Christopher Chen

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).

Clopidogrel plus aspirin versus aspirin alone for reducing embolisation in patients with acute symptomatic cerebral or carotid artery stenosis (CLAIR study): A randomised, open-label, blinded-endpoint trial

BACKGROUND Few randomised clinical trials have investigated the use of antithrombotic drugs for early secondary prevention of stroke or transient ischaemic attack in patients with intracranial atherosclerotic stenosis. Microembolic signals, detected by transcranial doppler, are a surrogate marker of future stroke risk and have been used to show treatment efficacy in patients with extracranial carotid stenosis. We aimed to investigate whether treatment with clopidogrel plus aspirin reduced the number of microembolic signals detected with transcranial doppler ultrasound compared with aspirin alone in patients with recent stroke. METHODS The clopidogrel plus aspirin for infarction reduction in acute stroke or transient ischaemic attack patients with large artery stenosis and microembolic signals (CLAIR) trial was a randomised, open-label, blinded-endpoint trial. Between Oct 28, 2003, and Nov 19, 2008, patients with acute ischaemic stroke or transient ischaemic attack who had symptomatic large artery stenosis in the cerebral or carotid arteries and in whom microembolic signals were present on transcranial doppler were randomly assigned within 7 days of symptom onset to receive clopidogrel (300 mg for the first day, then 75 mg daily) plus aspirin (75-160 mg daily) or aspirin alone (75-160 mg daily) for 7 days. Patients were randomly assigned in blocks of four or six by use of a randomisation website. Monitoring of microembolic signals on transcranial doppler was done on days 2 and 7. The primary endpoint was the proportion of patients who had microembolic signals on day 2. Analysis was by modified intention to treat. All analyses were done by an investigator masked to both patient identity and the day the recording was taken. This trial is registered with the Centre for Clinical Trials, Chinese University of Hong Kong, number CUHK_CCT00164. FINDINGS 100 patients were randomly assigned to clopidogrel plus aspirin (n=47) or aspirin monotherapy (n=53). 93 of 100 patients had symptomatic intracranial stenosis in either the intracranial internal carotid artery or the middle cerebral artery: 45 of 46 in the dual therapy group and 48 of 52 in the monotherapy group. At day 2, 14 of 45 patients in the dual therapy group and 27 of 50 patients in the monotherapy group for whom data were available had at least one microembolic signal on transcranial doppler (relative risk reduction 42.4%, 95% CI 4.6-65.2; p=0.025). Adverse events were similar in the two groups. No patients had intracranial or severe systemic haemorrhage, but two patients in the dual therapy group had minor haemorrhages. INTERPRETATION Combination therapy with clopidogrel and aspirin is more effective than aspirin alone in reducing microembolic signals in patients with predominantly intracranial symptomatic stenosis. Clinical trials are now warranted to investigate whether this combination treatment also results in a reduction in stroke incidence.

The Montreal Cognitive Assessment (MoCA) is superior to the Mini-Mental State Examination (MMSE) for the detection of vascular cognitive impairment after acute stroke

BACKGROUND The majority of patient with post-stroke Vascular Cognitive Impairment (VCI) have Vascular Cognitive Impairment No Dementia (VCIND). The Mini-Mental State Examination (MMSE) has been criticized as a poor screening test for VCIND due to insensitivity to visuospatial and executive function impairments. The Montreal Cognitive Assessment (MoCA) was designed to be more sensitive to such deficits and may therefore be a superior screening instrument for VCIND. METHODS Stable patients within 14days of their index stroke without significant physical disability, aphasia, dysarthria, active psychiatric illness or pre-existing dementia were eligible. Cognitive and neurological measures were administered after informed consent. RESULTS 100 patients were recruited. Of the 57 patients with unimpaired MMSE scores, 18 (32%) patients had an impaired MoCA score. By comparison, only 2 out of the 41 (4.9%) patients with unimpaired MoCA scores had impaired MMSE scores. Moreover, MMSE domain subtest scores could not differentiate between groups of differing screening test results, whilst MoCA domain subtest scores (Visuospatial/Executive Function, Attention and Recall) could. CONCLUSION The MoCA is more sensitive than the MMSE in screening for cognitive impairment after acute stroke. Longitudinal studies are required to establish the prognostic value of MoCA and MMSE evaluation in the acute post-stroke period for cognitive impairment as defined by the standard method of formal neuropsychological evaluation 3-6 months after stroke.

Diagnostic criteria for vascular cognitive disorders: A VASCOG statement

Background:Several sets of diagnostic criteria have been published for vascular dementia since the 1960s. The continuing ambiguity in vascular dementia definition warrants a critical reexamination. Methods:Participants at a special symposium of the International Society for Vascular Behavioral and Cognitive Disorders (VASCOG) in 2009 critiqued the current criteria. They drafted a proposal for a new set of criteria, later reviewed through multiple drafts by the group, including additional experts and the members of the Neurocognitive Disorders Work Group of the fifth revision of Diagnostic and Statistical Manual (DSM-5) Task Force. Results:Cognitive disorders of vascular etiology are a heterogeneous group of disorders with diverse pathologies and clinical manifestations, discussed broadly under the rubric of vascular cognitive disorders (VCD). The continuum of vascular cognitive impairment is recognized by the categories of Mild Vascular Cognitive Disorder, and Vascular Dementia or Major Vascular Cognitive Disorder. Diagnostic thresholds are defined. Clinical and neuroimaging criteria are proposed for establishing vascular etiology. Subtypes of VCD are described, and the frequent cooccurrence of Alzheimer disease pathology emphasized. Conclusions:The proposed criteria for VCD provide a coherent approach to the diagnosis of this diverse group of disorders, with a view to stimulating clinical and pathologic validation studies. These criteria can be harmonized with the DSM-5 criteria such that an international consensus on the criteria for VCD may be achieved.

The Montreal Cognitive Assessment is superior to the Mini-Mental State Examination in detecting patients at higher risk of dementia.

BACKGROUND To examine the discriminant validity of the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE) in detecting patients with cognitive impairment at higher risk for dementia at a memory clinic setting. METHODS Memory clinic patients were administered the MoCA, MMSE, and a comprehensive formal neuropsychological battery. Mild cognitive impairment (MCI) subtypes were dichotomized into two groups: single domain-MCI (sd-MCI) and multiple domain-MCI (md-MCI). Area under the receiver operating characteristic curve (ROC) analysis was used to compare the discriminatory ability of the MoCA and the MMSE. RESULTS Two hundred thirty patients were recruited, of which 136 (59.1%) were diagnosed with dementia, 61 (26.5%) with MCI, and 33 (14.3%) with no cognitive impairment (NCI). The majority of MCI patients had md-MCI (n = 36, 59%). The MoCA had significantly larger AUCs than the MMSE in discriminating md-MCI from the lower risk group for incident dementia (NCI and sd-MCI) [MoCA 0.92 (95% CI, 0.86-0.98) vs. MMSE 0.84 (95% CI, 0.75-0.92), p = 0.02). At their optimal cut-off points, the MoCA (19/20) remained superior to the MMSE (23/24) in detecting md-MCI [sensitivity: 0.83 vs. 0.72; specificity: 0.86 vs. 0.83; PPV: 0.79 vs. 0.72; NPV: 0.89 vs. 0.83; correctly classified: 85.1% vs. 78.7%]. CONCLUSION The MoCA is superior to the MMSE in the detection of patients with cognitive impairment at higher risk for incident dementia at a memory clinic setting.

Regional Multiple Pathology Scores Are Associated with Cognitive Decline in Lewy Body Dementias.

Dementia with Lewy bodies (DLB) and Parkinsons disease dementia (PDD) are characterized by the presence of α‐synuclein‐containing Lewy bodies and Lewy neurites. However, both dementias also show variable degrees of Alzheimers disease (AD) pathology (senile plaques and neurofibrillary tangles), particularly in areas of the cortex associated with higher cognitive functions. This study investigates the contribution of the individual and combined pathologies in determining the rate of cognitive decline. Cortical α‐synuclein, phosphorylated tau (phosphotau) and Aβ plaque pathology in 34 PDD and 55 DLB patients was assessed semi‐quantitatively in four regions of the neocortex. The decline in cognition, assessed by Mini Mental State Examination, correlated positively with the cortical α‐synuclein load. Patients also had varying degrees of senile Aβ plaque and phosphotau pathology. Regression analyses pointed to a combined pathology (Aβ plaque plus phosphotau plus α‐synuclein‐positive features), particularly in the prefrontal cortex (BA9) and temporal lobe neocortex with the superior and middle temporal gyrus (BA21, 22), being a major determining factor in the development of dementia. Thus, cognitive decline in Lewy body dementias is not a consequence of α‐synuclein‐induced neurodegeneration alone but senile plaque and phosphorylated tau pathology also contribute to the overall deficits.

Severity of CIND and MCI predict incidence of dementia in an ischemic stroke cohort

Background: The utility of poststroke cognitive status, namely dementia, cognitive impairment no dementia (CIND), mild cognitive impairment (MCI), and no cognitive impairment (NCI), in predicting dementia has been previously examined. However, no studies to date have compared the ability of subtypes of MCI and CIND to predict dementia in a poststroke population. Methods: A cohort of ischemic stroke patients underwent neuropsychological assessment annually for up to 5 years. Dementia was defined using the DSM-IV criteria. Univariate and multivariable Cox proportional regression was performed to determine the ability of MCI subtypes, CIND severity, and individual domains of impairment to predict dementia. Results: A total of 362 patients without dementia were followed up for a mean of 3.4 years (17% drop out), with 24 developing incident dementia. Older age, previous and recurrent stroke, and CIND and MCI subtypes were significant predictors of dementia. In multivariable analysis controlling for treatment allocation, patients who were older, had previous or recurrent stroke, and had either CIND moderate or multiple domain MCI with amnestic component were at elevated risk for dementia. In multivariable domain analysis, recurrent strokes, age, and previous strokes, verbal memory, and visual memory were significant predictors of dementia. Receiver operating characteristic curve analysis showed that CIND moderate (area under the curve: 0.893) and multiple domain MCI with amnestic component (area under the curve: 0.832) were significant predictors of conversion to dementia. All other classifications of cognitive impairment had areas under the curve less than 0.7. Conclusion: Stroke patients with cognitive impairment no dementia (CIND) moderate are at higher risk of developing dementia, while CIND mild patients are not at increased risk of developing dementia.

Danqi Piantang Jiaonang (DJ), a Traditional Chinese Medicine, in Poststroke Recovery

Background and Purpose— Stroke is a leading cause of death and disability worldwide. Despite improvements in acute stroke treatment, many patients only make a partial or poor recovery. Therefore, there is a need for treatments that would further improve outcome. Danqi Piantang Jiaonang (DJ; NeuroAid), a traditional Chinese medicine widely used in China to improve recovery after stroke, has been compared with another traditional Chinese medicine in 2 unpublished randomized clinical trials. The results of these studies were pooled and reanalyzed to assess efficacy and safety. Methods— Six hundred five subjects were randomized in 2 randomized double-blinded, controlled trials to receive either DJ or Buchang Naoxintong Jiaonang. Subjects were treated for 1 month. Inclusion criteria were: (1) patients with recent (from 10 days to 6 months) ischemic stroke; (2) patients satisfying Western diagnostic standards for stroke and traditional Chinese medicine standards for diagnosis of apoplexy; and (3) Diagnostic Therapeutic Effects of Apoplexy score ≥10. Results— The functional outcome, measured by the Comprehensive Function Score component of the Diagnostic Therapeutic Effects of Apoplexy scale, showed a statistically significant superiority of DJ over the control treatment group (relative risk, 2.4; 95% CI, 1.28 to 4.51; P=0.007). Tolerance was excellent in both groups. Conclusions— The pooled analysis of 2 unpublished trials of DJ, a traditional Chinese medicine currently approved in China to improve neurological recovery after stroke, shows good tolerability and superiority of DJ over another traditional Chinese medicine also approved for stroke. A large double-blind randomized clinical trial is required to further assess the safety and efficacy of DJ.

Brief screening tests during acute admission in patients with mild stroke are predictive of vascular cognitive impairment 3–6 months after stroke

Objectives To determine the prognostic value of brief cognitive screening tests administered in the subacute stroke phase (initial 2 weeks) for the detection of significant cognitive impairment 3–6 months after stroke, the authors compared the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE). Methods Patients with ischaemic stroke and transient ischaemic attack were assessed with both MoCA and MMSE within 14 days after index stroke, followed by a formal neuropsychological evaluation of seven cognitive domains 3–6 months later. Cognitive outcomes were dichotomised as either no–mild (impairment in ≤2 cognitive domains) or moderate–severe (impairment in ≥3 cognitive domains) vascular cognitive impairment. Area under the receiver operating characteristic (ROC) curve analysis was used to compare discriminatory ability. Results 300 patients were recruited, of whom 239 received formal neuropsychological assessment 3–6 months after the stroke. 60 (25%) patients had moderate–severe VCI. The overall discriminant validity for detection of moderate–severe cognitive impairment was similar for MoCA (ROC 0.85 (95% CI 0.79 to 0.90) and MMSE (ROC 0.83 (95% CI 0.77 to 0.89)), p=0.96). Both MoCA (21/22) and MMSE (25/26) had similar discriminant indices at their optimal cutoff points; sensitivity 0.88 versus 0.88; specificity 0.64 versus 0.67; 70% versus 72% correctly classified. Moreover, both tests had similar discriminant indices in detecting impaired cognitive domains. Conclusions Brief screening tests during acute admission in patients with mild stroke are predictive of significant vascular cognitive impairment 3–6 months after stroke.

Retinal ganglion cell analysis using high-definition optical coherence tomography in patients with mild cognitive impairment and Alzheimer's disease.

BACKGROUND Alzheimers disease (AD) is a neurodegenerative disorder with emerging evidence that it is associated with retinal ganglion cell loss; however, few data exist to establish this association. OBJECTIVE To determine whether macular ganglion cell-inner plexiform layer (GC-IPL) and retinal nerve fiber layer (RNFL), as quantitatively measured by non-invasive in vivo spectral-domain optical coherence tomography (SD-OCT), are altered in patients with AD and mild cognitive impairment (MCI). METHODS Patients with AD and MCI were recruited from dementia/memory clinics, and cognitively normal controls were selected from the Singapore Epidemiology of Eye Disease program. SD-OCT (Cirrus HD-OCT, software version 6.0.2, Carl Zeiss Meditec Inc, Dublin, CA) was used to measure the GC-IPL and RNFL thicknesses. RESULTS Compared with cognitively normal controls (n = 123), patients with AD (n = 100) had significantly reduced GC-IPL thicknesses in all six (superior, superonasal, inferonasal, inferior, inferotemporal, and superotemporal) sectors (mean differences from -3.42 to -4.99 μm, all p < 0.05) and reduced RNFL thickness in superior quadrant (-6.04 μm, p = 0.039). Patients with MCI (n = 41) also had significantly reduced GC-IPL thicknesses compared with controls (mean differences from -3.62 to -5.83 μm, all p < 0.05). Area under receiver operating characteristic curves of GC-IPL were generally higher than that of RNFL to discriminate AD and MCI from the controls. CONCLUSIONS Our data strengthens the link between retinal ganglion cell neuronal and optic nerve axonal loss with AD, and suggest that assessment of macular GC-IPL can be a test to detect neuronal injury in early AD and MCI.