The effects of different familial Alzheimer's disease mutations on APP processing in vivo

BACKGROUND: Disturbed amyloid precursor protein (APP) processing is considered to be central to the pathogenesis of Alzheimer’s disease (AD). The autosomal dominant form of the disease, familial AD (FAD), may serve as a model for the sporadic form of AD. In FAD the diagnosis of AD is reliable and presymptomatic individuals carrying FAD mutations can give valuable insights into the earliest stages of the disease where therapeutic interventions are thought to be the most effective. METHODS:In the current cross-sectional study, products of APP processing (e.g., sAPPα, sAPPβ, Aβ38, Aβ40 and Aβ42) were measured in the cerebrospinal fluid (CSF) of individuals carrying one of three FAD mutations, APPswe (p.KM670/671NL), APParc (p.E693G) and PSEN1 (p.H163Y), as well as in non-mutation carriers from the same families. RESULTS: We observed pathological APP processing in presymptomatic carriers of FAD mutations, with different profiles of APP and Aβ isoforms in the three mutation carrier groups, APPswe (p.KM670/671NL), APParc (p.E693G) and PSEN1 (p.H163Y), except for the well-established decrease in CSF Aβ42 that was found with all mutations. CONCLUSIONS: These findings add to the current evidence that AD pathophysiology differs between disease-causing mutations and can be monitored in the presymptomatic disease stage by CSF analyses. This may also be important from a therapeutic standpoint, by opening a window to monitor effects of disease-modifying drugs on AD pathophysiology

Identification and analysis of a novel scavenger receptor-like protein conserved in <i>Plasmodium</i> species

In October 2002, the complete sequence of the genome of the human malaria parasite Plasmodium falciparum was published. The data showed that as many as 60% of all identified open reading frames were unique to the parasite, with no known homologues in other species. Identification and characterization of novel molecules that may provide targets for drug and vaccine design is crucial to fight malaria. The aim of this project has been to analyse a novel gene and protein in Plasmodium. A short nucleotide fragment was originally identified in Plasmodium chabaudi chabaudi (AS) and the complete sequence subsequently obtained using Vectorette PCR. A singleexon gene was identified and Southern analysis showed the presence of a single copy in the P. chabaudi genome. Analysis of the protein secondary structure revealed a multidomain molecule consisting of an N-terminal secretion signal, two Scavenger Receptor Cysteine-Rich (SRCR) domains, three Limulus factor C, Coch-5b2 and Lgl1 (LCCL) modules and an LH2/PLAT domain. These motifs all have adhesive properties, and the protein was subsequently named Plasmodium SRCR LCCL Adhesive-like Protein (PSLAP). Multiple sequence alignment established that PSLAP is highly conserved within Plasmodium and also identified a paralogue in Toxoplasma gondii, suggesting it may play a specific and vital role in apicomplexan biology. Results from indirect immunofluoresence assays showed a punctate expression pattern contained within the parasite, indicating that the protein is distributed in vesicles. Northern analysis and immunofluorescence co-localisation studies showed transcription and expression in blood-stage gametocytes, demonstrating that PSLAP is a sexual stage protein

Dalby klosters dokumentatörer: Kontraster och likheter i sätten att närma sig ett medeltida monument

"De gamle byggnaderne å Dalby kungsgård wäcka naturligen tanke på forntiden, och kanske hos mången äfwen åstundan att weta hwilka märkliga personer, som bebott detta hus ..." Prosten Johan Åkermans personliga reflexioner kring det forna Dalby kloster från 1828 är förmodligen en av de äldsta kända nedtecknade betraktelserna av klostret. Redogörelsen utfördes i syfte att sammanställa forntidens märkvärdigheter inom pastoratet.1 Idag delar de flesta av oss Åkermans fascination över de ålderdomliga byggnaderna, även om vi närmar oss lämningarna annorlunda. Att studera hur vi har avbildat och tolkat fornlämningar och historiska byggnader under olika tidsperioder är ett forskningsfält som kan öka vår förståelse för äldre dokumentationsmaterial och samtidigt i högre grad medvetandegöra vårt sätt att betrakta byggnader idag

Innovative Therapy for Alzheimer’s Disease-With Focus on Biodelivery of NGF

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder associated with abnormal protein modification, inflammation and memory impairment. Aggregated amyloid beta (Aβ) and phosphorylated tau proteins are medical diagnostic features. Loss of memory in AD has been associated with central cholinergic dysfunction in basal forebrain, from where the cholinergic circuitry projects to cerebral cortex and hippocampus. Various reports link AD progression with declining activity of cholinergic neurons in basal forebrain. The neurotrophic molecule, nerve growth factor (NGF), plays a major role in the maintenance of cholinergic neurons integrity and function, both during development and adulthood. Numerous studies have also shown that NGF contributes to the survival and regeneration of neurons during aging and in age-related diseases such as AD. Changes in neurotrophic signaling pathways are involved in the aging process and contribute to cholinergic and cognitive decline as observed in AD. Further, gradual dysregulation of neurotrophic factors like NGF and brain derived neurotrophic factor (BDNF) have been reported during AD development thus intensifying further research in targeting these factors as disease modifying therapies against AD. Today, there is no cure available for AD and the effects of the symptomatic treatment like cholinesterase inhibitors (ChEIs) and memantine are transient and moderate. Although many AD treatment studies are being carried out, there has not been any breakthrough and new therapies are thus highly needed. Long-term effective therapy for alleviating cognitive impairment is a major unmet need. Discussion and summarizing the new advancements of using NGF as a potential therapeutic implication in AD are important. In summary, the intent of this review is describing available experimental and clinical data related to AD therapy, priming to gain additional facts associated with the importance of NGF for AD treatment, and encapsulated cell biodelivery (ECB) as an efficient tool for NGF delivery

Big data and data repurposing – using existing data to answer new questions in vascular dementia research

Introduction: Traditional approaches to clinical research have, as yet, failed to provide effective treatments for vascular dementia (VaD). Novel approaches to collation and synthesis of data may allow for time and cost efficient hypothesis generating and testing. These approaches may have particular utility in helping us understand and treat a complex condition such as VaD. Methods: We present an overview of new uses for existing data to progress VaD research. The overview is the result of consultation with various stakeholders, focused literature review and learning from the group’s experience of successful approaches to data repurposing. In particular, we benefitted from the expert discussion and input of delegates at the 9th International Congress on Vascular Dementia (Ljubljana, 16-18th October 2015). Results: We agreed on key areas that could be of relevance to VaD research: systematic review of existing studies; individual patient level analyses of existing trials and cohorts and linking electronic health record data to other datasets. We illustrated each theme with a case-study of an existing project that has utilised this approach. Conclusions: There are many opportunities for the VaD research community to make better use of existing data. The volume of potentially available data is increasing and the opportunities for using these resources to progress the VaD research agenda are exciting. Of course, these approaches come with inherent limitations and biases, as bigger datasets are not necessarily better datasets and maintaining rigour and critical analysis will be key to optimising data use

Mesenchymal stromal-cell transplants induce oligodendrocyte progenitor migration and remyelination in a chronic demyelination model.

Demyelinating disorders such as leukodystrophies and multiple sclerosis are neurodegenerative diseases characterized by the progressive loss of myelin that may lead toward a chronic demyelination of the brain¿s white matter, impairing normal axonal conduction velocity and ultimately causing neurodegeneration. Current treatments modifying the pathological mechanisms are capable of ameliorating the disease; however, frequently, these therapies are not sufficient to repress the progressive demyelination into a chronic condition and permanent loss of function. To this end, we analyzed the effect that bone marrowderived mesenchymal stromal cell (BM-MSC) grafts exert in a chronically demyelinated mouse brain. As a result, oligodendrocyte progenitors were recruited surrounding the graft due to the expression of various trophic signals by the grafted MSCs. Although there was no significant reaction in the non-grafted side, in the grafted regions oligodendrocyte progenitors were detected. These progenitors were derived from the nearby tissue as well as from the neurogenic niches, including the subependymal zone and dentate gyrus. Once near the graft site, the cells matured to myelinating oligodendrocytes. Finally, electrophysiological studies demonstrated that axonal conduction velocity was significantly increased in the grafted side of the fimbria. In conclusion, we demonstrate here that in chronic demyelinated white matter, BM-MSC transplantation activates oligodendrocyte progenitors and induces remyelination in the tissue surrounding the stem cell graft

Mild cognitive impairment and deficits in instrumental activities of daily living: a systematic review

Introduction: There is a growing body of evidence that subtle deficits in instrumental activities of daily living (IADL) may be present in mild cognitive impairment (MCI). However, it is not clear if there are IADL domains that are consistently affected across patients with MCI. In this systematic review, therefore, we aimed to summarize research results regarding the performance of MCI patients in specific IADL (sub)domains compared with persons who are cognitively normal and/or patients with dementia. Methods: The databases PsycINFO, PubMed and Web of Science were searched for relevant literature in December 2013. Publications from 1999 onward were considered for inclusion. Altogether, 497 articles were retrieved. Reference lists of selected articles were searched for potentially relevant articles. After screening the abstracts of these 497 articles, 37 articles were included in this review. Results: In 35 studies, IADL deficits (such as problems with medication intake, telephone use, keeping appointments, finding things at home and using everyday technology) were documented in patients with MCI. Financial capacity in patients with MCI was affected in the majority of studies. Effect sizes for group differences between patients with MCI and healthy controls were predominantly moderate to large. Performance-based instruments showed slight advantages (in terms of effect sizes) in detecting group differences in IADL functioning between patients with MCI, patients with Alzheimer’s disease and healthy controls. Conclusion: IADL requiring higher neuropsychological functioning seem to be most severely affected in patients with MCI. A reliable identification of such deficits is necessary, as patients with MCI with IADL deficits seem to have a higher risk of converting to dementia than patients with MCI without IADL deficits. The use of assessment tools specifically designed and validated for patients with MCI is therefore strongly recommended. Furthermore, the development of performance-based assessment instruments should be intensified, as they allow a valid and reliable assessment of subtle IADL deficits in MCI, even if a proxy is not available. Another important point to consider when designing new scales is the inclusion of technology-associated IADL. Novel instruments for clinical practice should be time-efficient and easy to administer

Anticholinergic burden and risk of stroke and death in people with different types of dementia

Background. Anticholinergic burden is associated with poorer cognitive and functional outcomes in people with dementia. However, the impact of anticholinergics on significant adverse outcomes such as stroke has not been studied previously. Objective. To investigate the association between total anticholinergic cognitive burden (ACB) and risk of stroke and death in people with different dementia subtypes. Methods. This was a cohort study of 39107 people with dementia and no prior history of stroke registered in the Swedish Dementia Registry (SveDem) from 2008 – 2014. Data were extracted from the Swedish Prescribed Drug Register, the Swedish National Patient Register and the Swedish Total Population Register. Competing risk regression models were used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between time-varying ACB score and risk of stroke and all-cause mortality. Results. During a mean follow-up period of 2.31 (standard deviation 1.66) years, 11224 (28.7%) individuals had a stroke or died. Compared with non-users of anticholinergic medications, ACB score of 1 (HR 1.09, 95%CI 1.04 – 1.14) and ACB score of ≥2 (HR 1.20, 95%CI 1.14 – 1.26) increased the risk of developing the composite outcome of stroke and death. When stratifying by dementia disorder, the association remained significant in Alzheimer’s disease, mixed dementia and vascular dementia. Conclusions. The use of anticholinergic medicines may be associated with an increased risk of stroke and death in people with dementia. A dose-response relationship was observed. Careful consideration should be made when prescribing medications with anticholinergic properties to people with dementia.FORTEAccepte