To present the testretest and contrast dose effect results of cerebral blood volume (CBV) functional MRI (fMRI) in healthy human volunteers using ferumoxytol (Feraheme), an ultrasmall-superparamagnetic iron oxide (USPIO) nanoparticle.... more
To present the testretest and contrast dose effect results of cerebral blood volume (CBV) functional MRI (fMRI) in healthy human volunteers using ferumoxytol (Feraheme), an ultrasmall-superparamagnetic iron oxide (USPIO) nanoparticle. This was an open-label, two-period, fixed-sequence study in healthy young volunteers. In eight subjects, using a 3 Tesla field strength system, blood oxygen level dependent (BOLD) and CBV fMRI were acquired in response to a visual black-and-white checkboard stimulation paradigm using an escalating ferumoxytol dose design (250, 350, and 510 mg iron). Multiple outcome measures were analyzed including absolute percent signal change (|PSC|, primary endpoint), its contrast-to-noise ratio (CNR) and corresponding z-score, percent CBV change (ΔCBV) and respective CNR, concentration of Fe, and baseline CBV. The |PSC| in the visual cortex increased with ferumoxytol dose and was up to 3 × higher than BOLD fMRI. Test-retest reliability was comparable for BOLD and CBV fMRI. Intraclass correlation coefficients (ICCs) for |PSC| were 0.3 (one-sided 95% lower confidence limit = 0.00), 0.81 (0.47), 0.48 (0.00), and 0.3 (0.00) for BOLD and the 250-, 350-, and 510-mg doses of ferumoxytol, respectively. For ΔCBV, ICCs were 0.77 (0.37), 0.48 (0.00), and 0.49 (0.00) for 250 mg, 350 mg, and 510 mg, respectively. This work demonstrates that CBV fMRI techniques and endpoints are dose dependent, robust and have good test-retest repeatability. It also confirms previous findings that USPIO enhances sensitivity of fMRI stimulus-response endpoints. 1 J. Magn. Reson. Imaging 2016.
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Posterior eye shape assessment by magnetic resonance imaging (MRI) is used to study myopia. We tested the hypothesis that optical coherence tomography (OCT), as an alternative, could measure posterior eye shape similarly to MRI. Macular... more
Posterior eye shape assessment by magnetic resonance imaging (MRI) is used to study myopia. We tested the hypothesis that optical coherence tomography (OCT), as an alternative, could measure posterior eye shape similarly to MRI. Macular spectral-domain OCT and brain MRI images previously acquired as part of the Singapore Epidemiology of Eye Diseases study were analyzed. The right eye in the MRI and OCT images was automatically segmented. Optical coherence tomography segmentations were corrected for optical and display distortions requiring biometry data. The segmentations were fitted to spheres and ellipsoids to obtain the posterior eye radius of curvature (Rc) and asphericity (Qxz). The differences in Rc and Qxz measured by MRI and OCT were tested using paired t-tests. Categorical assignments of prolateness or oblateness using Qxz were compared. Fifty-two subjects (67.8 ± 5.6 years old) with spherical equivalent refraction from +0.50 to -5.38 were included. The mean paired differen...
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The apolipoprotein E4 (ApoE4) is the strongest genetic risk factor for Alzheimer's disease (AD). The AD brain was shown to be insulin resistant at end stage, but the... more
The apolipoprotein E4 (ApoE4) is the strongest genetic risk factor for Alzheimer's disease (AD). The AD brain was shown to be insulin resistant at end stage, but the interplay between insulin signaling, ApoE4 and Aβ across time, and their involvement in memory decline is unclear. To investigate insulin response in the ageing mouse hippocampus, we crossed the human ApoE-targeted replacement mice with the mutant human amyloid precursor protein (APP) mice (ApoExAPP). While hippocampal Aβ levels were comparable between ApoE3xAPP and ApoE4xAPP mice at 26 weeks, insulin response was impaired in the ApoE4xAPP hippocampus. Insulin treatment was only able to stimulate insulin signaling and increased AMPA-GluR1 phosphorylation in forskolin pre-treated hippocampal slices from ApoE3xAPP mice. In ApoE4xAPP mice, insulin dysfunction was also associated with poorer spatial memory performance. Using dissociated hippocampal neuron in vitro, we showed that insulin response in ApoE3 and ApoE4 neurons increased AMPA receptor-mediated miniature excitatory postsynaptic current (mEPSC) amplitudes and GluR1-subunit insertion. Pre-treatment of ApoE3 neurons with Aβ42 did not affect insulin-mediated GluR1 subunit insertion. However, impaired insulin sensitivity observed only in the presence of ApoE4 and Aβ42, attenuated GluR1-subunit insertion. Taken together, our results suggest that ApoE4 enhances Aβ inhibition of insulin-stimulated AMPA receptor function, which accelerates memory impairment in ApoE4xAPP mice.
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Dementia is a major public health burden characterized by impaired cognition and loss of function. There are limited treatment options due to inadequate understanding of its pathophysiology and underlying causative mechanisms.... more
Dementia is a major public health burden characterized by impaired cognition and loss of function. There are limited treatment options due to inadequate understanding of its pathophysiology and underlying causative mechanisms. Discovery-driven iTRAQ-based quantitative proteomics techniques were applied on frozen brain samples to profile the proteome from vascular dementia (VaD) and age-matched nondementia controls to elucidate the perturbed pathways contributing to pathophysiology of VaD. The iTRAQ quantitative data revealed significant up-regulation of protein-l-isoaspartate O-methyltransferase and sodium-potassium transporting ATPase, while post-translational modification analysis suggested deamidation of catalytic and regulatory subunits of sodium-potassium transporting ATPase. Spontaneous protein deamidation of labile asparagines, generating abnormal l-isoaspartyl residues, is associated with cell aging and dementia due to Alzheimer's disease and may be a cause of neurodegeneration. As ion channel proteins play important roles in cellular signaling processes, alterations in their function by deamidation may lead to perturbations in membrane excitability and neuronal function. Structural modeling of sodium-potassium transporting ATPase revealed the close proximity of these deamidated residues to the catalytic site during E2P confirmation. The deamidated residues may disrupt electrostatic interaction during E1 phosphorylation, which may affect ion transport and signal transduction. Our findings suggest impaired regulation and compromised activity of ion channel proteins contribute to the pathophysiology of VaD.
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Research Interests: Cognitive Science, Neurology, Neuroimaging, Depression, Cognition, and 15 moreActivities of Daily Living, Gait, Stroke, Humans, Walking, Clinical Sciences, Mood Disorders, Time Factors, Age Factors, Neurosciences, Cognition disorders, Psychomotor Performance, Severity of Illness Index, Neuropsychological Tests, and Recovery of Function
Studies on the impact of small vessel disease (SVD) on cognition generally focus on white matter hyperintensity (WMH) volume. The extent to which WMH location relates to cognitive performance has received less attention, but is likely to... more
Studies on the impact of small vessel disease (SVD) on cognition generally focus on white matter hyperintensity (WMH) volume. The extent to which WMH location relates to cognitive performance has received less attention, but is likely to be functionally important. We examined the relation between WMH location and cognition in a memory clinic cohort of patients with sporadic SVD. A total of 167 patients with SVD were recruited from memory clinics. Assumption-free region of interest-based analyses based on major white matter tracts and voxel-wise analyses were used to determine the association between WMH location and executive functioning, visuomotor speed and memory. Region of interest-based analyses showed that WMHs located particularly within the anterior thalamic radiation and forceps minor were inversely associated with both executive functioning and visuomotor speed, independent of total WMH volume. Memory was significantly associated with WMH volume in the forceps minor, indep...
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Numerous diagnostic criteria have tried to tackle the variability in clinical manifestations and problematic diagnosis of vascular cognitive impairment (VCI) but none have been universally accepted. These criteria have not been readily... more
Numerous diagnostic criteria have tried to tackle the variability in clinical manifestations and problematic diagnosis of vascular cognitive impairment (VCI) but none have been universally accepted. These criteria have not been readily comparable, impacting on clinical diagnosis rates and in turn prevalence estimates, research, and treatment. The Vascular Impairment of Cognition Classification Consensus Study (VICCCS) involved participants (81% academic researchers) from 27 countries in an online Delphi consensus study. Participants reviewed previously proposed concepts to develop new guidelines. VICCCS had a mean of 122 (98-153) respondents across the study and a 67% threshold to represent consensus. VICCCS redefined VCI including classification of mild and major forms of VCI and subtypes. It proposes new standardized VCI-associated terminology and future research priorities to address gaps in current knowledge. VICCCS now proposed a consensus-based updated conceptualization of VCI...
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The Stroke and Cognition consortium (STROKOG) aims to facilitate a better understanding of the determinants of vascular contributions to cognitive disorders and help improve the diagnosis and treatment of vascular cognitive disorders... more
The Stroke and Cognition consortium (STROKOG) aims to facilitate a better understanding of the determinants of vascular contributions to cognitive disorders and help improve the diagnosis and treatment of vascular cognitive disorders (VCD). Longitudinal studies with ≥75 participants who had suffered or were at risk of stroke or TIA and which evaluated cognitive function were invited to join STROKOG. The consortium will facilitate projects investigating rates and patterns of cognitive decline, risk factors for VCD, and biomarkers of vascular dementia. Currently, STROKOG includes 25 (21 published) studies, with 12,092 participants from five continents. The duration of follow-up ranges from 3 months to 21 years. Although data harmonization will be a key challenge, STROKOG is in a unique position to reuse and combine international cohort data and fully explore patient level characteristics and outcomes. STROKOG could potentially transform our understanding of VCD and have a worldwide impact on promoting better vascular cognitive outcomes.
Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide... more
Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinni...
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We examined the risk factors of cortical cerebral microinfarcts (CMIs) on 3T MRI and their association with cognitive impairment. Participants (aged 60 years and older) from the multiethnic Epidemiology of Dementia In Singapore Study... more
We examined the risk factors of cortical cerebral microinfarcts (CMIs) on 3T MRI and their association with cognitive impairment. Participants (aged 60 years and older) from the multiethnic Epidemiology of Dementia In Singapore Study underwent detailed neuropsychological testing and 3T brain MRI. Cortical CMIs were graded using a previously validated protocol. Cognitive impairment was categorized into cognitive impairment, no dementia (CIND)-mild, CIND-moderate, and dementia. Cognitive function was summarized as composite and domain-specific z scores. Among 861 participants, 54 (6.3%) had ≥1 cortical CMI. In multivariate-adjusted models, the risk factors of cortical CMIs were increasing age, Malay ethnicity, hypertension, diabetes, history of stroke, and markers of both large (cortical infarcts and intracranial stenosis) and small (lacunar infarcts, white matter hyperintensities, cerebral microbleeds) vessel disease. Presence of cortical CMIs was associated with CIND-moderate (odds ...
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Intracranial stenosis is a common vascular lesion observed in Asian and other non-Caucasian stroke populations. However, its role in cognitive impairment and dementia has been under-studied. We, therefore, examined the association of... more
Intracranial stenosis is a common vascular lesion observed in Asian and other non-Caucasian stroke populations. However, its role in cognitive impairment and dementia has been under-studied. We, therefore, examined the association of intracranial stenosis with cognitive impairment, dementia and their subtypes in a memory clinic case-control study, where all subjects underwent detailed neuropsychological assessment and 3 T neuroimaging including three-dimensional time-of-flight magnetic resonance angiography. Intracranial stenosis was defined as ≥50% narrowing in any of the intracranial arteries. A total of 424 subjects were recruited of whom 97 were classified as no cognitive impairment, 107 as cognitive impairment no dementia, 70 vascular cognitive impairment no dementia, 121 Alzheimer's Disease, and 30 vascular dementia. Intracranial stenosis was associated with dementia (age/gender/education - adjusted odds ratios (OR): 4.73, 95% confidence interval (CI): 1.93-11.60) and vasc...
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The diversity of Singapore's... more
The diversity of Singapore's population affords a unique opportunity to study ethnic variability in the dementias. We sought to explore the effects of ethnicity on the frequency of Alzheimer disease and vascular dementia in a large Singaporean sample. A total of 357 patients were studied: 190 with vascular dementia and 167 with Alzheimer disease. Vascular dementia was more common among Chinese and Malays, whereas Alzheimer disease was more common in Indians and Eurasians. Factors that may contribute to the observed ethnic variability in dementia etiologies include differential frequency of the ApoE-e4 allele, frequency of vascular risk factors, lifestyle choices, and cultural attitudes toward health care utilization.
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Research Interests: Australia, Causality, Comorbidity, Stroke, Prospective studies, and 18 moreHumans, Female, Male, Brain Ischemia, Incidence, Risk factors, Clinical Sciences, Aged, Middle Aged, Adult, Internal medicine Doppler ultrasonography, Risk Factors, Cross Sectional Studies, Acute Ischemic Stroke, Neurosciences, Carotid Stenosis, Cohort Studies, and Carotid Arteries
This meeting successfully catalyzed the establishment of a new working alliance between clinical dementia researches in Asia and identified common goals for the group to attain. The progress toward achieving these goals will be examined... more
This meeting successfully catalyzed the establishment of a new working alliance between clinical dementia researches in Asia and identified common goals for the group to attain. The progress toward achieving these goals will be examined at the next Asia regional meeting, which is being planned for October 2002 in Beijing, China. This new regional working group will work with the IWG to overcome the existing methodological and regulatory obstacles impeding dementia treatment trials in Asia.
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ABSTRACT To evaluate the correlation of the mean and minimal apparent diffusion coefficient values (ADC(mean) , ADC(minimal) ) and dynamic magnetic resonance imaging (MRI) findings with prognostic factors in invasive ductal carcinoma. A... more
ABSTRACT To evaluate the correlation of the mean and minimal apparent diffusion coefficient values (ADC(mean) , ADC(minimal) ) and dynamic magnetic resonance imaging (MRI) findings with prognostic factors in invasive ductal carcinoma. A total of 107 women with invasive ductal cancer underwent breast MRI. The ADC(mean) and ADC(minimal) of the cancers were computed. MRI findings were retrospectively evaluated according to the Breast Imaging Reporting and Data System (BI-RADS) lexicon: mass or nonmass type, mass shape, mass margin, nonmass distribution, and enhancement pattern. Histological records were reviewed for tumor size, lymph node metastasis, histologic grade, and expression of estrogen receptors (ER), progesterone receptors (PR), c-erbB-2(HER2), Ki-67, and epidermal growth factor receptors (EGFR). Correlations of ADC values and MR findings with prognostic factors were determined using the Mann-Whitney U-test and the Kruskal-Wallis test. The mean ADC(minimal) was 0.78 ± 0.24 (× 10⁻³ mm² /s), and the mean ADC(mean) was 1.01 ± 0.23 (× 10⁻³ mm² /s). There was a significant correlation of the ADC(mean) value with ER expression (P = 0.027) and HER2 expression (P = 0.018). There was no significant relationship between ADC(minimal) and prognostic factors or between ADC(mean) and traditional prognostic factors, PR, Ki-67 and EGFR. The majority of the mass type lesions were less than 5 cm in size and the majority of nonmass type lesions were more than 2 cm in size (P = 0.022). The margin of mass was significantly associated with lymph node metastasis (P = 0.031), ER expression (P = 0.013), PR expression (P = 0.036), HER2 expression (P = 0.019), and EGRF expression (P = 0.041). The rim internal enhancement was significantly correlated with Ki-67 expression (P = 0.008). The low ADC(mean) value was related to positive expression of ER and negative expression of HER2. A spiculated margin was related to a good prognosis, but rim enhancement was associated with a poor prognosis.
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Intracranial large artery disease (ICLAD) is a common stroke subtype that carries a poor prognosis. We studied the association of arterial stiffness, a recognized risk factor for atherosclerosis and ICLAD among ethnic Chinese and South... more
Intracranial large artery disease (ICLAD) is a common stroke subtype that carries a poor prognosis. We studied the association of arterial stiffness, a recognized risk factor for atherosclerosis and ICLAD among ethnic Chinese and South Asian ischemic stroke patients. In this prospective study, we recruited consecutive ischemic stroke patients of Chinese and South Asian ethnicity. ICLAD was assessed by transcranial color-coded Doppler or magnetic resonance angiographic studies. Arterial stiffness was measured by carotid-femoral pulse wave velocity (cPWV). Among the 268 patients studied, the prevalence of ICLAD was 54% and median cPWV was 11.4 m/s (interquartile range 9.0-13.6 m/s). Patients with ICLAD had higher cPWV compared with those without (median 11.7 vs. 11.0 m/s, P = 0.015). In multivariate analysis, patients with ICLAD were significantly more likely to have cPWV measurements in the highest quintile (>14.1 m/s) compared with patients without ICLAD independently of other covariates [odds ratio 2.21, P = 0.038]. This study revealed a novel association between arterial stiffness and ICLAD among ischemic stroke patients. The findings suggest that arterial stiffness may be involved in the pathophysiology of ICLAD. Future studies should investigate the effects of reducing arterial stiffness among stroke patients with ICLAD.
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Research Interests: Psychometrics, Dementia, Magnetic Resonance Imaging, Singapore, Localization, and 15 moreStroke, Brain, Complication, Humans, Female, Male, The, Clinical Sciences, Aged, Middle Aged, Nuclear Magnetic Resonance Imaging, Neurosciences, Functional Laterality, Psychiatric Status Rating Scales, and Neuropsychological Tests
Research Interests: Education, Singapore, Natural History, Stroke, Humans, and 24 moreVascular dementia, Female, Male, Follow-up studies, The, Risk factors, Cognitive Performance, Clinical Sciences, Aged, Middle Aged, Longitudinal Studies, Cognitive impairment, Visual Memory, Age Factors, Disease Progression, Verbal Memory, Risk Factors, Indexation, Ischaemic Stroke, Neurosciences, Cognition disorders, Transient ischaemic attack, Cohort Studies, and Neuropsychological Tests
Densities of serotonin transporters (5-HTT) in the postmortem neocortex of behaviorally assessed... more
Densities of serotonin transporters (5-HTT) in the postmortem neocortex of behaviorally assessed Alzheimer's disease (AD) patients and aged controls were measured by radioligand binding with [3H]citalopram. It was found that 5-HTT sites in the temporal cortex of AD patients with prominent antemortem anxiety were unaltered compared with controls, but were reduced in non-anxious AD subjects. Furthermore, homozygosity for the high activity allele of a functional polymorphism in the 5-HTT gene promoter region (5-HTTLPR) was associated with both increased [3H]citalopram binding and occurrence of anxiety in the AD subjects. Since serotonin-synthesizing neurons are known to be lost in the AD cortex, this study suggests that the preservation of 5-HTT may exacerbate serotonergic deficits and underlie anxiety symptoms in AD.
Research Interests: Cognitive Science, Anxiety, Temporal Lobe, Humans, Female, and 16 moreSerotonin Transporter, Male, Membrane transport proteins, Aged, Genotype, Analysis of Variance, Radioligand Assay, Tritium, Neocortex, ANXIETY, Citalopram, Alzheimer Disease, Neurosciences, Frontal Lobe, Serotonin Uptake Inhibitors, and Case Control Studies
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This is the first study to assess cerebral microinfarcts (CMIs) on 3 tesla (3T) magnetic resonance imaging (MRI) in a memory clinic population. We included 238 consecutive patients (aged 72.5 ± 9.1 years) from a memory clinic in... more
This is the first study to assess cerebral microinfarcts (CMIs) on 3 tesla (3T) magnetic resonance imaging (MRI) in a memory clinic population. We included 238 consecutive patients (aged 72.5 ± 9.1 years) from a memory clinic in Singapore. All patients underwent extensive neurological and neuropsychological testing and 3T MRI on the same day. Cortical CMI rating criteria were adapted from a previous study on 7T MRI. We analyzed the frequency and association of cortical CMIs with demographic, clinical, cognition, and other MRI findings. Seventy-five patients (32%) had cortical CMIs (median 1, range 1-43). Patients with CMIs showed worse cognitive functioning on MMSE, and in the domains of language and visuoconstruction. The presence of CMIs was related to other markers of small vessel disease, but most strongly larger cortical infarcts. Patients with CMIs were more often diagnosed with vascular dementia. Cortical CMIs on 3T MRI are a novel marker of cerebrovascular disease in dementia.
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Aggressive behavior in dementia is a major clinical management problem. Postmortem brain tissue was obtained from 24 patients with Alzheimer disease (AD) and 25 comparison cases. [3H] Prazosin binding to alpha1-AdR was determined.... more
Aggressive behavior in dementia is a major clinical management problem. Postmortem brain tissue was obtained from 24 patients with Alzheimer disease (AD) and 25 comparison cases. [3H] Prazosin binding to alpha1-AdR was determined. Aggressive behavior was significantly correlated with alpha1-adrenoceptor number in patients with AD (R(s)=0.454, N=24). Furthermore, patients receiving ongoing neuroleptics had significantly higher Bmax for [3H] prazosin (21 +/- 2, N=9) than those who were not (16 +/- 1, N=15). Upregulation of alpha1-AdR is associated with aggressive behavior and chronic treatment with neuroleptic medication.
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Glutamatergic deficits are well-established neurochemical findings in Alzheimer's disease (AD) and are thought to underlie both cognitive and behavioral symptoms of the disease. However, it is unclear whether subcortical ischemic... more
Glutamatergic deficits are well-established neurochemical findings in Alzheimer's disease (AD) and are thought to underlie both cognitive and behavioral symptoms of the disease. However, it is unclear whether subcortical ischemic vascular dementia (SIVD) and mixed SIVD/AD (MixD) manifest similar changes in the glutamatergic system. To measure the immunoreactivities of NMDA receptor GluN1, GluN2A, and GluN2B subunits in SIVD and MixD. Postmortem neocortical tissues from a cohort of well-characterized, longitudinally followed-up patients with SIVD and MixD, together with age-matched controls, were processed for immunoblotting with GluN subunit-specific antibodies. There was a significant reduction of GluN1 only in MixD, while significant increases of GluN2A and GluN2B were found only in SIVD. Furthermore, GluN1 loss and GluN2A/2B upregulation was associated respectively with higher Braak stages and lacunar infarct scores. Our data suggest that the differential alterations of GluN ...
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We studied the hypothesis that disturbances in 5-HT_{6} receptor function in the temporal cortex may contribute to clinical symptoms of Alzheimer's disease (AD). 5-HT_{6} density and 5-HT levels were significantly decreased in a... more
We studied the hypothesis that disturbances in 5-HT_{6} receptor function in the temporal cortex may contribute to clinical symptoms of Alzheimer's disease (AD). 5-HT_{6} density and 5-HT levels were significantly decreased in a cohort of AD patients prospectively assessed for cognitive/behavioral symptoms. cAMP formation after stimulation with the selective 5-HT_{6} receptor agonist E-6801 was significantly lower (p<0.01) in AD (170.02 +/- 27.53 pmol/mg prot.) compared to controls (823.33 +/-196.67). In addition, the ratio cAMP formation after stimulation with E-6801/5-HT_{6} receptor density was significantly lower (p< 0.01) in AD (6.67 +/- 0.83) compared to controls (16.67 +/- 3.33). Splitting these results by sex, 5-HT_{6} receptor activation was significantly lower…
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Research Interests: Malaysia, Singapore, Treatment, Diet, China, and 16 moreFolic acid, Ethnicity, India, Stroke, Humans, Female, Male, Risk factors, Homocysteine, Ethnic Groups, Clinical Sciences, Aged, Middle Aged, Genotype, Risk Factors, and Neurosciences
Serotonin1A receptor density and serotonin concentration were measured in the postmortem neocortex of 17 AD patients who had been prospectively assessed every four months with the Mini-Mental State Examination (MMSE) for a mean of 2.6... more
Serotonin1A receptor density and serotonin concentration were measured in the postmortem neocortex of 17 AD patients who had been prospectively assessed every four months with the Mini-Mental State Examination (MMSE) for a mean of 2.6 years till death. In the frontal cortex, serotonin levels correlated negatively with the annual rate of MMSE decline, while serotonin1A receptor density was positively correlated with the rate of MMSE decline. Our study suggests that reduced serotonin levels and increased serotonin1A receptor density are markers for accelerated cognitive decline in AD, and provides support for the use of serotonin1A antagonists in the treatment of AD.
Research Interests: Cognitive Science, Serotonin, Humans, Female, Male, and 15 moreNeurons, Aged, Serotonin Receptors, Sex Factors, Radioligand Assay, Neocortex, Age Factors, Disease Progression, Cognitive Decline, Alzheimer Disease, Neurosciences, Predictive value of tests, Cognition disorders, Down-Regulation, and Neuropsychological Tests
Neuropsychiatric behaviours in Alzheimer&#39;s disease (AD) patients have been associated with neocortical alterations of presynaptic cholinergic and muscarinic M2 receptor markers. In contrast, it is unclear whether non-M2 muscarinic... more
Neuropsychiatric behaviours in Alzheimer&#39;s disease (AD) patients have been associated with neocortical alterations of presynaptic cholinergic and muscarinic M2 receptor markers. In contrast, it is unclear whether non-M2 muscarinic receptors have a role to play in AD behavioural symptoms. To correlate the alterations of neocortical postsynaptic muscarinic receptors with clinical features of AD. [(3)H]4-DAMP were used in binding assays with lysates of Chinese hamster ovary (CHO) cells stably transfected with M1-M5 receptors. [(3)H]4-DAMP was further used to measure muscarinic receptors in the postmortem orbitofrontal cortex of aged controls and AD patients longitudinally assessed for cognitive decline and behavioural symptoms. [(3)H]4-DAMP binds to human postmortem brain homogenates and M1-, M3-, M4- and M5-transfected CHO lysates with subnanomolar affinity. Compared to the controls, the [(3)H]4-DAMP binding density is reduced only in AD patients with significant psychotic symptoms. The association between reduced [(3)H]4-DAMP binding and psychosis is independent of the effects of dementia severity or neurofibrillary tangle burden. This study suggests that the loss of non-M2 muscarinic receptors in the orbitofrontal cortex may be a neurochemical substrate of psychosis in AD and provides a rationale for further development of muscarinic receptor ligands in AD pharmacotherapy.
Research Interests: Psychopharmacology, Humans, Female, Animals, Male, and 15 moreOrbitofrontal cortex, Aged, Longitudinal Studies, SYNAPSES, Radioligand Assay, Neocortex, Psychotic Disorders, Transfection, Cognitive Decline, Neurofibrillary Tangles, Muscarinic Receptor, Alzheimer Disease, Cohort Studies, Piperidines, and Neuropsychological Tests
Research Interests: Cognitive Science, Nonparametric Statistics, Electrochemistry, Temporal Lobe, Humans, and 12 moreFemale, Male, Apolipoprotein E, Clinical Sciences, High Pressure Liquid Chromatography, Aged, Alzheimer Disease, Neurosciences, Frontal Lobe, Enzyme Linked Immunosorbent Assay, Gene Expression Regulation, and Neural Cell Adhesion Molecules
Research Interests: Psychopharmacology, Depression, Cognition, Behavior, Drug Use, and 18 moreAggressive Behavior, Serotonin, Hippocampus, Prospective studies, Humans, Female, Serotonin Transporter, Male, Follow-up studies, Aged, Major Depression, Serotonin Receptors, Autopsy, Longitudinal Studies, Citalopram, Depressive Symptoms, Protein Binding, and Alzheimer Disease
There is currently no standardized process for long-term follow-up care. As a result, management of poststroke care varies greatly, and the needs of stroke survivors are not fully addressed. The Post Stroke Checklist was developed by the... more
There is currently no standardized process for long-term follow-up care. As a result, management of poststroke care varies greatly, and the needs of stroke survivors are not fully addressed. The Post Stroke Checklist was developed by the Global Stroke Community Advisory Panel as a means of standardizing long-term stroke care. Since its development, the Post Stroke Checklist has gained international recognition from various stroke networks and is endorsed by the World Stroke Organization to support improved stroke survivor follow-up and care. The aim of this study was to evaluate the feasibility and usefulness of the Post Stroke Checklist in clinical practice and assess its relevance to stroke survivors in pilot studies in the United Kingdom and Singapore. The Post Stroke Checklist was administered to stroke survivors in the United Kingdom (n = 42) and Singapore (n = 100) by clinicians. To assess the feasibility of the Post Stroke Checklist in clinical practice, an independent resear...
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To investigate the prognostic value of the neurocognitive status measured by screening instruments, the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE), individually and in combination with the stroke... more
To investigate the prognostic value of the neurocognitive status measured by screening instruments, the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE), individually and in combination with the stroke severity scale, the National Institute of Health Stroke Scale (NIHSS), obtained at the subacute stroke phase or the baseline (≤2 weeks), for functional outcome 3-6 months later. Prospective observational study. Tertiary stroke neurology service. 400 patients with a recent ischaemic stroke or transient ischaemic attack (TIA) received NIHSS, MoCA and MMSE at baseline and were followed up 3-6 months later. At 3-6 months following the index event, functional outcome was measured by the modified Rankin Scale (mRS) scores. Most patients (79.8%) had a mild ischaemic stroke and less disability (median NIHSS=2, median mRS=2 and median premorbid mRS=0), while a minority of patients had TIA (20.3%). Baseline NIHSS, MMSE and MoCA scores individually predicted mRS scor...
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Changes in the cortisol diurnal rhythm have been found in neuropsychiatric diseases, including anxiety and depression. The aim of this study was to investigate the reliability and reproducibility of cortisol diurnal rhythm in healthy... more
Changes in the cortisol diurnal rhythm have been found in neuropsychiatric diseases, including anxiety and depression. The aim of this study was to investigate the reliability and reproducibility of cortisol diurnal rhythm in healthy males, through determination of the inter- and intrasubject variability, to facilitate evaluation of this biomarker for drug target engagement. This openlabel, 2-period study design evaluated serum cortisol release over a 24-hour period in 18 healthy males. A cosinor model was used to model the cortisol diurnal rhythm, and the inter- and intrasubject coefficients of variation (CVs) were calculated across the 2 periods. Three significant cortisol concentration peaks were observed at ~ 7 AM, 1 PM, and 7 PM. The intersubject CVs (%) for the amplitude, acrophase, and midline estimating statistic of rhythm (MESOR) were 18.2, 19.3, and 16.8, respectively. The intrasubject CVs (%) were 11.2, 7.6, and 6.9, respectively. The inter- and intrasubject CVs (%) for the lunch-induced 1 PM peak and the&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; dinner-induced 7 PM peak were 22.1, 17.3, 44.7, and 22.1 respectively. Assessment of serum cortisol diurnal rhythm suggests that the amplitude, acrophase, and MESOR, but not the meal-induced peaks, have the potential to be a reliable biomarker in drug development targeting the hypothalamic- pituitary-adrenocortical (HPA) axis.
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Research Interests:
Intracranial large artery disease (ICLAD) is a major cause of ischemic stroke. Retinal microvascular changes are associated with stroke, including small vessel cerebral disease and extracranial carotid disease. We examined the... more
Intracranial large artery disease (ICLAD) is a major cause of ischemic stroke. Retinal microvascular changes are associated with stroke, including small vessel cerebral disease and extracranial carotid disease. We examined the relationship between ICLAD and retinal microvascular changes. This is a prospective cohort of 802 acute ischemic stroke patients. Retinal changes were assessed from photographs by graders masked to clinical data. ICLAD was evaluated using prespecified criteria. ICLAD was not associated with ipsilateral retinal arteriolar/venular caliber, focal arteriolar narrowing, or arteriovenous nicking. Severe enhanced arteriolar light reflex was independently associated with any ICLAD (P=0.006) and severe ICLAD (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001). Enhanced arteriolar light reflex, but not retinal vessel caliber, was related to ICLAD. These data suggest that retinal microvascular signs have specific associations with large cerebral vessel disease.
Research Interests:
Research Interests:
Elevated concentrations of homocysteine are associated with cerebral small vessel disease (CSVD). B-vitamin supplementation with folate and vitamins B12 and B6 reduces homocysteine concentrations. In a substudy of the VITAmins TO Prevent... more
Elevated concentrations of homocysteine are associated with cerebral small vessel disease (CSVD). B-vitamin supplementation with folate and vitamins B12 and B6 reduces homocysteine concentrations. In a substudy of the VITAmins TO Prevent Stroke (VITATOPS) trial, we assessed the hypothesis that the addition of once-daily supplements of B vitamins would reduce the progression of CSVD-related brain lesions. A total of 359 patients with recent stroke or transient ischemic attack, who were randomly allocated to double-blind treatment with placebo or b vitamins, underwent brain MRI at randomization and after 2 years of B-vitamin supplementation. MR images were analyzed blinded to treatment allocation. Outcomes related to the prespecified hypothesis were progression of white matter hyperintensities and incident lacunes. We also explored the effect of B-vitamin supplementation on the incidence of other ischemic abnormalities. After 2 years of treatment with b vitamins or placebo, there was no significant difference in white matter hyperintensities volume change (0.08 vs 0.13 cm3; P=0.419) and incidence of lacunes (8.0% vs 5.9%, P=0.434; odds ratio=1.38). In a subanalysis of patients with MRI evidence of severe CSVD at baseline, b-vitamin supplementation was associated with a significant reduction in white matter hyperintensities volume change (0.3 vs 1.7 cm3; P=0.039). Daily B-vitamin supplementation for 2 years did not significantly reduce the progression of brain lesions resulting from presumed CSVD in all patients with recent stroke or transient ischemic attack but may do so in the subgroup of patients with recent stroke or transient ischemic attack and severe CSVD. http://vitatops.highway1.com.au/. Unique identifier: NCT00097669 and ISRCTN74743444.