49 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
LRRK2 genetics and expression in the Parkinsonian brain
No full textMutations in LRRK2 have been established as a common genetic cause of Parkinson’s
disease (PD). Variation in gene expression of PARK loci has previously been
demonstrated in PD pathogenesis, although it has not been described in detail for
LRRK2 expression in the human brain. This study further elucidates the role of
LRRK2 in development of PD by describing an investigation into the role of LRRK2
genetics and expression in the human brain.
The G2019S mutation is a common LRRK2 mutation that exhibits a clinical and
pathological phenotype indistinguishable from idiopathic PD. Thus, the study of
G2019S mutation is a recurrent theme. The frequency of G2019S was estimated in
unaffected subjects that lived or shared a cultural heritage to the predicted founding
populations of the mutation, and was found not to be common in these populations.
Morphological analysis revealed a ubiquitous expression for LRRK2 mRNA and
protein in the human brain. In-situ hybridisation data suggests that LRRK2 mRNA is
present as a low copy number mRNA in the human brain. A semi-quantitative
analysis of LRRK2 immunohistochemistry revealed extensive regional variation in
the LRRK2 protein levels, although the weakest immunoreactivity was consistently
identified in the nigrostriatal dopamine region. No difference was observed in the
morphological localisation of LRRK2 mRNA and protein in unaffected, IPD or
G2019S positive PD subjects.
Dysregulation of LRRK2 mRNA expression and the effects of cis- acting genetic
variation on these levels were demonstrated. A widespread decrease of LRRK2
mRNA was observed in IPD and G2019S positive PD subjects in comparison to
unaffected controls. Furthermore, non-coding genetic variation was also
demonstrated to have an effect on the LRRK2 transcriptional activity in PD subjects.
Collectively, these findings suggest that LRRK2 has an important physiological role,
and a dysregulation in its levels could affect auxiliary mechanisms that contribute to
PD pathogenesis. This data also supports the possibility of a shared mechanism
contributing to the identical phenotype of IPD and G2019S linked PD
Using support vector machines with multiple indices of diffusion for automated classification of mild cognitive impairment
No full textFew studies have looked at the potential of using diffusion tensor imaging (DTI) in conjunction with machine learning algorithms in order to automate the classification of healthy older subjects and subjects with mild cognitive impairment (MCI). Here we apply DTI to 40 healthy older subjects and 33 MCI subjects in order to derive values for multiple indices of diffusion within the white matter voxels of each subject. DTI measures were then used together with support vector machines (SVMs) to classify control and MCI subjects. Greater than 90% sensitivity and specificity was achieved using this method, demonstrating the potential of a joint DTI and SVM pipeline for fast, objective classification of healthy older and MCI subjects. Such tools may be useful for large scale drug trials in Alzheimer’s disease where the early identification of subjects with MCI is critical
Differential modulation of cocaine’s discriminative cue by repeated and variable stress exposure: Relation to monoamine transporter levels
No full textKohut, S.J., et al., Differential modulation of cocaine’s discriminative cue by repeated and variable stress exposure: Relation to monoamine transporter levels, Neuropharmacology (2012), doi:10.1016/j.neuropharm.2012.03.012Discriminative stimulus functions of drugs of abuse play an important role in the acquisition, maintenance and reinstatement of drug-taking behavior. The present study tested whether two different schedules of stressor presentation, i.e., repeated and variable, for 10 days, can modify the discriminative stimulus effects of cocaine in male rats trained to discriminate cocaine (10 mg/kg, i.p.) from saline. Dopamine (DAT), serotonin (SERT) and norepinephrine (NET) transporter levels in mesocorticolimbic areas were also measured using western blotting after stress exposure to determine if the relative ratio of these proteins may explain differences in behavior. Rats exposed to both repeated and variable stress displayed shifts in the cocaine doseeresponse curve but with different patterns of responding. In handled controls, ED50 values for cocaine-like responding were stable after 10 days of handling compared to baseline. Repeated stress produced a transient left-ward shift in cocaine-like responding, indicating increased sensitivity to the cocaine cue. ED50 values after variable stress did not differ from baseline, although maximal cocaine-like responding was lower at the two highest doses of cocaine tested at which variably stressed rats exhibited more saline-like responding. Alterations in DAT and NET were found in the Repeated Stress group and DAT and SERT in the Variable Stress group in select brain regions which may be responsible for differences in behavior
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
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
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
Adversarial testing of global neuronal workspace and integrated information theories of consciousness
No full text\ua9 2025. The Author(s). Different theories explain how subjective experience arises from brain activity1,2. These theories have independently accrued evidence, but have not been directly compared3. Here we present an open science adversarial collaboration directly juxtaposing integrated information theory (IIT)4,5 and global neuronal workspace theory (GNWT)6-10 via a theory-neutral consortium11-13. The theory proponents and the consortium developed and preregistered the experimental design, divergent predictions, expected outcomes and interpretation thereof12. Human participants (n = 256) viewed suprathreshold stimuli for variable durations while neural activity was measured with functional magnetic resonance imaging, magnetoencephalography and intracranial electroencephalography. We found information about conscious content in visual, ventrotemporal and inferior frontal cortex, with sustained responses in occipital and lateral temporal cortex reflecting stimulus duration, and content-specific synchronization between frontal and early visual areas. These results align with some predictions of IIT and GNWT, while substantially challenging key tenets of both theories. For IIT, a lack of sustained synchronization within the posterior cortex contradicts the claim that network connectivity specifies consciousness. GNWT is challenged by the general lack of ignition at stimulus offset and limited representation of certain conscious dimensions in the prefrontal cortex. These challenges extend to other theories of consciousness that share some of the predictions tested here14-17. Beyond challenging the theories, we present an alternative approach to advance cognitive neuroscience through principled, theory-driven, collaborative research and highlight the need for a quantitative framework for systematic theory testing and building
