Geert Jan Biessels

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).

Diabetic neuropathies: Update on definitions, diagnostic criteria, estimation of severity, and treatments

Preceding the joint meeting of the 19th annual Diabetic Neuropathy Study Group of the European Association for the Study of Diabetes (NEURODIAB) and the 8th International Symposium on Diabetic Neuropathy in Toronto, Canada, 13–18 October 2009, expert panels were convened to provide updates on classification, definitions, diagnostic criteria, and treatments of diabetic peripheral neuropathies (DPNs), autonomic neuropathy, painful DPNs, and structural alterations in DPNs.

Brain Imaging in Patients With Diabetes A systematic review

Diabetes is associated with impaired cognitive functioning and an increased risk of dementia (1,2). Patients with type 1 diabetes may show mild to moderate slowing of mental speed and diminished mental flexibility, whereas learning and memory are relatively spared (3). In patients with type 2 diabetes, cognitive impairment may be relatively more pronounced, particularly affecting verbal memory or complex information processing (4,5). The pathogenesis is still uncertain, but chronic hyperglycemia, vascular disease, repeated hypoglycemic episodes, and possibly direct effects of insulin on the brain have been implicated (6). Brain imaging studies can help to clarify the pathogenesis. An increasing number of studies report both focal vascular and more global (e.g., atrophy) cerebral changes, but the results are not always consistent. Our aim was to systematically review brain imaging studies in patients with diabetes. Data on the relation of imaging with cognition and with relevant disease variables were also recorded. Medline and EMBASE (1966 to February 2006) were searched with the following medical subject heading terms: computed tomography (CT) and magnetic resonance imaging (MRI) studies: white matter, leukoaraiosis, lacunar infarction, subcortical, periventricular, brain, cerebral, hippocampus, atrophy, MRI, magnetic resonance imaging, CT, and tomography; magnetic resonance spectroscopy (MRS) studies: magnetic resonance spectroscopy, MRS, brain, and cerebral; positron emission tomography (PET), single-photon emission CT (SPECT), and Xenon-enhanced CT studies: cerebral blood flow, glucose metabolism, brain, cerebral, PET, SPECT, Xenon, positron emission tomography, single-photon emission tomography, and tomography; all combined with “diabetes.” The abstracts were screened and potentially relevant articles retrieved. These articles were included if they met the following four criteria: 1 ) original article, written in English, on brain imaging in adult patients with diabetes in comparison with control subjects; 2 ) diagnostic criteria for diabetes specified; 3 ) sample size of at least 20 diabetic patients, or a total sample …

Type 2 diabetes mellitus, hypertension, dyslipidemia and obesity: A systematic comparison of their impact on cognition

Vascular risk factors, such as type 2 diabetes mellitus, hypertension, dyslipidemia and obesity, have been associated with an increased risk of cognitive dysfunction, particularly in the elderly. The aim of this systematic review was to compare these risk factors with regard to the nature and magnitude of the associated cognitive decrements. Cross-sectional and longitudinal studies that assessed cognitive functioning in non-demented persons in relation to diabetes/impaired glucose metabolism (k = 36), hypertension (k = 24), dyslipidemia (k = 7) and obesity (k = 6) and that adjusted or matched for age, gender and education were included. When possible, effect sizes (Cohens d) were computed per cognitive domain. Diabetes and hypertension were clearly associated with cognitive decrements; the results for obesity and dyslipidemia were less consistent. Effect sizes were moderate (median approximately -0.3) for all risk factors. Decline was found in all cognitive domains, although the effects on cognitive speed, mental flexibility and memory were most consistent. Methodological aspects of included studies and implications of these findings are discussed.

Diabetes, hyperglycaemia, and acute ischaemic stroke

Diabetes and ischaemic stroke often arise together. People with diabetes have more than double the risk of ischaemic stroke after correction for other risk factors, relative to individuals without diabetes. Multifactorial treatment of risk factors for stroke-in particular, lifestyle factors, hypertension, and dyslipidaemia-will prevent a substantial number of these disabling strokes. Hyperglycaemia occurs in 30-40% of patients with acute ischaemic stroke, also in individuals without a known history of diabetes. Admission hyperglycaemia is associated with poor functional outcome, possibly through aggravation of ischaemic damage by disturbing recanalisation and increasing reperfusion injury. Uncertainty surrounds the question of whether glucose-lowering treatment for early stroke can improve clinical outcome. Achievement of normoglycaemia in the early stage of stroke can be difficult, and the possibility of hypoglycaemia remains a concern. Phase 3 studies of glucose-lowering therapy in acute ischaemic stroke are underway.

Hyperglycemia in acute ischemic stroke: pathophysiology and clinical management

Patients with acute ischemic stroke frequently test positive for hyperglycemia, which is associated with a poor clinical outcome. This association between poor glycemic control and an unfavorable prognosis is particularly evident in patients with persistent hyperglycemia, patients without a known history of diabetes mellitus, and patients with cortical infarction. To date, however, only one large clinical trial has specifically investigated the effect of glycemic control on stroke outcome. This trial failed to show a clinical benefit, but had several limitations. Despite a lack of clinical evidence supporting the use of glycemic control in the treatment of patients with stroke, international guidelines recommend treating this subset of critically ill patients for hyperglycemia in the hospital setting. This treatment regime is, however, particularly challenging in patients with stroke, and is associated with an increased risk of the patient developing hypoglycemia. Here we review the available evidence linking hyperglycemia to a poor clinical outcome in patients with ischemic stroke. We highlight the pathophysiological mechanisms that might underlie the deleterious effects of hyperglycemia on acute stroke prognosis and systematically review the literature concerning tight glycemic control after stroke. Finally, we provide directions on the use of insulin treatment strategies to control hyperglycemia in this patient group.

Cognitive dysfunction in patients with type 2 diabetes.

People with diabetes mellitus are at increased risk of cognitive dysfunction and dementia. This review explores the nature and severity of cognitive changes in patients with type 2 diabetes. Possible risk factors such as hypo‐ and hyperglycemia, vascular risk factors, micro‐ and macrovascular complications, depression and genetic factors will be examined, as well as findings from brain imaging and autopsy studies. We will show that type 2 diabetes is associated with modest cognitive decrements in non‐demented patients that evolve only slowly over time, but also with an increased risk of more severe cognitive deficits and dementia. There is a dissociation between these two ‘types’ of cognitive dysfunction with regard to affected age groups and course of development. Therefore, we hypothesize that the mild and severe cognitive deficits observed in patients with type 2 diabetes reflect separate processes, possibly with different risk factors and aetiologies. Copyright

Methodological considerations on tract-based spatial statistics (TBSS)

Having gained a tremendous amount of popularity since its introduction in 2006, tract-based spatial statistics (TBSS) can now be considered as the standard approach for voxel-based analysis (VBA) of diffusion tensor imaging (DTI) data. Aiming to improve the sensitivity, objectivity, and interpretability of multi-subject DTI studies, TBSS includes a skeletonization step that alleviates residual image misalignment and obviates the need for data smoothing. Although TBSS represents an elegant and user-friendly framework that tackles numerous concerns existing in conventional VBA methods, it has limitations of its own, some of which have already been detailed in recent literature. In this work, we present general methodological considerations on TBSS and report on pitfalls that have not been described previously. In particular, we have identified specific assumptions of TBSS that may not be satisfied under typical conditions. Moreover, we demonstrate that the existence of such violations can severely affect the reliability of TBSS results. With TBSS being used increasingly, it is of paramount importance to acquaint TBSS users with these concerns, such that a well-informed decision can be made as to whether and how to pursue a TBSS analysis. Finally, in addition to raising awareness by providing our new insights, we provide constructive suggestions that could improve the validity and increase the impact of TBSS drastically.

Diabetic polyneuropathies: update on research definition, diagnostic criteria and estimation of severity

Prior to a joint meeting of the Neurodiab Association and International Symposium on Diabetic Neuropathy held in Toronto, Ontario, Canada, 13‐18 October 2009, Solomon Tesfaye, Sheffield, UK, convened a panel of neuromuscular experts to provide an update on polyneuropathies associated with diabetes (Toronto Consensus Panels on DPNs, 2009). Herein, we provide definitions of typical and atypical diabetic polyneuropathies (DPNs), diagnostic criteria, and approaches to diagnose sensorimotor polyneuropathy as well as to estimate severity. Diabetic sensorimotor polyneuropathy (DSPN), or typical DPN, usually develops on long‐standing hyperglycaemia, consequent metabolic derangements and microvessel alterations. It is frequently associated with microvessel retinal and kidney disease—but other causes must be excluded. By contrast, atypical DPNs are intercurrent painful and autonomic small‐fibre polyneuropathies. Recognizing that there is a need to detect and estimate severity of DSPN validly and reproducibly, we define subclinical DSPN using nerve conduction criteria and define possible, probable, and confirmed clinical levels of DSPN. For conduct of epidemiologic surveys and randomized controlled trials, it is necessary to pre‐specify which attributes of nerve conduction are to be used, the criterion for diagnosis, reference values, correction for applicable variables, and the specific criterion for DSPN. Herein, we provide the performance characteristics of several criteria for the diagnosis of sensorimotor polyneuropathy in healthy subject‐ and diabetic subject cohorts. Also outlined here are staged and continuous approaches to estimate severity of DSPN. Copyright

Metabolic and vascular determinants of impaired cognitive performance and abnormalities on brain magnetic resonance imaging in patients with type 2 diabetes

Aims/hypothesisThe determinants of cerebral complications of type 2 diabetes are unclear. The present study aimed to identify metabolic and vascular factors that are associated with impaired cognitive performance and abnormalities on brain MRI in patients with type 2 diabetes.MethodsThe study included 122 patients and 56 controls. Neuropsychological test scores were divided into five cognitive domains and expressed as standardised z values. Brain MRI scans were rated for white matter lesions (WML), cortical and subcortical atrophy, and infarcts. Data on glucose metabolism, vascular risk factors and micro- and macrovascular disease were collected.ResultsPatients with type 2 diabetes had more cortical (p < 0.001) and subcortical (p < 0.01) atrophy and deep WML (p = 0.02) than the control group and their cognitive performance was worse. In multivariate regression analyses within the type 2 diabetes group, hypertension (p < 0.05) and a history of vascular events (p < 0.01) were associated with worse cognitive performance, while statin use was associated (p < 0.05) with better performance. Retinopathy and brain infarcts on MRI were associated with more severe cortical atrophy (both p < 0.01) and statin use with less atrophy (p < 0.05). Insulin level and brain infarcts were associated with more severe WML and statin use with less severe WML (all p < 0.05).Conclusions/interpretationType 2 diabetes is associated with modest impairments in cognition, as well as atrophy and vascular lesions on MRI. This ‘diabetic encephalopathy’ is a multifactorial condition, for which atherosclerotic (macroangiopathic) vascular disease is an important determinant. Chronic hyperglycaemia, hyperinsulinaemia and hypertension may play additional roles.