64 research outputs found
The association of blood pressure variability with dementia and cognitive impairment: a systematic review and meta-analysis
No full textAbstracts of the 19th International SHR Symposium, as published in Journal of Hypertension.
P09 Cerebrovascular disease, stroke and cognitive dysfunction.
Part of Joint Meeting ESH-ISH 2021 On-air (11th-14th April 2021)
Objective:
A body of empirical work demonstrates that high within-individual blood pressure variability (BPV) holds prognostic value to predict stroke and transient ischemic attack. The magnitude of association between BPV and other neurological outcomes remains less clear. We aimed to summarise the current evidence on whether BPV is associated to dementia and cognitive impairment in healthy older adults.
Design and method:
Electronic databases were searched for full text articles and conference abstracts in English. Prospective and cross-sectional cohort studies or clinical trials in adults without cognitive impairment at baseline were eligible. Measures of BPV included any metric over any duration (i.e. visit-to-visit BPV, day-to-day BPV, 24-hour BPV), but not day-night patterns. Outcomes included: 1. incident dementia, 2. cognitive impairment (change in cognition over time), 3. the combined endpoint of dementia and cognitive impairment, and 4. cognitive function (cross-sectional studies). If the association of mean BP with the study outcome was reported, this was extracted as well, to compare to prognostic ability of BPV with mean BP.
Results:
After screening of the initial search of 2214 references, 40 papers were included. Seven studies assessed incident dementia, 12 assessed cognitive impairment and 23 assessed cognitive function. The majority of studies assessed visit-to-visit BPV (n = 23), followed by 24-hour BPV (n = 14) and day-to-day BPV (n = 3). Increased systolic BPV was associated with the combined endpoint of dementia and cognitive impairment (odds ratio [OR] 1.24, 95% confidence interval [CI] 1.14–1.35), however mean systolic BP was not (OR = 1.13, 95% CI 0.87 to 1.45). There was no evidence of heterogeneity between BPV and mean systolic BP effect sizes (p = 0.47 for comparison, I2 = 0%). Results for diastolic BP(V) were similar. Meta-analysis for all outcomes will be available in May 2020 at the conference.
Conclusions:
On the basis of the available studies, high fluctuations in systolic BP were associated with cognitive impairment. However, there was large methodological and statistical heterogeneity among studies. To clarify whether BPV is an independent risk factor for dementia and cognitive impairment, future work should involve an individual participant data meta-analysis to overcome heterogeneity in analytical approaches.
Rianne De Heus, Phillip Tully, Na Variable Brain Consortiu
The association of blood pressure variability with dementia and cognitive impairment: A systematic review and meta-analysis
No full textObjective: A body of empirical work demonstrates that high within-individual blood pressure variability (BPV) holds prognostic value to predict stroke and transient ischemic attack. The magnitude of association between BPV and other neurological outcomes remains less clear. We aimed to summarise the current evidence on whether BPV is associated to dementia and cognitive impairment in healthy older adults. Design and method: Electronic databases were searched for full-text articles and conference abstracts in English. Prospective and cross-sectional cohort studies or clinical trials in adults without cognitive impairment at baseline were eligible. Measures of BPV included any metric over any duration (i.e. visit-to-visit BPV, day-to-day BPV, 24-hour BPV), but not day-night patterns. Outcomes included: 1. incident dementia, 2. cognitive impairment (change in cognition over time), 3. the combined endpoint of dementia and cognitive impairment, and 4. cognitive function (cross-sectional studies). If the association of mean BP with the study outcome was reported, this was extracted as well, to compare to prognostic ability of BPV with mean BP. Results: After screening of the initial search of 2214 references, 40 papers were included. Seven studies assessed incident dementia, 12 assessed cognitive impairment and 23 assessed cognitive function. The majority of studies assessed visit-to-visit BPV (n=23), followed by 24-hour BPV (n=14) and day-to-day BPV (n=3). Increased systolic BPV was associated with the combined endpoint of dementia and cognitive impairment (odds ratio [OR] 1.24, 95% confidence interval [CI] 1.14-1.35), however mean systolic BP was not (OR = 1.13, 95% CI 0.87 to 1.45). There was no evidence of heterogeneity between BPV and mean systolic BP effect sizes (p=0.47 for comparison, I² = 0%). Results for diastolic BP(V) were similar. Meta-analysis for all outcomes will be available in May 2020 at the conference. Conclusions: On the basis of the available studies, high fluctuations in systolic BP were associated with cognitive impairment. However, there was large methodological and statistical heterogeneity among studies. To clarify whether BPV is an independent risk factor for dementia and cognitive impairment, future work should involve an individual participant data meta-analysis to overcome heterogeneity in analytical approache
Epileptic high-frequency network activity in a model of non-lesional temporal lobe epilepsy
No full textHigh-frequency cortical activity, particularly in the 250–600 Hz (fast ripple) band, has been implicated in playing a crucial role in epileptogenesis and seizure generation. Fast ripples are highly specific for the seizure initiation zone. However, evidence for the association of fast ripples with epileptic foci depends on animal models and human cases with substantial lesions in the form of hippocampal sclerosis, which suggests that neuronal loss may be required for fast ripples. In the present work, we tested whether cell loss is a necessary prerequisite for the generation of fast ripples, using a non-lesional model of temporal lobe epilepsy that lacks hippocampal sclerosis. The model is induced by unilateral intrahippocampal injection of tetanus toxin. Recordings from the hippocampi of freely-moving epileptic rats revealed high-frequency activity (4100 Hz), including fast ripples. High-frequency activity was present both during interictal discharges and seizure onset. Interictal fast ripples proved a significantly more reliable marker of the primary epileptogenic zone than the presence of either interictal discharges or ripples (100–250 Hz). These results suggest that fast ripple activity should be considered for its potential value in the pre-surgical workup of non-lesional temporal lobe epilepsy
Identification of Type 1 Diabetes-Associated DNA Methylation Variable Positions That Precede Disease Diagnosis
No full textMonozygotic (MZ) twin pair discordance for childhood-onset Type 1 Diabetes (T1D) is similar to 50%, implicating roles for genetic and non-genetic factors in the aetiology of this complex autoimmune disease. Although significant progress has been made in elucidating the genetics of T1D in recent years, the non-genetic component has remained poorly defined. We hypothesized that epigenetic variation could underlie some of the non-genetic component of T1D aetiology and, thus, performed an epigenome-wide association study (EWAS) for this disease. We generated genome-wide DNA methylation profiles of purified CD14(+) monocytes (an immune effector cell type relevant to T1D pathogenesis) from 15 T1D-discordant MZ twin pairs. This identified 132 different CpG sites at which the direction of the intra-MZ pair DNA methylation difference significantly correlated with the diabetic state, i.e. T1D-associated methylation variable positions (T1D-MVPs). We confirmed these T1D-MVPs display statistically significant intra-MZ pair DNA methylation differences in the expected direction in an independent set of T1D-discordant MZ pairs (P = 0.035). Then, to establish the temporal origins of the T1D-MVPs, we generated two further genome-wide datasets and established that, when compared with controls, T1D-MVPs are enriched in singletons both before (P = 0.001) and at (P = 0.015) disease diagnosis, and also in singletons positive for diabetes-associated autoantibodies but disease-free even after 12 years follow-up (P = 0.0023). Combined, these results suggest that T1D-MVPs arise very early in the etiological process that leads to overt T1D. Our EWAS of T1D represents an important contribution toward understanding the etiological role of epigenetic variation in type 1 diabetes, and it is also the first systematic analysis of the temporal origins of disease-associated epigenetic variation for any human complex disease
Central and peripheral determinants of fatigue in acute hypoxia
No full textThis thesis was submitted for the degree of Docter of Philosophy and awarded by Brunel University on 24th March 2011.Fatigue is defined as an exercise-induced decrease in maximal voluntary force produced by a muscle. Fatigue may arise from central and/or peripheral mechanisms. Supraspinal fatigue (a component of central fatigue) is defined as a suboptimal output from the motor cortex and measured using transcranial magnetic stimulation (TMS). Reductions in O2 supply (hypoxia) exacerbate fatigue and as the severity of hypoxia increases, central mechanisms of fatigue are thought to contribute more to exercise intolerance. In study 1, the feasibility of TMS to measure cortical voluntary activation and supraspinal fatigue of human knee-extensors was determined. TMS produced reliable measurements of cortical voluntary activation within- and between-days, and enabled the assessment of supraspinal fatigue. In study 2, the mechanisms of fatigue during single-limb exercise in normoxia (arterial O2 saturation [SaO2] ~98%), and mild to severe hypoxia (SaO2 93-80%) were determined. Hypoxia did not alter neuromuscular function or cortical voluntary activation of the knee-extensors at rest, despite large reductions in cerebral oxygenation. Maximal force declined by ~30% after single-limb exercise in all conditions, despite reduced exercise time in severe-hypoxia compared to normoxia (15.9 ± 5.4 vs. 24.7 ± 5.5 min; p < 0.05). Peripheral mechanisms of fatigue contributed more to the reduction in force generating capacity of the knee-extensors following single-limb exercise in normoxia and mild- to moderate-hypoxia, whereas supraspinal fatigue played a greater role in severe-hypoxia. In study 3, the effect of constant-load cycling exercise to the limit of tolerance in hypoxia (SaO2 ~80%) and normoxia was investigated. Time to the limit of tolerance was significantly shorter in hypoxia compared to normoxia (3.6 ± 1.3 vs. 8.1 ± 2.9 min; p < 0.001). The reductions in maximal voluntary force and knee-extensor twitch force at task-failure were not different in hypoxia compared to normoxia. However, the level of supraspinal fatigue was exacerbated in hypoxia, and occurred in parallel with reductions in cerebral oxygenation and O2 delivery. Supraspinal fatigue contributes to the decrease in whole-body exercise tolerance in hypoxia, presumably as a consequence of inadequate O2 delivery to the brain
Influência do jogo Reversi na memória de trabalho em alunos com diagnóstico de TDAH
No full textDissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Filosofia e Ciências Humanas. Programa de Pós-Graduação em Psicologia.O presente estudo teve por objetivo verificar quais as influências do jogo Reversi na memória de trabalho de alunos com diagnóstico de TDAH. Participaram da pesquisa 4 sujeitos entre 11 e 13 anos. Dois sujeitos eram do sexo masculino, com diagnóstico de Hiperatividade e dois sujeitos do sexo feminino com diagnóstico de Déficit de Atenção. Foram realizados seis encontros sendo o primeiro e o último para a realização da bateria de monitoramento cognitivo Proa. Nos outros encontros foi realizada a prática do jogo Reversi onde foram aferidos os dados referentes a frequencia cardíaca (FC), variabilidade da frequencia cardíaca (VFC) e os comportamentos referentes a prática do jogo: tempo de jogada, tempo de reação, número de sequencias certas, número de sequencias erradas, numero de sequencias mediadas, tempo de interação visual entre o jogador e o mediador e entre o jogador e o tabuleiro. Os resultados apresentaram correlações positivas entre os comportamentos de mediar, número de sequencias erradas e os índices psicofisiológicos de DP RR, rMSSD, pNN50, e BF, indicando um possível esforço mental durante a realização das partidas. Os sujeitos diagnosticados com TDAH do subtipo Desatento apresentaram na bateria de monitoramento Proa uma melhora na tarefa de memória de trabalho entre o pré-teste e o pós-teste. Esse estudo buscou realizar uma relação inicial entre os aspectos psicofisiológicos, comportamentais e cognitivos durante a realização de uma partida do jogo de tabuleiro Reversi.The present study aimed to verify the influences of the game Reversi in working memory of students diagnosed with ADHD. The participants were four subjects between 11 and 13 years. Two subjects were male, diagnosed with hyperactivity and two female subjects with a diagnosis of Attention Deficit. There were six meetings with the first and the last to perform the battery of cognitive monitoring Proa. In other meetings were held to practice the game Reversi where the data were measured the frequency rate (HR), heart rate variability (HRV) and behaviors regarding the practice of the game: play time, reaction time, number of threads right, wrong number of threads, number of sequences mediated, time visual interaction between the player and mediator and between the player and the board. The results showed positive correlations between the behaviors mediate the wrong number of threads and psychophysiological indices of RR SD, rMSSD, pNN50, and LF, indicating a possible mental effort during the course of matches. Subjects diagnosed with ADHD Inattentive subtype present in the battery monitoring Proa an improvement in working memory task between the pretest and posttest. This study tried to do an initial relationship between the psycho-physiological aspects, behavioral, cognitive, during the course of a departure from the board game Reversi
Single nucleotide polymorphisms associated with the human electroencephalogram during desflurane anaesthesia
No full textGeneral anaesthesia is an induced state that enables a person to endure surgical procedures without pain or recollection. There is substantial individual variability in the response to anaesthesia and in order to avoid adverse effects caused by either under- or over-sedation, anaesthetic drug administration must be tailored to suit the individual patient. This requires a means to monitor the depth of general anaesthesia. The electroencephalogram (EEG) records the electrical activity of the brain and enables effects of anaesthetic drugs on brain functioning to be monitored. Quantitative EEG monitors, such as the Bispectral (BIS) index monitor, process the raw EEG and provide a numerical output that is often used to measure the depth of general anaesthesia during surgery. Due to a number of factors including clinical conditions and genetic variability in the EEG, the BIS value can at times be misleading.
To identify genetic variations associated with EEG phenotypes relevant to anaesthesia monitoring, an association analysis was performed for 34 single nucleotide polymorphisms (SNPs) in a sample of 125 surgical patients undergoing general, gynaecological or orthopaedic surgery. During surgery, patients were anaesthetised with the volatile anaesthetic agent desflurane, the depth of anaesthesia was measured using BIS monitoring and the raw was also EEG recorded. SNP genotyping was performed for 13 SNPs in five candidate genes; SGIP1, GABRA2, CACNA1G, HCN1 and HCN2, using the polymerase chain reaction and restriction fragment length polymorphism analysis. An additional 21 SNPs in 15 genes involved in various inflammatory and other immune-related pathways were genotyped by Sequenom MassARRAY at the Australian Genome Research Facility.
Six SNPs in five different genes were found to be associated with spindle amplitude (SGIP1, GABRA2, HCN1, IL1B and MYD88), and a further five SNPs were associated with either delta frequency (IL10), or end tidal desflurane concentration (ETDC) (CACNA1G, CRP, MYD88 and TGFB1). The strongest associations were identified for a single SNP located in the 3' UTR of MYD88 (rs6853). The rs6853 A/G genotype was associated with higher median spindle amplitude (p = 0.0040) and spindle amplitude relative to ETDC (p = 0.0006), and lower EDTC (p = 0.0095) than the A/A genotype. No rs6853 G/G homozygotes were identified in the study sample.
MYD88 acts as an adaptor protein in the interleukin-1 receptor and toll-like receptor signalling pathways. Within the brain, cytokines are thought to act as neuronal modulators and influence neurotransmitter signalling and ion channel activity. The association of MYD88 with spindle amplitude, in conjunction with IL1B, suggests that cytokines may influence the EEG during general anaesthesia. Thus cytokine mediated regulation of neuronal activity is speculated to underlie the reported associations. All reported effect sizes were small (0.77- to 1.55-fold) and associated genes had four distinct types of function; ion channels, neurotransmitter signalling, endocytosis, and cytokine signalling. This suggests that numerous genes in different pathways, each with a small, possibly additive effect, are involved in regulating the EEG during general anaesthesia
The molecular genetics of bipolar affective disorder : South African populations, endophenotypes, and environmental influence
No full textIncludes bibliographical references.The identification of the genetic variants underpinning bipolar disorder (BPD) has been impeded by a complex pattern of inheritance that may include by genetic heterogeneity, genetic epistasis, gene-environment interactions, incomplete penetrance and variable expressivity. In this thesis three strategies were employed to ameliorate these confounding factors. The first strategy was to focus on a theoretically genetically-homogeneous population with BPD. A unique South African sample including 190 individuals of the relativity reproductively-isolated Afrikaner population yielded promising evidence of linkage to chromosome 1 q31-32 and weaker peaks at lOq23 and 13q32, regions previously implicated in the disorder. A family-based analysis suggested that the 3' variable number tandem repeat (VNTR) variant of the dopamine transporter gene (DAT) is associated with bipolar-spectrum illness in the 132-strong sample of British ancestry. The second strategy was to carry out genetic linkage and association analyses using quantitative traits (elldophenotypes) that were closely associated with BPD. As part of this process a variety of personality traits were evaluated in the cohort, and anxiety related, novelty-seeking, hyperthymic, and cyclothymic personality traits were found to aggregate in participants with BPD and to a lesser extent repeated unipolar illness (MDE-R). These traits were therefore used as quantitative markers or endophenotypes of BPD. The quantitative linkage analysis indicated that a variant in the region of 13q32 may influence the development of novelty-seeking-related traits in the largest Afrikaner pedigree, while the personality trait, ""Stability"", was weakly linked to 4p16 in the total sample. The catechol-o-methytransferase (COM1) Va1l58Mct and the Brain Derived Neurotrophic Factor (BDNF) Va1l66Met polymorphisms were associated with mood-labile-cyclothymic and hyperthymic·-novelty-seeking traits, respectively. the DA T VNTR and the Notch4 exonic repeat variants were associated with a broad range of ""pathological"" personality traits in the sa11lples of British and Afrikaner origin, respectively. The sample was also evaluated with a battery of neuropsychological tasks and the BPD 1 and MDE-R groups displayed both verbal and visual memory recall deficits while the BPD 1 sample also suffered from recognition memory deficits. The neurocognitive trait, ""Memory"" was therefore used as a second endophenotype generating potential linkage signals on IOq23 and 22q 11. The exonic 48bp VNTR polymorphism in the dopamine 4 receptor (DRD4) gene was associated with '""Memory"" performance. As a third strategy, a potentially important aetiological factor, childhood trauma, was measured, and used to test for gene-environment interactions between the various candidate genes and bipolar-illness or BPD-related endophenotypes in the cohort. BPD and M DE-R individuals displayed significantly higher levels of emotional and physical abuse, and the former variable was also associated with the development of anxiety-related and unstable personality traits. A functional variant of the COM1 gene was found to interact with abuse to predispose to anxiety-related, unstable cyclothymic and novelty-seeking related personality traits. The combination of childhood abuse and possession of low-activity MAO-A gene variants was also associated the development of more anxious and unstable personality traits. All interaction between sexual abuse and the B])NF gene modulated performance on verbal and visual memory tasks. A similar interaction between the ApoE gene and sexual abuse was observed. Although a number of theoretical obstacles remain to be resolved, the analyses of isolated populations coupled with the use of endophenotypes and the testing or gene environment interactions, holds out great promise for the eventual elucidation of the genetic basis of hi polar affective disorder
Identification and evaluation of biomarkers for Huntington’s disease
No full textHuntington’s disease (HD) is a devastating, incurable inherited neurodegenerative disorder that
commonly affects adults in mid-life. Despite encouraging results from in vitro and animal trials,
disease-modifying therapeutic trials in HD are limited by a lack of tools to track disease progression.
HD is clinically heterogeneous, and current clinical rating scales lack sensitivity and specificity,
particularly over relatively short time periods. Improvements in the precision of objective
measurement of disease progression in HD could lead to state markers (biomarkers) better able to
predict onset, detect progression and measure the effects of therapeutic intervention. Biomarkers
capable of detecting disease-related changes in premanifest gene carriers will be essential for
clinical trials of treatments to delay onset. Imaging, clinical and cognitive assessment as well as
laboratory markers have all been proposed as biomarkers, but few measures have been quantified
over short time intervals or shown to be predictive of clinical change over longer periods.
A robust panel of biomarkers from a number of modalities will be necessary to progress to
interventional clinical trials of disease-modifying therapies in HD, using biomarkers to measure the
success or failure of an intervention. Such cross-validation requires simultaneous multimodal
biomarker evaluation within a suitable cohort of subjects studied longitudinally.
This thesis describes a multi-modal approach to the discovery and evaluation of potential
biomarkers for Huntington's disease in a large cohort of human volunteers. After reviewing the
relevant features of Huntington's disease and current state of biomarker research in Huntington's
disease, several approaches to, and outcomes from, biomarker discovery and evaluation are
described, including proteomic profiling, targeted ELISA, multiplex inflammatory profiling and
measurement of whole-brain atrophy by longitudinal magnetic resonance imaging. The thesis draws
together these different approaches and summarises the contributions to both biomarker research
and our understanding of the neurobiology of HD that the work has generated
Models of verbal working memory capacity: What does it take to make them work?
No full textTheories of working memory (WM) capacity limits will be more useful when we know what aspects of performance are governed by the limits and what aspects are governed by other memory mechanisms. Whereas considerable progress has been made on models of WM capacity limits for visual arrays of separate objects, less progress has been made in understanding verbal materials, especially when words are mentally combined to form multiword units or chunks. Toward a more comprehensive theory of capacity limits, we examined models of forced-choice recognition of words within printed lists, using materials designed to produce multiword chunks in memory (e.g., leather brief case). Several simple models were tested against data from a variety of list lengths and potential chunk sizes, with test conditions that only imperfectly elicited the interword associations. According to the most successful model, participants retained about 3 chunks on average in a capacity-limited region of WM, with some chunks being only subsets of the presented associative information (e.g., leather brief case retained with leather as one chunk and brief case as another). The addition to the model of an activated long-term memory component unlimited in capacity was needed. A fixed-capacity limit appears critical to account for immediate verbal recognition and other forms of WM. We advance a model-based approach that allows capacity to be assessed despite other important processing contributions. Starting with a psychological-process model of WM capacity developed to understand visual arrays, we arrive at a more unified and complete model.</p
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