Vincent Mok

Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration

Summary Cerebral small vessel disease (SVD) is a common accompaniment of ageing. Features seen on neuroimaging include recent small subcortical infarcts, lacunes, white matter hyperintensities, perivascular spaces, microbleeds, and brain atrophy. SVD can present as a stroke or cognitive decline, or can have few or no symptoms. SVD frequently coexists with neurodegenerative disease, and can exacerbate cognitive deficits, physical disabilities, and other symptoms of neurodegeneration. Terminology and definitions for imaging the features of SVD vary widely, which is also true for protocols for image acquisition and image analysis. This lack of consistency hampers progress in identifying the contribution of SVD to the pathophysiology and clinical features of common neurodegenerative diseases. We are an international working group from the Centres of Excellence in Neurodegeneration. We completed a structured process to develop definitions and imaging standards for markers and consequences of SVD. We aimed to achieve the following: first, to provide a common advisory about terms and definitions for features visible on MRI; second, to suggest minimum standards for image acquisition and analysis; third, to agree on standards for scientific reporting of changes related to SVD on neuroimaging; and fourth, to review emerging imaging methods for detection and quantification of preclinical manifestations of SVD. Our findings and recommendations apply to research studies, and can be used in the clinical setting to standardise image interpretation, acquisition, and reporting. This Position Paper summarises the main outcomes of this international effort to provide the STandards for ReportIng Vascular changes on nEuroimaging (STRIVE).

Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease.

To the Editors:Curcumin is a polyphenolic molecule that comprises approximately 5% of turmeric, giving the spice its color but not flavor. It is used in processed foods as a yellow coloring. 1 Because of its anti-inflammatory and antioxidant properties, curcumin has been tested in animal models of A

Cerebral Microbleeds as a Risk Factor for Subsequent Intracerebral Hemorrhages Among Patients With Acute Ischemic Stroke

Background and Purpose— Cerebral microbleeds (MBs) detected by gradient-echo MRI are considered evidence of advanced microangiopathy with potential for further bleeding. The goal of this study was to determine whether the presence of MBs is a risk factor for subsequent intracerebral hemorrhage among patients with acute ischemic stroke. Methods— We prospectively examined patients hospitalized with acute cerebral infarction with gradient-echo T2*-weighted MRI for the presence of MBs. We recorded demographics, medical history, and stroke severity. Patients were then followed up for the development of stroke, other vascular events, and death. Results— One hundred twenty-one consecutive patients with a mean age of 67.96±10.97 years were recruited. MBs were present in 43 patients (35.5%). During follow-up of 27.15±11.68 months, 16 patients had recurrent stroke. There was no difference between patients with or without MB for the development of ischemic stroke (5 and 6 respectively, P =0.841). However, 4 patients (9.3%) with MBs and 1 patient (1.3%) without an MB had intracerebral hemorrhage during follow-up (P =0.053). Of the 5 patients who developed subsequent intracerebral hemorrhages, 3 were treated with aspirin and 2 with anticoagulation. Two of the intracerebral hemorrhages occurred in the site where asymptomatic MBs were found at baseline. Conclusions— MBs appear to be a risk factor for subsequent intracerebral hemorrhage among patients with ischemic stroke in this small cohort of Chinese stroke patients. A large cohort study is required to confirm this observation.

Cognitive impairment and functional outcome after stroke associated with small vessel disease

Objectives: Although stroke associated with small vessel disease (SSVD) can induce both motor and cognitive impairment, the latter has received less attention. We aimed to evaluate the frequency of the varying severity levels of cognitive impairment, the determinants of severe cognitive impairment, and the association of cognitive impairment with functional outcome after SSVD. Methods: Consecutive patients admitted to hospital because of SSVD were assessed at 3 months after stroke. We performed a semi-structured clinical interview to screen for cognitive symptoms. Severity of cognitive symptoms was graded according to the Clinical Dementia Rating Scale (CDR). Performance on psychometric tests (Mini-Mental State Examination, Alzheimer’s Disease Assessment Scale (cognition subscale), Mattis Dementia Rating Scale (initiation/perseverence subscale; MDRS I/P)) of patients of different CDR gradings was compared with that of 42 healthy controls. Basic demographic data, vascular risk factors, stroke severity (National Institute of Health Stroke Scale; NIHSS), pre-stroke cognitive decline (Informant Questionnaire on Cognitive Decline in the Elderly; IQCODE), functional outcome (Barthel index; BI), Instrumental Activities Of Daily Living; IADL), and neuroimaging features (site of recent small infarcts, number of silent small infarcts, white matter changes) were also compared among the groups. Regression analyses were performed to find predictors of severe cognitive impairment and poor functional outcome. Results: Among the 75 included patients, 39 (52%) complained of cognitive symptoms. The number of patients in each CDR grading was as follows: 39 (52%) had a CDR of 0, 26 (34.7%) had a CDR of 0.5, 10 (13.3%) had a CDR of ⩾1. Pre-stroke IQCODE and previous stroke predicted CDR⩾1. The NIHSS was associated with more impaired BI. The NIHSS and MDRS I/P contributed most to impaired IADL. Conclusions: Half of the patients with SSVD complained of varying severity of cognitive problems 3 months after stroke. Pre-stroke cognitive decline and previous stroke predict severe cognitive impairment post stroke. Stroke severity and executive dysfunction contribute most to a poor functional outcome.

Preladenant in patients with Parkinson's disease and motor fluctuations: a phase 2, double-blind, randomised trial

BACKGROUND Preladenant is an adenosine 2A (A₂(A)) receptor antagonist. In animal models of Parkinsons disease, preladenant monotherapy improves motor function without causing dyskinesia and, as an adjunct to levodopa, it improves motor function without worsening dyskinesia. We aimed to assess the efficacy and safety of preladenant in patients with Parkinsons disease and motor fluctuations who were receiving levodopa and other antiparkinsonian drugs. METHODS In this phase 2, dose-finding trial, patients with Parkinsons disease who were receiving levodopa were enrolled and treated at 44 sites in 15 countries between December, 2006, and November, 2008. Assignment to treatment was done centrally with an interactive voice response system, according to a block randomisation schedule that was computer generated by the sponsor. Patients were assigned to receive 1, 2, 5, or 10 mg oral preladenant twice daily, or matching placebo for 12 weeks. Patients, study staff, investigators, and all sponsor personnel were masked to treatment assignment. The primary outcome was change in mean daily off time from baseline to week 12, as assessed by home diaries. Efficacy analysis included all patients who received at least one dose of study drug and had data for assessments after baseline. This trial is registered with ClinicalTrials.gov, number NCT00406029. FINDINGS 253 patients were randomised to receive preladenant (1 mg [n=49], 2 mg [n=49], 5 mg [n=49], 10 mg [n=57]) or placebo (n=49), of whom 234 on preladenant (1 mg [n=47], 2 mg [n=48], 5 mg [n=45], 10 mg [n=49]) and placebo (n=45) were eligible for the efficacy analysis. Mean daily off time from baseline to week 12 was reduced versus placebo in patients on 5 mg preladenant (difference -1·0 h, 95% CI -2·1 to 0·0; p=0·0486) and 10 mg preladenant (-1·2 h, -2·2 to -0·2; p=0·019). Changes in mean daily off time versus placebo were not significant for 1 mg preladenant (0·2 h, -0·9 to 1·2; p=0·753) or 2 mg preladenant (-0·7 h, -1·7 to 0·3; p=0·162). The most common adverse events in the combined preladenant group versus placebo were worsening of Parkinsons disease (22 [11%] vs 4 [9%]), somnolence (20 [10%] vs 3 [6%]), dyskinesia (18 [9%] vs 6 [13%]), nausea (17 [9%] vs 5 [11%]), constipation (15 [8%] vs 1 [2%]), and insomnia (15 [8%] vs 4 [9%]). INTERPRETATION 5 and 10 mg preladenant twice daily might be clinically useful to reduce off time in patients with Parkinsons disease and motor fluctuations. FUNDING Schering-Plough, a subsidiary of Merck.

A randomized controlled trial of surgery vs steroid injection for carpal tunnel syndrome

Background: Decompressive surgery and steroid injection are widely used forms of treatment for carpal tunnel syndrome (CTS) but there is no consensus on their effectiveness in comparison to each other. The authors evaluated the efficacy of surgery vs steroid injection in relieving symptoms in patients with CTS. Methods: The authors conducted a randomized, single blind, controlled trial. Fifty patients with electrophysiologically confirmed idiopathic CTS were randomized and assigned to open carpal tunnel release (25 patients) or to a single injection of steroid (25 patients). Patients were followed up at 6 and 20 weeks. The primary outcome was symptom relief in terms of the Global Symptom Score (GSS), which rates symptoms on a scale of 0 (no symptoms) to 50 (most severe). Nerve conduction studies and grip strength measurements were used as secondary outcome assessments. Results: At 20 weeks after randomization, patients who underwent surgery had greater symptomatic improvement than those who were injected. The mean improvement in GSS after 20 weeks was 24.2 (SD 11.0) in the surgery group vs 8.7 (SD 13.0) in the injection group (p < 0.001); surgical decompression also resulted in greater improvement in median nerve distal motor latencies and sensory nerve conduction velocity. Mean grip strength in the surgical group was reduced by 1.7 kg (SD 5.1) compared with a gain of 2.4 kg (SD 5.5) in the injection group. Conclusion: Compared with steroid injection, open carpal tunnel release resulted in better symptomatic and neurophysiologic outcome but not grip strength in patients with idiopathic carpal tunnel syndrome over a 20-week period.

The Validity, Reliability and Clinical Utility of the Hong Kong Montreal Cognitive Assessment (HK-MoCA) in Patients with Cerebral Small Vessel Disease

Background/Aims: To evaluate the psychometric properties of the Hong Kong Montreal Cognitive Assessment (HK-MoCA) in patients with cerebral small vessel disease (SVD). Methods: 40 SVD patients and 40 matched controls were recruited. Concurrent and criterion validity, inter-rater and test-retest reliability, internal consistency of the HK-MoCA were examined and clinical observations were made. Results: Performance on the HK-MoCA was significantly predicted by both executive (β = 0.23, p = 0.013) and non-executive (β = 0.64, p < 0.001) composite scores. It differentiated SVD patients from controls (area under the curve = 0.81, p < 0.001) with an optimal cutoff at 21/22. Reliability, internal consistency and clinical utility were good. Conclusion: The HK-MoCA is a useful cognitive screening instrument for use in SVD patients.

Validation of a new REM sleep behavior disorder questionnaire (RBDQ-HK)☆

OBJECTIVES There are limited screening instruments for diagnosis of REM sleep behavior disorder (RBD) and none for quantifying the severity of disease. We aimed to validate a 13-item self-reported RBD questionnaire (RBDQ-HK) for diagnostic and monitoring purposes. METHODS Based on ICSD-II and our previous clinical and empirical work, the RBDQ-HK questionnaire was designed and administered in patients attending university-affiliated sleep clinic and psychiatric out-patient clinic, and subjects from the general population. ROC curve and exploratory factor analysis were employed to evaluate the scale, which had a score ranging from 0 to 100. RESULTS One hundred and seven RBD patients [mean age 62.6 (15.5) years; male 70.1%] and 107 control subjects [mean age 55.3 (9.0) years, male 57.9%] completed the questionnaire. The diagnoses of all the study subjects were independently ascertained by clinical interview and PSG. RBD patients had a significantly higher total RBDQ-HK score [mean (s.d.): 32.1 (16.1), range 3-71] than the control group [9.5 (10.2), range 0-55] (p<0.005). The RBDQ-HK demonstrated robust psychometric properties with moderate sensitivity (82.2%), specificity (86.9%), positive predictive value (PPV; 86.3%), and negative predictive value (NPV; 83.0%), high internal consistency and test-retest reliability. Exploratory factor analysis revealed two components (dream-related and behavioral factors) that corresponded to the essential clinical features of RBD. The best cut-off for total score (range 0-100) was at 18/19 and the best cut-off for factor 2 (behavioral factors including sleep talking, shouting, limb movements and sleep-related injuries, range 0-70) was at 7/8. CONCLUSIONS The RBDQ-HK has satisfactory validity and reliability as a measure of clinical RBD symptoms and severity. It may serve as an effective tool for diagnosis and evaluation of the disease course to facilitate future clinical and research studies.

Large-scale replication and heterogeneity in Parkinson disease genetic loci

Objective: Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown. Methods: Investigators from the Genetic Epidemiology of Parkinsons Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry. Results: In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78–0.87 (LAMP3, BST1, and MAPT) and susceptibility per-allele odds ratios of 1.14–1.43 (STK39, GAK, SNCA, LRRK2, SYT11, and HIP1R). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (I2 estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA, LRRK2, LAMP3, HIP1R, and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD. Conclusion: Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity. Neurology® 2012;79:659–667

Automatic Detection of Cerebral Microbleeds From MR Images via 3D Convolutional Neural Networks

Cerebral microbleeds (CMBs) are small haemorrhages nearby blood vessels. They have been recognized as important diagnostic biomarkers for many cerebrovascular diseases and cognitive dysfunctions. In current clinical routine, CMBs are manually labelled by radiologists but this procedure is laborious, time-consuming, and error prone. In this paper, we propose a novel automatic method to detect CMBs from magnetic resonance (MR) images by exploiting the 3D convolutional neural network (CNN). Compared with previous methods that employed either low-level hand-crafted descriptors or 2D CNNs, our method can take full advantage of spatial contextual information in MR volumes to extract more representative high-level features for CMBs, and hence achieve a much better detection accuracy. To further improve the detection performance while reducing the computational cost, we propose a cascaded framework under 3D CNNs for the task of CMB detection. We first exploit a 3D fully convolutional network (FCN) strategy to retrieve the candidates with high probabilities of being CMBs, and then apply a well-trained 3D CNN discrimination model to distinguish CMBs from hard mimics. Compared with traditional sliding window strategy, the proposed 3D FCN strategy can remove massive redundant computations and dramatically speed up the detection process. We constructed a large dataset with 320 volumetric MR scans and performed extensive experiments to validate the proposed method, which achieved a high sensitivity of 93.16% with an average number of 2.74 false positives per subject, outperforming previous methods using low-level descriptors or 2D CNNs by a significant margin. The proposed method, in principle, can be adapted to other biomarker detection tasks from volumetric medical data.