The role of REST in transcriptional and epigenetic dysregulation in Huntington's disease

Huntington's disease (HD) is a devastating disorder that affects approximately 1 in 10,000 people and is accompanied by neuronal dysfunction and neurodegeneration. HD manifests as a progressive chorea, a decline in mental abilities accompanied by behavioural, emotional and psychiatric problems followed by, dementia, and ultimately, death. The molecular pathology of HD is complex but includes widespread transcriptional dysregulation. Although many transcriptional regulatory molecules have been implicated in the pathogenesis of HD, a growing body of evidence points to the pivotal role of RE1 Silencing Transcription Factor (REST). In HD, REST, translocates from the cytoplasm to the nucleus in neurons resulting in repression of key target genes such as BDNF. Since these original observations, several thousand direct target genes of REST have been identified, including numerous non-coding RNAs including both microRNAs and long non-coding RNAs, several of which are dysregulated in HD. More recently, evidence is emerging that hints at epigenetic abnormalities in HD brain. This in turn, promotes the notion that targeting the epigenetic machinery may be a useful strategy for treatment of some aspects of HD. REST also recruits a host of histone and chromatin modifying activities that can regulate the local epigenetic signature at REST target genes. Collectively, these observations present REST as a hub that coordinates transcriptional, posttranscriptional and epigenetic programmes, many of which are disrupted in HD. We identify several spokes emanating from this REST hub that may represent useful sites to redress REST dysfunction in HD.

Transcriptional dysregulation of coding and non-coding genes in cellular models of Huntington's disease

HD (Huntington's disease) is a late onset heritable neurodegenerative disorder that is characterized by neuronal dysfunction and death, particularly in the cerebral cortex and medium spiny neurons of the striatum. This is followed by progressive chorea, dementia and emotional dysfunction, eventually resulting in death. HD is caused by an expanded CAG repeat in the first exon of the HD gene that results in an abnormally elongated polyQ (polyglutamine) tract in its protein product, Htt (Huntingtin). Wild-type Htt is largely cytoplasmic; however, in HD, proteolytic N-terminal fragments of Htt form insoluble deposits in both the cytoplasm and nucleus, provoking the idea that mutHtt (mutant Htt) causes transcriptional dysfunction. While a number of specific transcription factors and co-factors have been proposed as mediators of mutHtt toxicity, the causal relationship between these Htt/transcription factor interactions and HD pathology remains unknown. Previous work has highlighted REST [RE1 (repressor element 1)-silencing transcription factor] as one such transcription factor. REST is a master regulator of neuronal genes, repressing their expression. Many of its direct target genes are known or suspected to have a role in HD pathogenesis, including BDNF (brain-derived neurotrophic factor). Recent evidence has also shown that REST regulates transcription of regulatory miRNAs (microRNAs), many of which are known to regulate neuronal gene expression and are dysregulated in HD. Thus repression of miRNAs constitutes a second, indirect mechanism by which REST can alter the neuronal transcriptome in HD. We will describe the evidence that disruption to the REST regulon brought about by a loss of interaction between REST and mutHtt may be a key contributory factor in the widespread dysregulation of gene expression in HD.

The effects of flavonoid and other polyphenol consumption on cognitive performance: A systematic research review of human experimental and epidemiological studies

Literature reviews suggest flavonoids, a sub-class of polyphenols, are beneficial for cognition. This is the first review examining the effect of consumption of all polyphenol groups on cognitive function. Inclusion criteria were polyphenol vs. control interventions and epidemiological studies with an objective measure of cognitive function. Participants were healthy or mildly cognitively impaired adults. Studies were excluded if clinical assessment or diagnosis of Alzheimer’s disease, dementia, or cognitive impairment was the sole measure of cognitive function, or if the polyphenol was present with potentially confounding compounds such as caffeine (e.g. tea studies) or Ginkgo Biloba. 28 studies were identified; 4 berry juice studies, 4 cocoa studies, 13 isoflavone supplement studies, 3 other supplement studies, and 4 epidemiological surveys. Overall, 16 studies reported cognitive benefits following polyphenol consumption. Evidence suggests that consuming additional polyphenols in the diet can lead to cognitive benefits, however, the observed effects were small. Declarative memory and particularly spatial memory appear most sensitive to polyphenol consumption and effects may differ depending on polyphenol source. Polyphenol berry fruit juice consumption was most beneficial for immediate verbal memory, whereas isoflavone based interventions were associated with significant improvements for delayed spatial memory and executive function. Comparison between studies was hampered by methodological inconsistencies. Hence, there was no clear evidence for an association between cognitive outcomes and polyphenol dose response, duration of intervention, or population studied. In conclusion, however, the findings do imply that polyphenol consumption has potential to benefit cognition both acutely and chronically.

Intrastriatal transplantation of adult human neural crest-derived stem cells improves functional outcome in parkinsonian rats

Parkinson's disease (PD) is considered the second most frequent and one of the most severe neurodegenerative diseases, with dysfunctions of the motor system and with nonmotor symptoms such as depression and dementia. Compensation for the progressive loss of dopaminergic (DA) neurons during PD using current pharmacological treatment strategies is limited and remains challenging. Pluripotent stem cell-based regenerative medicine may offer a promising therapeutic alternative, although the medical application of human embryonic tissue and pluripotent stem cells is still a matter of ethical and practical debate. Addressing these challenges, the present study investigated the potential of adult human neural crest-derived stem cells derived from the inferior turbinate (ITSCs) transplanted into a parkinsonian rat model. Emphasizing their capability to give rise to nervous tissue, ITSCs isolated from the adult human nose efficiently differentiated into functional mature neurons in vitro. Additional successful dopaminergic differentiation of ITSCs was subsequently followed by their transplantation into a unilaterally lesioned 6-hydroxydopamine rat PD model. Transplantation of predifferentiated or undifferentiated ITSCs led to robust restoration of rotational behavior, accompanied by significant recovery of DA neurons within the substantia nigra. ITSCs were further shown to migrate extensively in loose streams primarily toward the posterior direction as far as to the midbrain region, at which point they were able to differentiate into DA neurons within the locus ceruleus. We demonstrate, for the first time, that adult human ITSCs are capable of functionally recovering a PD rat model.

Varieties of semantic ‘access’ deficit in Wernicke’s aphasia and semantic aphasia

Comprehension deficits are common in stroke aphasia, including in cases with (i) semantic aphasia (SA), characterised by poor executive control of semantic processing across verbal and nonverbal modalities, and (ii) Wernicke’s aphasia (WA), associated with poor auditory-verbal comprehension and repetition, plus fluent speech with jargon. However, the varieties of these comprehension problems, and their underlying causes, are not well-understood. Both patient groups exhibit some type of semantic ‘access’ deficit, as opposed to the ‘storage’ deficits observed in semantic dementia. Nevertheless, existing descriptions suggest these patients might have different varieties of ‘access’ impairment – related to difficulty resolving competition (in SA) vs. initial activation of concepts from sensory inputs (in WA). We used a case-series design to compare WA and SA patients on Warrington’s paradigmatic assessment of semantic ‘access’ deficits. In these verbal and non-verbal matching tasks, a small set of semantically-related items are repeatedly presented over several cycles so that the target on one trial becomes a distractor on another (building up interference and eliciting semantic ‘blocking’ effects). WA and SA patients were distinguished according to lesion location in the temporal cortex, but in each group, some individuals had additional prefrontal damage. Both of these aspects of lesion variability – one that mapped onto classical ‘syndromes’ and one that did not – predicted aspects of the semantic ‘access’ deficit. Both SA and WA cases showed multimodal semantic impairment, although as expected the WA group showed greater deficits on auditory-verbal than picture judgements. Distribution of damage in the temporal lobe was crucial for predicting the initially beneficial effects of stimulus repetition: WA cases showed initial improvement with repetition of words and pictures, while in SA, semantic access was initially good but declined in the face of competition from previous targets. Prefrontal damage predicted the harmful effects of repetition: the ability to re-select both word and picture targets in the face of mounting competition was linked to left prefrontal damage in both groups. Therefore, SA and WA patients have partially distinct impairment of semantic ‘access’ but, across these syndromes, prefrontal lesions produce declining comprehension with repetition in both verbal and non-verbal tasks.

Sensory and consumer science methods used with older adults: a review of current methods and recommendations for the future

Capturing the sensory perception and preferences of older adults, whether healthy or with particular disease states, poses major methodological challenges for the sensory community. Currently a vastly under researched area, it is at the same time a vital area of research as alterations in sensory perception can affect daily dietary food choices, intake, health and wellbeing. Tailored sensory methods are needed that take into account the challenges of working with such populations including poor access leading to low patient numbers (study power), cognitive abilities, use of medications, clinical treatments and context (hospitals and care homes). The objective of this paper was to review current analytical and affective sensory methodologies used with different cohorts of healthy and frail older adults, with focus on food preference and liking. We particularly drew attention to studies concerning general ageing as well as to those considering age-related diseases that have an emphasis on malnutrition and weight loss. Pubmed and Web of Science databases were searched to 2014 for relevant articles in English. From this search 75 papers concerning sensory acuity, 41 regarding perceived intensity and 73 relating to hedonic measures were reviewed. Simpler testing methods, such as directional forced choice tests and paired preference tests need to be further explored to determine whether they lead to more reliable results and better inter-cohort comparisons. Finally, sensory quality and related quality of life for older adults suffering from dementia must be included and not ignored in our future actions.

The Genetics of Alzheimer`s Disease in Brazil: 10 Years of Analysis in a Unique Population

Alzheimer`s Disease (AD) is the most common type of dementia among the elderly, with devastating consequences for the patient, their relatives, and caregivers. More than 300 genetic polymorphisms have been involved with AD, demonstrating that this condition is polygenic and with a complex pattern of inheritance. This paper aims to report and compare the results of AD genetics studies in case-control and familial analysis performed in Brazil since our first publication, 10 years ago. They include the following genes/markers: Apolipoprotein E (APOE), 5-hidroxytryptamine transporter length polymorphic region (5-HTTLPR), brain-derived neurotrophin factor (BDNF), monoamine oxidase A (MAO-A), and two simple-sequence tandem repeat polymorphisms (DXS1047 and D10S1423). Previously unpublished data of the interleukin-1 alpha (IL-1 alpha) and interleukin-1 beta (IL-1 beta) genes are reported here briefly. Results from others Brazilian studies with AD patients are also reported at this short review. Four local families studied with various markers at the chromosome 21, 19, 14, and 1 are briefly reported for the first time. The importance of studying DNA samples from Brazil is highlighted because of the uniqueness of its population, which presents both intense ethnical miscegenation, mainly at the east coast, but also clusters with high inbreeding rates in rural areas at the countryside. We discuss the current stage of extending these studies using high-throughput methods of large-scale genotyping, such as single nucleotide polymorphism microarrays, associated with bioinformatics tools that allow the analysis of such extensive number of genetics variables, with different levels of penetrance. There is still a long way between the huge amount of data gathered so far and the actual application toward the full understanding of AD, but the final goal is to develop precise tools for diagnosis and prognosis, creating new strategies for better treatments based on genetic profile.

Apolipoprotein E genotype is related to nitric oxide production in platelets

The presence of the, 4 allele of apolipoprotein E (APOE) is considered a risk factor for sporadic Alzheimer`s disease (AD). Our recent data demonstrated that the systemic modulation of oxidative stress in platelets and erythrocytes is disrupted in aging and AD. In this study, the relationship between APOE genotype and oxidative stress markers, both in AD patients and controls, was evaluated. The AD group showed an increase in the content of thiobarbituric acid-reactive substances (TBARS) and in the activities of nitric oxide synthase (NOS) and Na, K-ATPase, when compared to controls. Both groups had a similar cGMP content and superoxide dismutase activity. APOE epsilon 4 allele carriers showed higher NOS activity than non-carriers. These results suggest a possible influence of APOE genotype on nitric oxide (NO) production that might enhance the effects of age-related specific factor(s) associated with neurodegenerative disorders. Copyright (C) 2008 John Wiley & Sons, Ltd.

The Prospective and Retrospective Memory Questionnaire: A population-based random sampling study

The Prospective and Retrospective Memory Questionnaire (PRMQ) has been shown to have acceptable reliability and factorial, predictive, and concurrent validity. However, the PRMQ has never been administered to a probability sample survey representative of all ages in adulthood, nor have previous studies controlled for factors that are known to influence metamemory, such as affective status. Here, the PRMQ was applied in a survey adopting a probabilistic three-stage cluster sample representative of the population of Sao Paulo, Brazil, according to gender, age (20-80 years), and economic status (n=1042). After excluding participants who had conditions that impair memory (depression, anxiety, used psychotropics, and/or had neurological/psychiatric disorders), in the remaining 664 individuals we (a) used confirmatory factor analyses to test competing models of the latent structure of the PRMQ, and (b) studied effects of gender, age, schooling, and economic status on prospective and retrospective memory complaints. The model with the best fit confirmed the same tripartite structure (general memory factor and two orthogonal prospective and retrospective memory factors) previously reported. Women complained more of general memory slips, especially those in the first 5 years after menopause, and there were more complaints of prospective than retrospective memory, except in participants with lower family income.

Influence of education and depressive symptoms on cognitive function in the elderly

Objective: The purpose of the present study was to investigate the influence that education and depression have on the performance of elderly people in neuropsychological tests. Methods: The study was conducted at the Institute of Psychiatry, University of Sao Paulo School of Medicine, Hospital das Clinicas. All of the individuals evaluated were aged 60 or older. The study sample consisted of 59 outpatients with depressive disorders and 51 healthy controls. We stratified the sample by level of education: low = 1-4 years of schooling; high = 5 or more years of schooling. Evaluations consisted of psychiatric assessment, cognitive assessment, laboratory tests and cerebral magnetic resonance imaging. Results: We found that level of education influenced all the measures of cognitive domains investigated (intellectual efficiency, processing speed, attention, executive function and memory) except the Digit Span Forward and Fuld Object Memory Evaluation (immediate and delayed recall), whereas depressive symptoms influenced some measures of memory, attention, executive function and processing speed. Although the combination of a low level of education and depression had a significant negative influence on Stroop Test part B, Trail Making Test part B and Logical Memory (immediate recall), we found no other significant effects of the interaction between level of education and depression. Conclusion: The results of this study underscore the importance of considering the level of education in the analysis of cognitive performance in depressed elderly patients, as well as the relevance of developing new cognitive function tests in which level of education has a reduced impact on the results.

Omvårdnad vid förstoppning hos dementa personer : undersköterskors och vårdbiträdens reflektioner

Constipation is a common problem for people with dementia and it may result in discomfort, suffering and lower quality of life. Nurses in municipal nursing homes have difficult to observe and prevent these problems because they do not participate in the daily caring work. The aim of this study was to illustrate the nurse assistants’ reflections about the care they gave people with dementia and constipation. Main questions vas how they became aware of such problems and what they did when someone had problem with constipation. It also asked about their methods to prevent constipation and if they thought anything could be done better in the future. The method used was a qualitative interview study. The study included eight nurse assistants who worked in municipal nursing homes for people with dementia. The interviews where tape recorded, then written and analysed with a phenomenological method. The result illustrate how the nurse assistants used their sense for observing and their personal feelings to share the experience with the person. This gave trust and renders possibility to get knowledge and also gave opportunity to prevent problems and give help, in a way that not reduced dignity for the person. Bowel control, fluid, food and the possibility to get out for a walk was important. It was also important to have enough time for sharing reflections. Small units gave possibility to personal knowledge.

Betydelsen av taktil massage i omvårdnaden av dementa patienter- En systematisk litteraturstudie

Syftet med denna systematiska litteraturstudie var att se vilka effekter taktil massage ger hos personer med demens. Sökning av artiklar har gjorts på databaserna CINAHL, ELIN@Dalarna och PubMed där sökorden dementia, massage, nursing, older people, Therapeutic touch och touch användes i olika kombinationer. Litteraturstudien består av kvantitativa och kvalitativa artiklar. Artiklarna skulle vara vetenskapliga och inte publicerade före 1995, de skulle även svara på syfte och frågeställning. För att säkerställa att kvalitén på artiklarna var hög granskades de med en granskningsmall. Sammanlagt ligger fjorton artiklar till grund för resultatet i denna litteraturstudie. Resultatet visade att taktil massage har goda effekter i omvårdnaden av dementa. Personalen upplevde att de dementa blev hjälpta av taktil massage. De dementa sänkte sina röster och hade inte samma skrikbeteende som innan. Studierna har också visat att tablettanvändning minskade hos patienterna då de regelbundet fick taktil massage. Personalen växte som vårdare då de använde sig av taktil massage. Efter att projektet var avslutat så kände personalen en bättre sammanhållning i gruppen.

Berörd av beröring : Effekter och användning av beröring på demenssjuka personer- En litteraturstudie

Syftet med denna litteraturstudie var att beskriva olika former av beröring samt dess effekt för personer med sjukdomen demens. Sökningarna har gjorts i databaserna Pubmed, Cinahl och sökmotorn ELIN@du.se med sökorden: massage, dementia, nursing, home, touch, older, patients, therapeutic touch, care och therapy. Artiklarna var utförda mellan år 2000 till 2009 och var kvalitativa och kvantitativa och utgjorde urvalet. För att värdera de utvalda artiklarna användes granskningsmallar. Resultat visade att beröring gav positiva effekter på stress och agiterat beteende såsom skrikbeteende och fysiskt upprört beteende. Beröringen bidrog till att patienterna slappnade av fick lättare att somna. Beröringen minskade oro, depression och nedstämdhet och bidrog till en högre grad av välmående. Beröringen gav däremot ingen effekt på fysiskt aggressivt beteende. Användning av beröring förstärkte relationen mellan vårdare och patient. Beröringen ska ges med full uppmärksamhet till patienten. Patienten ska kunna avbryta beröringen om den upplevs som obehaglig. Slutsatsen som uppsatsförfattarna drog var att beröring gav positiva effekter, oberoende var på kroppen beröringen gavs samt vilken sorts beröring som gavs. Beröringen ska även ske tillsammans med en god kommunikation med den dementa personen för att uppnå bäst resultat.

Sällskapsdjurs effekt på beteendeproblem hos äldre med demenssjukdom : En systematisk litteraturstudie

Syftet med studien var att studera hur sällskapsdjur kan påverka demenssjukas beteendeproblem och vara ett komplement till medicinsk behandling med lugnande läkemedel hos patienter med demens.Studien genomfördes som en systematisklitteraturstudie. Metoden författarna använde sig av var att de valde ut 9 stycken vetenskapliga artiklar från år 1999-2009 som hittats i olika databaser och referenslistor. Artiklarna analyserades genom att texten delades upp i de olika kategorierna lugnade effekt/oro, aggression, kontakt/beröring och läkemedelsanvändande. Resultatet visade att beteendeproblemen som aggression och oro, i flera av studierna blev bättre i sällskapsdjurs närvaro, men bara under den tiden som deltagarna fick animal assisted therapy (AAT). När deltagarna blev utan AAT försämrades deras beteendeproblem igen. Olika slags typer av sällskapsdjur användes vid behandling med AAT. Hunden visades vara det sällskapsdjur som användes mest. Slutsatsen blev att de flesta studierna visade på en positiv effekt på närheten av ett sällskapsdjur inom demensvården. Alla studier kunde inte visa på en signifikant skillnad men vårdpersonals upplevelse var att de demenssjuka hade en tendens till förbättrande av sina beteendeproblem.

Hur sjuksköterskor kommunicerar och bemöter patienter med demenssjukdom : en litteraturstudie

Syftet med denna litteraturstudie var att beskriva hur sjuksköterskor bemöter och kommunicerar med patienter med demenssjukdom. Författarna använde sig utav sökmotorn Elin och databasen Cinahl. Använda sökord var: Dementia, Treatment, Care, Nurse*, Nursing, Communication i olika kombinationer. Till resultatet användes 17 vetenskapliga artiklar som var publicerade mellan år 2000 och 2010 och var engelskspråkiga. Litteraturstudien bestod av elva kvalitativa och sex kvantitativa artiklar. Artiklarnas kvalitet värderades med hjälp av granskningsmallar. Resultatet visade att dåligt bemötande och kommunikation förekom från sjuksköterskor till patienter med demenssjukdom. Sjuksköterskor tilltalade patienter med demenssjukdom på ett infantilt språk och andra ignorerade dem. Metoder och råd kring hur sjuksköterskor kan bemöta och kommunicera med patienter med demenssjukdom fanns. Bland annat framkom att när sjuksköterskor använde sig utav personcentrerad vård ökade både positiv verbal och icke-verbal kommunikation hos patienterna med demenssjukdom. Kommunikationen ökade även när sjuksköterskorna använde sig utav metoden Snozelen, lika så genom att använda sig utav en 12- sidig minnesbok som stöd vid samtal. Stöd och hjälp från sjuksköterskan, främjar kommunikationen för patienter med demenssjukdom.