Diabetes is associated with cognitive dysfunction and an increased risk of dementia. This article addresses findings with brain MRI that may underlie cognitive dysfunction in diabetes. Studies in ...adults with type 1 diabetes show regional reductions in brain volume. In those with a diabetes onset in childhood, these volume reductions are likely to reflect the sum of changes that occur during brain development and changes that occur later in life due to exposure to diabetes-related factors. Type 2 diabetes is associated with global brain atrophy and an increased burden of small-vessel disease. These brain changes occur in the context of aging and often also in relation to an adverse vascular risk factor profile. Advanced imaging techniques detect microstructural lesions in the cerebral gray and white matter of patients with diabetes that affect structural and functional connectivity. Challenges are to further unravel the etiology of these cerebral complications by integrating findings from different imaging modalities and detailed clinical phenotyping and by linking structural MRI abnormalities to histology. A better understanding of the underlying mechanisms is necessary to establish interventions that will improve long-term cognitive outcomes for patients with type 1 and type 2 diabetes.
Cognitive dysfunction is increasingly recognized as an important comorbidity of diabetes mellitus. Different stages of diabetes-associated cognitive dysfunction exist, each with different cognitive ...features, affected age groups and prognoses and probably with different underlying mechanisms. Relatively subtle, slowly progressive cognitive decrements occur in all age groups. More severe stages, particularly mild cognitive impairment and dementia, with progressive deficits, occur primarily in older individuals (>65 years of age). Patients in the latter group are the most relevant for patient management and are the focus of this Review. Here, we review the evolving insights from studies on risk factors, brain imaging and neuropathology, which provide important clues on mechanisms of both the subtle cognitive decrements and the more severe stages of cognitive dysfunction. In the majority of patients, the cognitive phenotype is probably defined by multiple aetiologies. Although both the risk of clinically diagnosed Alzheimer disease and that of vascular dementia is increased in association with diabetes, the cerebral burden of the prototypical pathologies of Alzheimer disease (such as neurofibrillary tangles and neuritic plaques) is not. A major challenge for researchers is to pinpoint from the spectrum of diabetes-related disease processes those that affect the brain and contribute to development of dementia beyond the pathologies of Alzheimer disease. Observations from experimental models can help to meet that challenge, but this requires further improving the synergy between experimental and clinical scientists. The development of targeted treatment and preventive strategies will therefore depend on these translational efforts.
Cerebral small vessel disease (SVD) is an important cause of cognitive impairment. Important MRI manifestations of SVD include white matter hyperintensities (WMH) and lacunes. This narrative review ...addresses the role of anatomical lesion location in the impact of SVD on cognition, integrating findings from early autopsy studies with emerging findings from recent studies with advanced image analysis techniques. Early autopsy and imaging studies of small case series indicate that single lacunar infarcts in, for example the thalamus, caudate nucleus or internal capsule can cause marked cognitive impairment. However, the findings of such case studies may not be generalizable. Emerging location-based image analysis approaches are now being applied to large cohorts. Recent studies show that WMH burden in strategic white matter tracts, such as the forceps minor or anterior thalamic radiation (ATR), is more relevant in explaining variance in cognitive functioning than global WMH volume. These findings suggest that the future diagnostic work-up of memory clinic patients could potentially be improved by shifting from a global assessment of WMH and lacune burden towards a quantitative assessment of lesion volumes within strategic brain regions. In this review, a summary of currently known strategic regions for SVD-related cognitive impairment is provided, highlighting recent technical developments in SVD research. The potential and challenges of location-based approaches for diagnostic purposes in clinical practice are discussed, along with their potential prognostic and therapeutic applications.
Type 2 diabetes is associated with cognitive dysfunction and structural brain changes. Abnormalities in glucose regulation are involved in several complications related to type 2 diabetes, but their ...role in these cerebral complications is unclear. We systematically reviewed studies of the association between glucose regulation (glycaemia, hypoglycaemic events, insulin concentration, insulin resistance, and glucose-lowering treatment) and cognitive function and brain abnormalities on MRI in people with type 2 diabetes. The 86 papers included showed that glycaemia, particularly high HbA1c concentration and glucose variability, are negatively associated with cognitive function in people with type 2 diabetes without dementia. However, the strength of this association is weak, and HbA1c generally accounted for less than 10% of the variance in cognition. Importantly, few studies have measured long-term cerebral outcomes, such as dementia and structural brain changes on MRI, and the effect of glucose-lowering treatment on these outcomes. More randomised controlled trials are needed to establish the effect of glucose-lowering treatment on long-term cognitive function in people with type 2 diabetes.
Diabetes mellitus is associated with cognitive deficits and an increased risk of dementia, particularly in the elderly. These deficits are paralleled by neurophysiological and structural changes in ...the brain. In animal models of diabetes, impairments of spatial learning occur in association with distinct changes in hippocampal synaptic plasticity. At the molecular level these impairments might involve changes in glutamate-receptor subtypes, in second-messenger systems and in protein kinases. The multifactorial pathogenesis of diabetic encephalopathy is not yet completely understood, but clearly shares features with brain ageing and the pathogenesis of diabetic neuropathy. It involves both metabolic and vascular changes, related to chronic hyperglycaemia, but probably also defects in insulin action in the brain. Treatment with insulin might therefore not only correct hyperglycaemia, but could also directly affect the brain.
Vascular cognitive impairment is an umbrella term for cognitive dysfunction associated with and presumed to be caused by vascular brain damage. Autopsy studies have identified microinfarcts as an ...important neuropathological correlate of vascular cognitive impairment that escapes detection by conventional magnetic resonance imaging (MRI). As a frame of reference for future high-resolution MRI studies, we systematically reviewed the literature on neuropathological studies on cerebral microinfarcts in the context of vascular disease, vascular risk factors, cognitive decline and dementia. We identified 32 original patient studies involving 10,515 people. The overall picture is that microinfarcts are common, particularly in patients with vascular dementia (weighted average 62%), Alzheimer's disease (43%), and demented patients with both Alzheimer-type and cerebrovascular pathology (33%) compared with nondemented older individuals (24%). In many patients, multiple microinfarcts were detected. Microinfarcts are described as minute foci with neuronal loss, gliosis, pallor, or more cystic lesions. They are found in all brain regions, possibly more so in the cerebral cortex, particularly in watershed areas. Reported sizes vary from 50 μm to a few mm, which is within the detection limit of current high-resolution MRI. Detection of these lesions in vivo would have a high potential for future pathophysiological studies in vascular cognitive impairment.
Abstract
Objective
The objective is to formulate clinical practice guidelines for the treatment of diabetes in older adults.
Conclusions
Diabetes, particularly type 2, is becoming more prevalent in ...the general population, especially in individuals over the age of 65 years. The underlying pathophysiology of the disease in these patients is exacerbated by the direct effects of aging on metabolic regulation. Similarly, aging effects interact with diabetes to accelerate the progression of many common diabetes complications. Each section in this guideline covers all aspects of the etiology and available evidence, primarily from controlled trials, on therapeutic options and outcomes in this population. The goal is to give guidance to practicing health care providers that will benefit patients with diabetes (both type 1 and type 2), paying particular attention to avoiding unnecessary and/or harmful adverse effects.
Screening, treatment, and management of diabetes mellitus and complications in older patients.
Pooling of multicenter brain imaging data is a trend in studies on ageing related brain diseases. This poses challenges to MR-based brain segmentation. The performance across different field ...strengths of three widely used automated methods for brain volume measurements was assessed in the present study.
Ten subjects (mean age: 64 years) were scanned on 1.5T and 3T MRI on the same day. We determined robustness across field strength (i.e., whether measured volumes between 3T and 1.5T scans in the same subjects were similar) for SPM12, Freesurfer 5.3.0 and FSL 5.0.7. As a frame of reference, 3T MRI scans from 20 additional subjects (mean age: 71 years) were segmented manually to determine accuracy of the methods (i.e., whether measured volumes corresponded with expert-defined volumes).
Total brain volume (TBV) measurements were robust across field strength for Freesurfer and FSL (mean absolute difference as % of mean volume ≤ 1%), but less so for SPM (4%). Gray matter (GM) and white matter (WM) volume measurements were robust for Freesurfer (1%; 2%) and FSL (2%; 3%) but less so for SPM (5%; 4%). For intracranial volume (ICV), SPM was more robust (2%) than FSL (3%) and Freesurfer (9%). TBV measurements were accurate for SPM and FSL, but less so for Freesurfer. For GM volume, SPM was accurate, but accuracy was lower for Freesurfer and FSL. For WM volume, Freesurfer was accurate, but SPM and FSL were less accurate. For ICV, FSL was accurate, while SPM and Freesurfer were less accurate.
Brain volumes and ICV could be measured quite robustly in scans acquired at different field strengths, but performance of the methods varied depending on the assessed compartment (e.g., TBV or ICV). Selection of an appropriate method in multicenter brain imaging studies therefore depends on the compartment of interest.
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