bodies. While such a classification implies only a single type of protein should be present, recent studies have demonstrated dual tau and TDP-43 proteinopathy can occur, particularly in inherited FTLD. METHODS: We therefore investigated 33 patients with FTLD-tau (including 9 with MAPT mutation) for TDP-43 pathological changes, and 45 patients with FTLD-TDP (including 12 with hexanucleotide expansion in C9ORF72 and 12 with GRN mutation), and 23 patients with motor neurone disease (3 with hexanucleotide expansion in C9ORF72), for tauopathy. RESULTS: TDP-43 pathological changes, of the kind seen in many elderly individuals with Alzheimer's disease, were seen in only two FTLD-tau cases--a 70-year-old male with exon 10 + 13 mutation in MAPT, and a 73-year-old female with corticobasal degeneration. Such changes were considered to be secondary and probably reflective of advanced age. Conversely, there was generally only scant tau pathology, usually only within hippocampus and/or entorhinal cortex, in most patients with FTLD-TDP or MND. The extent of tau pathology in FTLD-TDP and MND, as with amyloid ? protein, may relate to increased age and possession of Apolipoprotein ?4 allele. CONCLUSION: We find no predilection or predisposition towards an accompanying TDP-43 pathology in patients with FTLD-tau, irrespective of presence or absence of MAPT mutation, or that genetic changes associated with FTLD-TDP predispose towards excessive tauopathy. Where the two processes coexist, this is limited and probably causatively independent of each other.

BACKGROUND Poor adherence frequently impaired the efficacy of therapy to maintain remission from inflammatory bowel diseases (IBD). There is a lack of practical and effective interventions to improve adherence. This study aimed to identify modifiable risk factors, which may yield targets for new interventions. METHODS Participants with IBD were recruited from hospital outpatient clinics and office-based gastroenterologists. Demographic and disease-related data were recorded by means of self-administered questionnaires. Modifiable risk factors were assessed with the validated Belief about Medicine Questionnaire, Hospital Anxiety and Depression Score, and short inflammatory bowel disease questionnaire. Adherence was assessed separately for 5-aminosalicylates, thiopurines, and biological agents using the validated Medicine Adherence Report Scale (good adherence defined as >16). RESULTS Nonadherence occurred in 102 of 356 participants (28.7%). Adherence increased significantly with more aggressive therapies (median Medicine Adherence Report Scale: 5-aminosalicylates 18, thiopurines 19, biological 20; P < 0.0001). Nonadherence was not associated with anxiety and depression or disease-related patient knowledge. Adherent patients had significantly higher belief of necessity for medication (P < 0.0001) and a trend toward lower concerns about medication (P = 0.08). Membership of an IBD patient organization was associated with better adherence (P < 0.0001). Concerns about medication rose significantly with more aggressive therapies (P = 0.009), but belief of necessity was similar for all medications. CONCLUSIONS Nonadherence occurs most frequently with 5-aminosalicylates. Belief of necessity may prove the key target for future interventions, although general IBD education is unlikely to yield an adherence benefit. Patient organization membership should be encouraged.

Aims:? We aimed to investigate the role of the nuclear carrier and binding proteins, transportin-1 (TRN1) and transportin-2 (TRN2), TATA-binding protein-associated factor 15 (TAF15) and Ewing's Sarcoma protein (EWS) in inclusion body formation in cases of Frontotemporal Lobar Degeneration (FTLD) associated with Fused in Sarcoma protein (FTLD-FUS). Methods:? Eight cases of FTLD-FUS (5 cases of atypical FTLD-U (aFTLD-U), 2 of Neuronal Intermediate Filament Inclusion Body Disease (NIFID) and 1 of Basophilic Inclusion Body Disease (BIBD)) were immunostained for FUS, TRN1, TRN2, TAF15 and EWS. 10 cases of FTLD associated with TDP-43 inclusions served as reference cases. Results:? The inclusion bodies in FTLD-FUS contained TRN1 and TAF15 and, to a lesser extent, EWS, but not TRN2. The patterns of immunostaining for TRN1 and TAF15 were very similar to that of FUS. None of these proteins was associated with tau or TDP-43 aggregations in FTLD. Conclusion:? Data suggest that FUS, TRN1 and TAF15 may participate in a functional pathway in an interdependent way, and imply that the function of TDP-43 may not necessarily be in parallel with, or complementary to, that of FUS, despite each protein sharing many similar structural elements. � 2012 The Authors. Neuropathology and Applied Neurobiology � 2012 British Neuropathological Society.

Aims: Microglia-driven neuroinflammation can play an important role in the pathophysiology of neurodegenerative disorders. In this study, we sought to characterize the distribution of microglial cell activation in 2 neurodegenerative dementias with distinct protein signatures, Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD) of the TDP subtype, and to determine if there was an anatomical correlation with the phenotypes most commonly associated with these conditions. Methods: The distribution and extent of microglial cell activation was assessed semiquantitatively in the hippocampal formation, cortical gray matter, and subcortical white matter of CD68-immunostained sections of the frontal, temporal, parietal, and occipital cortices from 15 pathologically confirmed cases of AD, 13 cases of FTLD, and 18 controls. Results: Significantly higher levels of microglial cell activation occurred in the subiculum in AD and FTLD than in controls. Additionally, AD had higher microglial activation in the CA1 and FTLD in the hippocampal white matter than the controls. Microglial activation was greater in the dentate gyrus molecular layer in AD than in FTLD. In the cortical regions, the 2 pathological groups differed only in frontal white matter, with the FTLD group showing higher microglial scores. FTLD showed higher microglial activation in the white matter compared to the respective gray matter in the entorhinal, temporal, and frontal regions. Conclusions: Our work expands the knowledge of the distribution and magnitude of microglial activation in these disorders. Additionally, we found some microglial circuit-specific patterns that could help to explain some of the clinical overlap between AD and FTLD-TDP, namely in memory deficits., This work was funded by “Bolsa para Investigação” of Centro Hospitalar do Porto.

Huntington's disease (HD) is a fatal autosomal-dominant neurodegenerative disorder that affects approximately 3-10 people per 100 000 in the Western world. The median age of onset is 40 years, with death typically following 15-20 years later. In this study, we biochemically profiled post-mortem frontal lobe and striatum from HD sufferers (n = 14) and compared their profiles with controls (n = 14). LC-LTQ-Orbitrap-MS detected a total of 5579 and 5880 features for frontal lobe and striatum, respectively. An ROC curve combining two spectral features from frontal lobe had an AUC value of 0.916 (0.794 to 1.000) and following statistical cross-validation had an 83% predictive accuracy for HD. Similarly, two striatum biomarkers gave an ROC AUC of 0.935 (0.806 to 1.000) and after statistical cross-validation predicted HD with 91.8% accuracy. A range of metabolite disturbances were evident including but-2-enoic acid and uric acid, which were altered in both frontal lobe and striatum. A total of seven biochemical pathways (three in frontal lobe and four in striatum) were significantly altered as a result of HD. This study highlights the utility of high-resolution metabolomics for the study of HD. Further characterization of the brain metabolome could lead to the identification of new biomarkers and novel treatment strategies for HD.

Inflammatory bowel diseases (IBDs) require maintenance medication to sustain remission and as a prophylaxis against the development of colorectal dysplasia. Non-adherence can compromise the effectiveness of treatment plans.Depending on study cohort and country, 7 - 72% of IBD patients do not adhere to maintenance medication plans. Non-adherence is associated with an increased number of flares and increased healthcare utilization costs. Several factors, such as experiencing side effects and demographic, socioeconomic, disease-specific and psychological variables have been associated with non-adherence in IBD. Data on demographic, socioeconomic and disease-specific variables are inconsistent, while data on psychological distress, patients' beliefs about medication and discordant doctor-patient relationships are more consistently associated with non-adherence. There has been a change towards investigation of modifiable factors for non-adherence in the recent literature.Currently, there is no simple and effective intervention to improve adherence to IBD maintenance medication. Anxiety, beliefs about medicines and the doctor-patient relationship are promising targets for interventions, but require further study.

Frontotemporal lobar degeneration (FTLD) is clinically, pathologically and genetically heterogeneous. Recent descriptions of a pathological sub-type that is ubiquitin positive, TDP-43 negative and immunostains positive for the Fused in Sarcoma protein (FUS) raises the question whether it is associated with a distinct clinical phenotype identifiable on clinical grounds, and whether mutations in the Fused in Sarcoma gene (FUS) might also be associated with FTLD. Examination of a pathological series of 118 cases of FTLD from two centres, showing tau-negative, ubiquitin-positive pathology, revealed FUS pathology in five patients, four classified as atypical FTLD with ubiquitin inclusions (aFTLD-U), and one as neuronal intermediate filament inclusion disease (NIFID). The aFTLD-U cases had youthful onset (22-46 years), an absence of strong family history, a behavioural syndrome consistent with frontotemporal dementia (FTD) and severe caudate atrophy. Their cognitive/behavioural profile was distinct, characterised by prominent obsessionality, repetitive behaviours and rituals, social withdrawal and lack of engagement, hyperorality with pica, and marked stimulus-bound behaviour including utilisation behaviour. They conformed to the rare behavioural sub-type of FTD identified previously by us as the "stereotypic" form, and linked to striatal pathology. Cognitive evaluation revealed executive deficits in keeping with subcortical-frontal dysfunction, but no cortical deficits in language, perceptuospatial skills or praxis. The patient with NIFID was older and exhibited aphasia and dyspraxia. No patient had clinical evidence of motor neurone disease during life, or a mutation in the FUS gene. In the complementary clinical study of 312 patients with clinical syndromes of FTLD, genetic analysis revealed a 6 bp deletion in FUS in 3 patients, of questionable significance. One presented a prototypical picture of FTD, another expressive language disorder, and the third semantic dementia. None showed the early onset age or distinctive 'stereotypic' picture of patients with aFTLD-U. We conclude that aFTLD-U is associated with a distinct clinical form of frontotemporal dementia, potentially allowing identification of such patients in life with a high degree of precision. Whether mutations in the FUS gene cause some cases of FTLD remains unresolved.

OBJECTIVES: Adherence is generally associated with improved treatment outcomes. Risk factors for non-adherence must be understood to improve adherence. A systematic review was undertaken to determine which variables were consistently associated with non-adherence to oral medication in inflammatory bowel disease (IBD). METHODS: The databases EMBASE, Medline, and PsycINFO were searched for titles relating to adherence, medication, and IBD (1980-2008). Primary, quantitative studies were included if they concerned adult patients with IBD, measured adherence to oral medication, and measured characteristics associated with adherence. The resulting 17 papers were independently reviewed by two researchers who also assessed their quality according to pre-defined criteria. The main outcome was the frequency with which demographic, clinical, treatment, and psychosocial variables were found to be statistically significantly associated with non-adherence. RESULTS: Non-adherence rates ranged from 7 to 72%, with most studies reporting that 30-45% of patients were non-adherent. No demographic, clinical, or treatment variables were consistently associated with non-adherence. Psychological distress and patients' beliefs about medications were both related to non-adherence in four out of five studies, and doctor-patient discordance was associated with non-adherence in two out of three studies. CONCLUSIONS: This is the largest review of factors associated with non-adherence in IBD. Demographic, clinical, and treatment variables were not consistently associated with non-adherence. Psychological distress, patients' beliefs about medications, and doctor-patient discordance were associated with non-adherence. These findings call into question some of the conclusions of earlier reviews that did not take into account nonsignificant findings. Practical suggestions for gastroenterologists and future research are discussed.

Approaches to chronic disease management have changed immensely over the past decade. Patients are no longer seen as passive recipients of care, and there is an expectation that those with chronic disease, such as inflammatory bowel disease (IBD), can be empowered through self−management programmes, which give them the confidence, skills and information to manage their condition independently. This article discusses the implementation of a guided self−management programme for patients with IBD by a specialist nurse.

BACKGROUND: The role of psychological factors in irritable bowel syndrome (IBS) remains unclear, particularly in a primary care setting, where relatively little research on this common and costly condition has been carried out. The aim of this study was to investigate the relative contribution of physical and psychological factors to health-related quality of life and health-care utilization in patients with functional bowel disease (IBS-like symptoms) in primary care. We also wished to establish the relevance of formal diagnostic criteria to IBS in the primary care setting. METHODS: This study used a cross-sectional design. Four hundred twenty patients with functional bowel disorders in primary care completed a series of measures, including bowel symptom status and severity, severity of psychological distress, personality, and quality of life. The number of visits to a general practitioner (GP) in the previous 12 months was recorded. RESULTS: The following variables were independently and highly significantly associated with health-related quality of life in patients with functional bowel disorders in primary care: total psychological symptom score, diarrhea severity, abdominal pain for >12 weeks, and abdominal distension. A similar pattern emerged between patients who met meet Rome II criteria for IBS and patients who did not meet Rome II criteria for IBS. Relatively few variables (either physical or psychological) had a major impact on the number of GP consultations, with the exception of frequency of bowel movements. CONCLUSION: This study confirms that psychological factors are significantly associated with health-related quality of life in patients with IBS in primary care. Physical symptom severity is also important. Relatively few symptom measures, either physical or psychological, have a major impact on doctor consultation rates in primary care.

Objectives: To determine if a whole-system approach to self-management in inflammatory bowel disease (IBD), using a guidebook developed with patients and physicians trained in patient-centred care, leads to cost-effective use of health system resources. Methods: Cost-effectiveness analysis over a one-year time horizon comparing the whole systems self-management approach to treatment with usual treatment. Nineteen hospitals in the northwest England were randomized to the intervention or to be controls; 651 patients (285 at intervention sites and 366 at control sites) with established IBD were included. The economic evaluation related differential health service costs, from a UK NHS perspective, to differences in quality-adjusted life years (QALYs) based on patients' responses to the EQ-5D. Results: The intervention was associated with a mean reduction in costs of £148 per patient and a small mean reduction in QALYs of 0.00022 per patient compared with the control group. This resulted in an incremental cost per QALY gained of £676,417 for treatment as usual and a probability of around 63% that the whole-system approach to self-management is cost-effective, assuming a willingness to pay up to £30,000 for an additional QALY. Conclusions: Although there is uncertainty associated with these estimates, more widespread use of this method in chronic disease management seems likely to reduce health care costs without evidence of adverse effect on patient outcomes.

Research evaluating self-management of chronic conditions points to the effectiveness of interventions’ changing the health behavior of individuals. However, we know little about how self-management is negotiated within health services. The authors designed a qualitative investigation to illuminate the quantitative findings of a randomized controlled trial (RCT) of a self-management program for people with inflammatory bowel disease. They conducted in-depth interviews with physicians and patients, and qualitative analysis illuminated the nature of doctor-patient encounters and possible reasons for lack of change in patient satisfaction with the consultation. The findings suggest that factors inhibiting effective patient-centered consultations include failure of physicians to incorporate expressed need relevant to people’s self-management activities fully, interpretation of selfmanagement as compliance with medical instructions, and the organization of outpatients’ clinics. Giving attention to these barriers might maximize the opportunities for patient selfmanagement of chronic illness based on a therapeutic alliance with health care professionals.

Alongside the steady progress of Moore?s Law, we sometimes see step function changes in price:performance ratios of IT. One such has produced ultra-low-cost computing (ULCC) over the past couple of years. In essence, this wraps computing peripherals around a cell phone hardware core; producing a computer for just a few tens of dollars. ULCC enables computing to reach applications and users that other computers cannot, and it is spinning out in multiple directions. In this article, we will focus on one ULCC development ? Raspberry Pi ? and one particular direction: use in developing countries.

A randomised controlled trial was undertaken to evaluate the impact of a patient-centred, evidence-based guidebook on knowledge, anxiety and quality of life (QoL) in patients with ulcerative colitis. The information in the book was developed closely with patients and focused on their identified needs. All 240 subjects in the study were on long-term follow-up for ulcerative colitis and were effectively responsible for the day-to-day management of their condition in the community. Outcomes were measured at 1 month and 9 months. Patients attended outpatient clinics at six hospitals: three hospitals were randomised to be control sites; and three were intervention sites where patients were given a copy of the guidebook. The results showed that patients receiving the guidebook demonstrated significantly better knowledge of their ulcerative colitis at 1 month, which persisted at 9 months, than patients in the control group. Anxiety and QoL scores were unchanged throughout. The present authors conclude that appropriate information is an essential prerequisite to greater patient involvement in chronic disease management. Patient-centred information increases knowledge without increasing anxiety and should be made available to patients through an appropriate health provider.

Introduction Many neurodegenerative diseases are characterised by accumulations of misfolded proteins that can colocalise with chaperone proteins (for example, heat shock protein 27 (HSP27)), which might act as modulators of protein aggregation. Methods The role of HSP27 in the pathogenesis of neurodegenerative disorders such as frontotemporal lobar degeneration (FTLD), Alzheimer’s disease (AD) and motor neuron disease (MND) was investigated. We used immunohistochemical and Western blot analysis to determine the distribution and amount of this protein in the frontal and temporal cortices of diseased and control subjects. Results HSP27 immunostaining presented as accumulations of granules within neuronal and glial cell perikarya. Patients with AD and FTLD were affected more often, and showed greater immunostaining for HSP27, than patients with MND and controls. In FTLD, there was no association between HSP27 and histological type. The neuropathological changes of FTLD, AD and MND were not immunoreactive to HSP27. Western blot analysis revealed higher HSP27 expression in FTLD than in controls, but without qualitative differences in banding patterns. Conclusions The pattern of HSP27 immunostaining observed may reflect the extent of ongoing neurodegeneration in affected brain areas and is not specific to FTLD, AD or MND. It may represent an accumulation of misfolded, damaged or unwanted proteins, awaiting or undergoing degradation.

Summary Background Ulcerative colitis is managed mainly in secondary care by regular outpatient reviews done by specialist clinicians. Alternatives would be to discharge patients to primary care or to provide open-access clinics, but neither of these options reduce patients' dependency on doctors or allow patients' involvement in disease management. We did a randomised controlled trial to assess an alternative to traditional outpatient care. Methods We randomly assigned 203 patients with ulcerative colitis who were undergoing hospital follow-up to receive patient-centred self-management training and follow-up on request (intervention group), or normal treatment and follow-up (control group). The main outcome was the interval between relapse and treatment, and secondary outcomes were rates of primary and secondary care consultation, quality of life, and acceptability to patients. Analysis was by intention to treat. Findings Intervention patients had relapses treated within a mean of 14·8 h (SD 19·1) compared with 49·6 h (65·1) in controls (difference 34·8 h [95% Cl 16·4–60·2]). Furthermore, intervention patients compared with controls made significantly fewer visits to hospital (0·9 vs 2·9 per patient per year, difference 2·0 [1·6–2·7]) and to the primary-care physician (0·3 vs 0·9 per patient per year, difference 0·6 [0·2–1·1], p Interpretation Self-management of ulcerative colitis accelerates treatment provision and reduces doctor visits, and does not increase morbidity. This approach could be used in long-term management of many other chronic diseases to improve health-service provision and use, and to reduce costs.

Background Cases of Frontotemporal Lobar Degeneration (FTLD) and Motor Neurone Disease (MND) associated with expansions in C9ORF72 gene are characterised pathologically by the presence of TDP-43 negative, but p62 positive, inclusions in granule cells of the cerebellum and in cells of dentate gyrus and area CA4 of the hippocampus. Results We screened 84 cases of pathologically confirmed FTLD and 23 cases of MND for the presence of p62 positive inclusions in these three brain regions, and identified 13 positive cases of FTLD and 3 of MND. All cases demonstrated expansions in C9ORF72 by Southern blotting where frozen tissues were available. The p62 positive inclusions in both cerebellum and hippocampus were immunostained by antibodies to dipeptide repeat proteins (DPR), poly Gly-Ala (poly-GA), poly Gly-Pro (poly-GP) and poly Gly-Arg (poly-GR), these arising from a putative non-ATG initiated (RAN) sense translation of the GGGGCC expansion. There was also some slight, but variable, immunostaining with poly-AP antibody implying some antisense translation might also occur, though the relative paucity of immunostaining could reflect poor antigen avidity on the part of the antisense antibodies. Of the FTLD cases with DPR, 6 showed TDP-43 type A and 6 had TDP-43 type B histology; one had FTLD-tau with the pathology of corticobasal degeneration. There were no qualitative or quantitative differences in the pattern of immunostaining with antibodies to DPR, or p62, proteins between TDP-43 type A and type B cases. Ratings for frequency of inclusions immunostained by these poly-GA, poly-GP and poly-GR antibodies broadly correlated with those for immunolabelled by p62 antibody in all three regions. Conclusion We conclude that DPR are a major component of p62 positive inclusions in FTLD and MND.

Adherence to medication that maintains remission by patients with ulcerative colitis (UC) is poor but little is known regarding patients' perception of medication benefit that may enhance adherence rates. The aims were to study patients' understanding and preference on methods of conveying statistical information and to study indicated thresholds for adherence to medication for UC.Four methods of displaying information on benefits of maintenance therapy were explained to patients with UC in remission: relative risk reduction [RR], absolute risk reduction [AR], number needed to treat [NNT] and optical representation via Cates plot [CP]. Patients' understanding and preference for each method were evaluated. Participants were asked to state minimum thresholds relating to relapse prevention and colorectal cancer risk reduction that they would require in order for them to adhere to medication for UC.Of 50 participants, 48% preferred data presentation by RR over CP (28%), AR (20%) and NNT (4%). 94% found RR easy to understand, better than AR (88%), CP (74%), or NNT (48%). For bowel cancer prevention, 94% indicated adherence for benefit levels of 61% RR but only 57% for the corresponding CP (P0.001). For relapse prevention, 78% of patients indicated adherence for benefit levels of 40% RR but only 43% for the corresponding CP (P0.001).Patients with UC prefer data presented by RR, and apply significantly higher thresholds for adherence when presented with CP compared to RR. Reduction of cancer risk may be a stronger motivator than maintenance of remission.

Frontotemporal lobar degeneration (FTLD) is a highly familial neurodegenerative disease. It has recently been shown that the most common genetic cause of FTLD and amyotrophic lateral sclerosis (ALS) is a hexanucleotide repeat expansion in C9ORF72. To investigate whether this expansion was specific to the FTLD/ALS disease spectrum, we genotyped the hexanucleotide repeat region of C9ORF72 in a large cohort of patients with Alzheimer's disease (AD). A normal range of repeats was found in all cases. We conclude that the hexanucleotide repeat expansion is specific to the FTLD/ALS disease spectrum.

TDP-43 immunoreactive (TDP-43-ir) pathological changes were investigated in the temporal cortex and hippocampus of 11 patients with autosomal dominant familial forms of Alzheimer's disease (FAD), 169 patients with sporadic AD [85 with early onset disease (EOAD) (i.e before 65 years of age), and 84 with late onset after this age (LOAD)], 50 individuals with Down's Syndrome (DS) and 5 patients with primary hippocampal sclerosis (HS). TDP-43-ir pathological changes were present, overall, in 34/180 of AD cases. They were present in 1/11 (9%) FAD, and 9/85 (10%) EOAD patients but were significantly more common (p = 0.003) in LOAD where 24/84 (29%) patients showed such changes. There were no demographic differences, other than onset age, between AD patients with or without TDP-43-ir pathological changes. Double immunolabelling indicated that these TDP-43-ir inclusions were frequently ubiquitinated, but were only rarely AT8 (tau) immunoreactive. Only 3 elderly DS individuals and 4/5 cases of primary HS showed similar changes. Overall, 21.7% of AD cases and 6% DS cases showed hippocampal sclerosis (HS). However, only 9% FAD cases and 16% EOAD cases showed HS, but 29% LOAD cases showed HS. The proportion of EOAD cases with both TDP-43 pathology and HS tended to be greater than those in LOAD, where nearly half of all the cases with TDP-43 pathology did not show HS. The presence of TDP-43-ir changes in AD and DS may therefore be a secondary phenomenon, relating more to ageing than to AD itself. Nevertheless, a challenge to such an interpretation comes from the finding in AD of a strong relationship between TDP-43 pathology and cognitive phenotype. Patients with TDP-43 pathology were significantly more likely to present with an amnestic syndrome than those without (p < 0.0001), in keeping with pathological changes in medial temporal lobe structures. HS was also associated more commonly with an amnestic presentation (p < 0.005), but this association disappeared when TDP-43-positive cases were excluded from the analysis. TDP-43 may, after all, be integral to the pathology of AD, and to some extent determine the clinical phenotype present.

Background: Nonadherence has been reported in over 40% of patients taking maintenance therapies (MT) for inflammatory bowel disease (IBD). Studies in other illness groups have shown that nonadherence is related to negative attitudes to treatment. The aim of this study was to assess patients' attitudes to MT for IBD (beliefs about personal need for MT and potential adverse effects) and to identify whether such beliefs are associated with adherence to MT. Methods: A cross-sectional survey was conducted in which 1871 members of the National Association for Colitis and Crohn's Disease (NACC) completed validated questionnaires assessing beliefs about MT and adherence to MT. Results: Low adherence to MT was reported by 29% of participants and was associated with doubts about personal need for MT (odds ratio [OR] = 0.56; 95% confidence interval [CI]: 0.48–0.64; P < 0.001) and concerns about potential adverse effects (OR = 1.66; 95% CI: 1.42–1.94; P < 0.001). Attitudinal analysis showed that while almost half (48%) of the participants were “accepting” of MT (high necessity, low concerns), a large proportion of the sample (42%) were “ambivalent” about MT (high necessity, high concerns), 6% were “sceptical” (low necessity, high concerns) and 4% were “indifferent” (low necessity, low concerns). Compared to those who were “accepting” of MT, participants in all 3 other attitudinal groups were significantly more likely to be nonadherent. Conclusions: The way in which patients judge their personal need for MT relative to their concerns about MT can be a significant barrier to adherence. Interventions to facilitate optimal adherence to MT for IBD should address such perceptual barriers. (Inflamm Bowel Dis 2008)

Introduction The 2WW pathway for direct access upper-GI endoscopy was introduced in 2000 by the Department of Health to encourage early diagnosis of upper-GI cancers. Referrals from Primary Care are influenced by disease and symptom awareness in the general public. Despite widespread education targeted at General Practice, upper-GI cancers are frequently diagnosed late and dyspepsia symptoms are not recognised as serious by the wider public. This study is designed to examine the referral demographics and outcomes in our centre of 2WW referral patients, prior to the introduction of the Be Clear on Cancer National Campaign, and highlight the need of such an education campaign locally. Method All direct-to-test 2 WW upper-GI cancer referrals at Salford Royal in 2014 were included. Patients were identified from the endoscopy booking system and records accessed from the Electronic Patient Record to identify confirmed cancer diagnoses and subsequent outcomes. Patients who did not attend scheduled endoscopy appointment (n = 6) and patients with previous known upper-GI cancer (n = 1) were excluded from the analysis. Results 345 patients were included in the study. Significantly more female patients were referred; F:M 195:150 (p Conclusion Despite both oesophageal and gastric cancer being more common in men than woman (3:1 and 2:1 respectively), men in Salford are much less likely to be referred by Primary Care for 2WW urgent endoscopy. Additionally, female patients are more likely to present with early, and therefore more curable disease. It is clear from local research that men are less likely to be aware of the symptoms of upper-GI cancer and therefore less likely to seek advice when they have alarm signs. The national Be Clear On Cancer initiative has recently been launched and has already been shown during the pilot scheme to increase endoscopy referral and cancer diagnosis rates.1It is anticipated that the recently launched heartburn awareness campaign will result in more cancer being diagnosed at an earlier (treatable) stage; time will tell if this ambitious target is realised. Disclosure of interest None Declared. Reference Data from the National Cancer Waiting Times (CWT) Monitoring Dataset provided by NHS England and accessed via Public Health England’s Knowledge & Intelligence Team (East Midlands Pilot data)

Functional abdominal symptoms are very common and account for nearly two million primary care consultations in Britain every year and produce significant morbidity. The aims of this study were to evaluate the impact of two self-help interventions on consultation rates and symptom severity in patients with a primary care diagnosis of irritable bowel syndrome.A total of 420 patients from 54 primary care centres were randomised either to receive self-help information in the form of a guidebook or the guidebook plus a "self-help" group meeting or to be in a control group receiving neither intervention. Data were collected using questionnaires and primary care records.At one year, patients in the guidebook group had a 60% reduction in primary care consultations (p0.001) and a reduction in perceived symptom severity (p0.001) compared with controls. Allocation to the self-help group conferred no additional benefit. Actual symptom scores did not change significantly in any group. Costs per patient were reduced by Pounds 73 (confidence interval Pounds 43, Pounds 103) or 40% per year.Introduction of a self-help guidebook results in a reduction in primary care consultations, a perceived reduction in symptoms, and significant health service savings. This suggests that patients attending their primary care physician with functional abdominal symptoms should be offered self-help information as part of their management.

To become active partners in chronic illness management, patients need relevant information which clearly explains treatment choices. This paper describes a method of producing information to feed into production of a guidebook for people with irritable bowel syndrome (IBS). Users were involved throughout the development process. Five focus groups were held involving 23 people with IBS out of 147 who responded to a newspaper article asking for help with a study of self-care in IBS. Qualitative analysis of transcripts from these meetings formed the basis of guidebook development. Patients described their experiences, coping strategies, experiences of the healthcare system, treatments and social consequences of the condition. Medical literature searches were made to find answers to identified areas of information need. The book includes direct quotes from patients describing their own experiences. Guided and practical ways of support are required for people with IBS who want to self-manage their condition.