Diabetic Microvascular Disease: An Endocrine Society Scientific Statement

Eugene J. Barrett; Zhenqi Liu; Mogher Khamaisi; George L. King; Ronald Klein; Barbara E. K. Klein; Timothy M. Hughes; Suzanne Craft; Barry I. Freedman; Donald W. Bowden; Aaron I. Vinik; Carolina M. Casellini


J Clin Endocrinol Metab. 2017;102(12):4343-4410. 

In This Article

Microvascular Disease and the Brain


Cognitive impairment is a common complication in T2DM.[275] Compared with the general population, the risk of dementia is 1.5 to 2.5 times greater for adults with T2DM.[276–278] Recent data suggest that microvascular pathologies play an important role in the associations between T2DM, Alzheimer's disease (AD), and vascular subtypes of dementia, but little is known about the microvascular mechanisms underlying these associations. There is increased interest in illuminating these mechanisms to tailor and implement intervention strategies aimed at preventing dementia, AD, and cognitive decline in T2DM, as well as in aging populations with T2DM risk factors.

Much work has focused on T2DM-related microvascular complications in peripheral organ systems, including the retina, kidney, and peripheral nerves. Although the brain is seldom discussed as a site of microvascular complications in T2DM, diabetes-associated vascular risk factors predispose individuals to both macrovascular and microvascular complications in the CNS (see Table 4). In particular, T2DMis an established risk factor for cerebral small vessel disease, as well as thrombo-embolic stroke.[279] Cerebrovascular damage in the form of small vessel disease is likely to be a major factor in the association between T2DM and dementia and could explain the increased risk of vascular dementia. Furthermore, data from experimental studies also suggest that metabolic disturbances associated with T2DM may accelerate the development of AD-type pathologies.[280,281]

Mechanisms for Microvascular Complications

Hyperinsulinemia and impaired insulin signaling. Insulin is known to have multiple functions in the CNS.[305] Although there is some controversy regarding whether insulin is synthesized in the adult brain, circulating insulin in the bloodstream is readily transported across the blood-brain barrier (BBB) by a saturable receptor-mediated process.[306–308] Hyperinsulinemia and insulin resistance may downregulate insulin transport across the BBB, leading to reduced insulin levels in the CNS.[309] In select brain circuits (such as the hippocampus), insulin-containing neurons, insulin receptors, and glucose transporter isoforms 4 and 8 are colocalized (,[310] providing an infrastructure for insulinstimulated glucose uptake into neurons to support cognitive function. In addition, other insulin-related mechanisms have also been implicated in normal hippocampal functioning.[311] Insulin receptors are located in the synapses of both astrocytes and neurons, where insulin signaling contributes to synaptogenesis and synaptic remodeling.[311] Insulin also modulates levels of neurotransmitters in the CNS (such as acetylcholine and norepinephrine) that influence cognitive function.[312,313] Given the multifactorial role of insulin in the brain, maintaining proper insulinhomeostasis and insulin receptor activity may be essential for proper brain function and memory.[310]

Chronic hyperinsulinemia is a key early factor in the process leading to insulin resistance and T2DM that may potentially mediate the relationships between T2DM and proinflammatory states, microvascular disease, and AD pathology. Whereas anti-inflammatory effects are observed with low doses of insulin, longterm hyperinsulinemia may exacerbate the inflammatory response and increase markers of oxidative stress.[314]

Intravenous infusions of insulin to levels associated with insulin resistance increased the levels of F2-isopostanes and cytokines in cerebrospinal fluid.[315] Hyperinsulinemia may also potentiate AD pathology [e.g., amyloid β (Aβ) plaques] by causing increased production but reduced extracellular degradation of Aβ, impaired insulin signaling, oxidative stress, inflammatory mechanisms, and coupling of neuronal components by AGEs.[316] The amyloid precursor protein produces Aβ (a peptide of 36 to 43 amino acids). Although best known as a main component of amyloid plaques in association with AD (e.g., Aβ42), there is evidence that Aβ is a highly multifunctional peptide with significant nonpathological activity, including protecting against metal-induced ROS, modifying cholesterol transport, and potentially acting as a transcription factor.[317] Hyperinsulinemia, at levels associated with insulin resistance, can elevate inflammatory markers and Aβ42 in the periphery and the CNS, which may increase the risk of AD.[305] Interestingly, AD pathology may have direct effects on insulin receptors and their signaling. Soluble Aβ can disrupt brain insulin signaling by binding to the insulin receptor,[318] suggesting interactions between T2DM, glucose metabolism in the brain, and AD pathology.

Aβ aggregation also occurs outside the CNS and often is associated with increased cell death.[319] Aβ deposits also occur from the aggregation of the polypeptide hormone islet amyloid polypeptide (IAPP). IAPP aggregates into Aβ deposits and may induce the depletion of islet β-cells in T2DM.[319] Aβ deposits are the most typical morphological islet lesion in T2DM. A recent study reported mixed IAPP and Aβ deposits in the brains of patients with T2DM and vascular dementia or AD.[295] The study found IAPP oligomers and plaques in the temporal lobe gray matter, blood vessels, and perivascular spaces in T2DM patients, but not controls. The study also detected IAPP deposition in blood vessels and brain parenchyma of patients with late-onset AD without clinically apparent T2DM.

Hyperglycemia. In many prediabetic adults, the degree of insulin resistance increases as insulin secretion by pancreatic cells declines, resulting in hyperglycemia of sufficient magnitude to warrant a T2DM diagnosis. Extracellular and intracellular hyperglycemia are two general pathophysiologic mechanisms by which hyperglycemia leads to irreversible tissue damage, even in prediabetic states.[320] Chronic hyperglycemia (both cellular and extracellular) leads to glycation end product formation (discussed later). This may have particular effects on the endothelial cell where intercellular glucose appears to be a significant driver of microvascular dysfunction (see Biochemical Pathways of Microvascular Injury). It also contributes to heart disease, microvascular complications, and intracellular hyperglycemia, and may increase the risk of developing dementia. Among participants without T2DM(random glucose <120 mg/dL), higher normal plasma glucose levels are associated with an increased risk of incident dementia.[299] Individuals with T2DM also had a similar relationship at glucose levels >170 mg/dL.[299] High glucose levels may contribute to an increased risk of dementia through several potential mechanisms, including acute and chronic hyperglycemia and insulin resistance[321] and increased microvascular disease of the CNS.[322–325]

Extracellular hyperglycemia can lead to intracellular hyperglycemia through the increased flux of glucose freely across the cell membrane of many cell types. Excess intracellular glucose not used for energy will enter the polyol pathway, leading to decreased levels of NADPH.[320] NADPH plays a central role in the production of NOand GSH.NOis an important vasodilator; therefore, reductions in NADPH may limit NO production with direct pathologic effects on vasodilation throughout the body, particularly in the kidneys and brain. NADPH also prevents ROS from accumulating and damaging cells, and thus reductions in NADPH can also increase oxidative stress.[326]

Oxidative stress. Oxidative stress in the cerebral parenchyma and blood vessels plays a critical role in the processes associated with cerebrovascular dysfunction, with NADPH oxidase being a major source of ROS.[327–329] ROS can alter vascular regulation through processes involving the formation of peroxynitrite from the reaction between NO and superoxide radical. Consequently, oxidative stress and ROS resulting from mitochondrial dysfunction have been strongly implicated in brain aging, AD, and vascular dementia.[326,330] Overall, several factors related to hyperglycemia may contribute to a chronic hypoperfusive state leading to microscopic tissue damage and regional specific syndromes.[331]

Advanced glycation end products. Another direct result of high circulating levels of unbound glucose is the formation of AGEs. AGEs accumulate with age in the human brain, and may be one possible mechanism linking T2DM to cognitive impairment.[332] One study found AGEs in hallmark neuropathologic features (e.g., neurofibrillary tangles and Aβ plaques) in patients with AD.[333] Older adults with cerebrovascular disease have higher AGEs in cortical neurons and cerebral vessels, which are related to the severity of cognitive impairment.[334] RAGE most likely plays an important role in the brain with respect to inflammation[335] and AD pathology. RAGE is expressed in astrocytes, microglia, and neurons, and is also highly expressed in the endothelial cells within the brain.[336] RAGE expression in the endothelium has important consequences for vascular inflammation and BBB integrity.[337] BBB integrity is an essential factor in Aβ equilibrium in the brain, which is regulated through LDL receptor-related protein 1 and RAGE. The RAGE protein mediates the influx, and the LDL receptor-related protein 1 mediates the efflux of amyloid protein through the BBB.[336] Patients with T2DMnot only produce endogenous AGEs at a higher rate, but they have an upregulation of RAGE expression in the brain.[338] Increased RAGE expression in the T2DMbrain might create an imbalance between the rates of influx and efflux of Aβ through the BBB, promoting uptake of Aβ into the brain and subsequent deposition of Aβ plaques.[339]

Summary of mechanisms. The characteristic metabolic deregulation of T2DM promotes changes in insulin signaling, glucose uptake, ROS formation, and inflammation in the microvasculature that affect BBB integrity. In the brain, hyperinsulinemia promotes insulin resistance and reduces insulin signaling, which is essential to glucose uptake, amyloid regulation, and vascular function. T2DMassociated hyperglycemia leads to the formation of proinflammatory AGEs, which increase RAGE expression in the endothelium and brain. RAGE expression is thought to play a crucial role in BBB integrity through regulating inflammation and the flux of Aβ across the BBB. These factors most likely play important roles in the development of microvascular brain complications and AD pathology seen in T2DM. Considerable progress has been made in imaging microvascular complications and Aβ pathology in living humans, which has enabled a better characterization of microvascular disease in the brain.

Assessment of Brain Complications in T2DM

Neuroimaging is currently the best way to examine the effects of microvascular disease and other brain abnormalities on the human brain in vivo. Neuroimaging techniques aimed at studying microstructural cerebral small vessel disease are the most common. More recent advances enable the imaging and quantification of microstructural and functional abnormalities of the brain, including regional cerebral blood flow (CBF) and functional activation. Recent concerted efforts to standardize the study of small vessel disease have resulted in a position paper from the Standards for Reporting Vascular Changes on n Euroimaging.[340] This paper sets the groundwork for the systematic evaluation of brain structure and function necessary for research using in vivo brain imaging.

Brain atrophy. Longitudinal observational cohorts of brain aging in the general population have shown that brain volume declines as people get older.[341] After adolescence, the total brain volume tends to slowly decrease with age until the fifth to sixth decade of life when volume loss accelerates.[342,343] The average rate of decline is estimated to between 0% and 4%/year.[343,344] It is generally accepted that atrophy is not consistent across brain regions and tissue compartments.[343,345,346] Brain atrophy is thought to be a result of both macrovascular and microvascular abnormalities in the brain.

T2DM is associated with greater total brain atrophy,[347,348] with possible preferential gray matter volume loss in cerebrum,[348] putamen,[348] medial temporal,[349–351] and frontal[350,352] regions. The longitudinal decline in total cerebral brain volume is associated with increasing age, T2DM, hypertension, current smoking, and evidence of cerebral small vessel disease.[353] Cerebellar atrophy shares similar risk factors with longitudinal cerebral atrophy, including T2DM, higher serum glucose, and evidence of cerebral small vessel disease,[353] but appears to be unrelated to hypertension and smoking or heavy drinking.[344,353] Although cerebral and cerebellar volumes do not entirely overlap, T2DM is the strongest common factor related to smaller volumes in both parts of the brain.[353] T2DM is associated with enlargement of the ventricles and higher white matter hyperintensities (WMHs).[354] Individuals with T2DM also had greater longitudinal changes in these measures over 4 years of follow-up, resulting in smaller brain volumes and increases in WMHs and ventricle enlargement.[354]

Recently, studies have directly assessed the relationship between insulin sensitivity and regional brain volume differences. Higher basal insulin resistance, measured by the homeostatic assessment of insulin resistance, was associated with less graymatter in hippocampus and prefrontal regions of the brain among adolescents and young adults without T2DM.[297] In cohorts of late middle-aged adults, greater insulin resistance was associated with both increased atrophy in regions affected by early AD[355] and worse cognitive performance.[356] In longitudinal studies, higher fasting insulin showed small but significant correlations with gray matter atrophy in orbitofrontal cortex and hippocampus.[357] Some studies, however, have not found a relationship between insulin resistance and hippocampus volume in late middle-aged[358] or elderly[359] adults.

The pathological basis for this T2DM-associated global and regional brain atrophy still needs to be resolved. It is likely that T2DM-associated factors, including glucose homeostasis and insulin resistance, play central roles. Yet, the results from the ACCORDMemory in Diabetes clinical trial provide an important caveat when considering the effect of glucose control on brain structure.[296] They showed that intensive glycemic control targeting HbA1c to <6.0%, compared with standard strategy targeting HbA1c to 7.0% to 7.9%, resulted in slightly greater total brain volume, but did not enhance cognition. Intensive therapy was also associated with abnormal white matter and increased mortality in the intensive therapy arm. The findings from the ACCORD-Memory in Diabetes trial thus do not support intensive therapy to reduce the adverse effects of T2DM on the brain.[296] However, these relationships are likely to be mediated by more detailed evidence of cerebrovascular disease and brain integrity. Atrophy is a relatively crude tool when used to assess microvascular complications in the brain.

Alterations in cerebral blood flow and glucose utilization. Clinicians can measure changes in innate brain function relating to cerebrovascular function and glucose utilization by positron emission tomography (PET) using the fludeoxyglucose F18 ligand-PET (FDG-PET) and by magnetic resonance imaging (MRI) through measures of CBF and functional connectivity known as functional MRI (Figure 6). FDG-PET provides insight into regional glucose metabolism in the brain and changes in regional CBF.

Figure 6.

Neuroimaging measures related to cerebral small vessel disease and concomitant pathologies.

Changes in CBF and glucose utilization on FDG-PET are thought to reflect synaptic dysfunction among regional brain networks. AD is characterized by a pattern of reduced CBF and cerebral glucose hypometabolism. Reductions in FDG-PET are associated with increased AD risk and can be observed years before dementia onset.[360,361] Reductions in FDG-PET and CBF are also present in T2DM. Among individuals with prediabetes and T2DM, greater insulin resistance was associated with an AD-like pattern of reduced cerebral glucose metabolic rate in frontal, parietotemporal, and cingulate regions of the brain.[362] Among cognitively normal individuals with a family history of AD, higher fasting glucose levels were significantly associated with lower cerebral glucose metabolic rate in areas differentially affected by AD.[363] FDG-PET imaging studies suggest that hypometabolism of glucose in the brains of individuals with T2DM and those who go on to develop AD may be a product of a generalized metabolic dysregulation of glucose. A recent study showed that impaired glucose tolerance measured in midlife was associated with longitudinal changes in regional CBF (measured using [15] O-water PET scans).[364]

Although MRI-defined total CBF is associated with cognitive functioning, there appears to be no relative differences in total CBF between T2DM patients and controls.[365] T2DM-related alterations in CBF may be regionally specific.[366] In T2DM, total CBF is associated with impaired cognition and total brain volume in cross-sectional analyses, but does not appear to predict changes in cognition or brain volumes over time.[367] Similar patterns have been reported with resting state functional MRIs for insulin-resistant adults.[368] Individuals with T2DM have reduced functional connectivity in brain networks related to AD compared with control subjects, which was associated with insulin resistance in selected brain regions, even when there were no observed between-group differences in brain structure or cognition. Taken together, PET and MRI studies of CBF suggest early alterations occur throughout the brain in areas affected by AD, and these reductions in CBF colocalize with areas of reduced glucose utilization in the brain.

Microvascular ischemia. Ischemia due to microvascular disease manifests itself in several ways in T2DM, including WMHs, subtle alterations in white matter integrity, and lacunar or microinfarction (Figure 6). White matter abnormalities are frequently detected as hyperintense regions on T2-weighted MRIs of the brain in an age-dependent fashion, especially in adults older than 60 years,[369] and these abnormalities may be associated with increased relative risk of stroke and the presence of retinal microvascular abnormalities.[369] Studies of WMH in T2DM show no consistent association. Discrepancies from early studies were attributed to methodological issues, including the use of crude visual rating scales.[370] Studies using semiquantitative rating scales find more consistent relationships between WMH and T2DM, HbA1c, and diabetes duration.[371] However, although some more recent studies using quantitative techniques to measure WMH volume show greater WMH volumes in T2DMcompared with controls,[372] others do not.[348] Diabetes duration, HbA1c and insulin levels, BP, and the presence of infarcts have all been linked to WMH severity.[371,373]

WMH can be considered a downstream event of microscopic white matter abnormalities that exist before they can be visualized on T2-weighted MRI.[374,375] MRI can quantify white matter integrity in several ways. White matter swelling related to fluid influx can be visualized by magnetization transfer imaging (MTI). MTI is a quantitative MRI technique that detects subtle tissue differences that occur with brain aging, beyond the accumulation of WMH and brain atrophy. MTI correlates with macromolecular attenuation, and therefore is believed to largely reflect myelin content. Hypertension and T2DM are associated with abnormalities in MTI within the brain.[376] Diffusion tensor imaging (DTI) is another form of MRI used to assess the microstructural integrity of the brain. DTI measures the diffusion (movement) of water molecules within each voxel. For example, water molecules restricted by dense membranes move less than unrestricted molecules. DTI is used to assess neuronal density in the gray matter. DTI enables the tractography of white matter tracts, which cannot be resolved using traditional MRI techniques. Furthermore, DTI enables the quantification of white matter integrity within the tracts in axonal and radial directions. Fractional anisotropy is a composite of the axonal and radial diffusivity of water molecules perpendicular to (radial) and along (axonal) the individual white matter tract. In simple terms, proper integrity of white matter tracts should result in high axonal diffusivity and high FAs along the tract. Axonal breaks and rarefication of the surrounding myelin result in lower diffusion of water molecules in the axonal plane and more diffusion in the radial plane, resulting in lower FAs. Several studies using DTI show white matter integrity may be compromised in children with T1DM[377,378] and adults with T2DM.[348,379,380] T2DM is associated with lower FAs in the total white matter, greater bilateral mean diffusivity for the hippocampus and dostolateral prefrontal cortex, and greater lateralized mean diffusivity for the posterior cingulate and right putamen.[348] Studies reporting differences in white matter microstructure between controls and T2DM patients do not report significant differences in WMH derived by conventional MRI scans. The associations between T2DM and lower FAs along select white matter tracts extend to other T2DMrelated conditions, including metabolic syndrome[381] and depression.[382]

Lacunar infarction is another form of microvascular brain disease that produces a round or ovoid, subcortical, fluid-filled cavity. This cavity is visible by brain computed tomography or MRI (signal similar to cerebrospinal fluid) and is between 3 and 15mmin diameter, consistent with a previous acute small subcortical infarct or hemorrhage in the territory of one perforating arteriole.[340] It is estimated that lacunar infarcts account for 25% of all ischemic strokes, with an annual incidence of ~15 per 100,000 people.[383] A meta-analysis of studies with brain MRIs in patients with T2DM showed that there was a significant association between T2DM and lacunar infarcts. Compared with the general population, the odds of having lacunar infarction are 1.3 times higher among individuals with T2DM and 2.2 times higher for those with concomitant vascular disease.[347] T2DM modifies the risk of short-term mortality and stroke recurrence among individuals with lacunar infarction. In patients with recent lacunar stroke, T2DM independently predicted ischemic stroke recurrence[384] and short-term and 5-year mortality.[383]

Recent data suggest that T2DMmay be more likely to contribute to the formation of small lacunes.[385] Researchers have hypothesized that small lacunes (≤7 mm) probably have a lipohyalinotic etiology, and that larger lacunes (8 to 20 mm) result from microatheroma. The presence of lacunes ≤7 mm was significantly associated with age, black ethnicity, hypertension, ever-smoking, T2DM, and HbA1c. The same risk factors predicted infarcts with lacunes <3 mm. Interestingly, lacunes 8 to 20 mm in size had a risk factor profile more indicative of atherosclerosis that was not associated with T2DM. Taken together, factors related to T2DM (such as HbA1c) may be more likely to contribute to the formation of smaller lacunes (even those <3 mm) than the formation of larger lacunes. Further research focused on cardiometabolic risk factors contributing to lacunar infarction size will elucidate the mechanisms that atherosclerosis and T2DM share.

Even smaller, cerebral microinfarcts (CMIs) are attracting increasing attention in microvascular brain research. They are considered to be the single most widespread form of brain infarction and thus a major component of the causal pathway between microvascular disease and cognitive dysfunction.[386,387] Autopsies reveal CMIs in ~43% of patients with AD, 62% of patients with vascular dementia, and 24% of nondemented elderly subjects.[367] CMIs are typically defined as sharply delineated microscopic ischemic lesions accompanied by cellular death or tissue necrosis, often associated with gliosis and cavitation.[388] CMIs can occur in both the white matter and subcortical regions of the brain, presumably more so in watershed areas.[367] Because of their small sizes (ranging from 50 mm to a few mm), CMIs escape detection by regular clinical MRI protocols. The introduction of high-field-strength 7.0 Tesla MRI, with its high-resolution imaging and isotropic voxel sizes in the submillimeter range, permits clinicians to see CMIs in vivo.[389]

In autopsy studies, CMIs were associated with increased measures of neuroinflammation, such as an elevated interleukin-6 concentration in the cortex. Of specific interest, in subjects with both T2DM and dementia, researchers observed different patterns between individuals who have or have not received medical diabetic therapy. Treated diabetic patients with dementia had the highest number of CMIs in the striatum, thalamus, and deep white matter.[390] The association between cerebral injury and diabetes treatment in T2DM patients with dementia could have etiologic or therapeutic implications.

Nonischemic microvascular complications. Microvascular injury can also manifest as nonischemic pathology, such as cerebral microbleeds (CMBs), enlarged perivascular spaces (EPVS), evidence of BBB breakdown, and cerebral amyloid deposition. Human studies on aging and neurodegeneration currently use ever-developing technologies for measuring these lesions.

CMBs are visible in MRIs[391] (Figure 6). CMBs commonly occur in patients with stroke, as well as in the general elderly population. The prevalence of CMBs in community-dwelling older adults is as high as 11.1% to 23.5%.[392,393] The presence of CMBs predicts the development of new CMBs.[394] Some controversy remains as to whether T2DM predisposes individuals to CMBs.[395] However, results from a meta-analysis showed that both T2DM and hypertension were associated with having more than a twofold increase in the odds of having CMBs.[396] CMBs appear to colocalize with Aβ deposits in brain tissue samples from nondemented older adults, suggesting a shared etiology.[397] PET imaging that uses amyloid-specific ligands (e.g., Pittsburgh compound B-PET) has openednew avenues to study amyloid deposits in the brain in vivo. One small study measured amyloid PET in AD patients with and without T2DM and found that the amyloid accumulation in AD patients was greater than in controls, but did not differ by T2DM status.[398] A recent study using Pittsburgh compound B-PET in a convenience sample of older adults found no association between in vivo brain Aβ burden and serial measures of glucose intolerance or insulin resistance.[399]

EPVS (also called Virchow-Robin spaces) are visible on T2-weighted MRIs and thought to represent the exvacuo dilatation that is secondary to cerebral tissue shrinkage after demyelination and axonal loss[400,401] (Figure 6). Once thought to be a normal phenomenon of aging, more recent studies show EPVS are associated with atherosclerosis,[402] dementia, and other markers of microvascular disease.[403,404] EPVS are found in young patients with T1DM[405] and have yet to be examined in T2DM. EPVS may be indicative of perivascular cells (pericytes and vascular smooth muscle cells), which are important regulators of vascular formation, stabilization, remodeling, and function.[406] Pericytes are integral components of the BBB and have a dramatic impact on microvascular integrity. They surround capillaries, contain contractile proteins, and are thought to regulate blood flow[407] and permeability.[408] Notably, a loss of brain pericytes and the resulting BBB breakdown have been shown to impair CNS function through leakage and by depositing several potentially vasculotoxic and neurotoxic blood-derived macromolecules, including fibrin, thrombin, plasmin, and hemoglobinderived hemosiderin, which causes accumulation of iron and ROS.[409] Research suggests that the loss of pericytes in the brain parallels pericyte loss in DR, leading to the breakdown of the BBB.[410] There are currently no neuroimaging techniques that enable us to see pericytes directly. Developing novelneuroimaging techniques, such as PET ligands specific for pericytes, may elucidate the in vivo role of pericyte loss in neurodegeneration and diabetes.

The cerebral microvascular endothelial cells, capillary BM, astrocyte endfeet, and pericytes are the structural components that comprise the BBB. The BBB regulates the normal neuronal and glial cell environment[411] by regulating the passage of circulating elements from blood into the brain. We are becoming increasingly more aware of changes in BBB integrity associated with aging and microvascular disease. Permeability of the BBB is an important aspect of microvascular complications in the brain and can be imaged in vivo using a MRI with intravenous gadolinium contrast enhancement.[412] Postcontrast enhancement of brain parenchyma and increased signal intensity in the cerebrospinal fluid are presumed indicators of increased BBB permeability, and we see these changes in patients with T2DM.[413] Postcontrast signal intensity increased more in the diabetic group than controls after administering gadolinium-diethylene triamine penta-acetic acid, particularly in the basal ganglia, an area known to be particularly vulnerable to cerebrovascular disease. The effects of T2DM on the BBB may contribute to increased risk of AD. Constituents of the endothelium, including RAGE, are important risk factors to consider when investigating T2DM-related BBB breakdown. Several novel neuroimaging techniques, including super paramagnetic nanoparticles and PET imaging ligands designed to image the BBB and its disruption, will provide useful tools for investigating BBB breakdown in the future.


Adults with T2DMhave an increased risk of dementia as they age. T2DM and its associated factors predispose individuals to both microvascular and macrovascular complications throughout the body and brain. Recent neuroimaging studies show that patients with T2DM go on to develop structural and functional brain abnormalities similar to older adults with dementia. Many of the strongest neuroimaging markers of brain abnormalities seen in T2DM are related to microvascular disease. Furthermore, individuals who have evidence of metabolic deregulation (hyperglycemia and insulin resistance), but do not have T2DM, show similar structural and functional brain abnormalities to those with frank T2DM. There is evidence that individuals with T2DMassociated microvascular complications in the periphery have an elevated risk of having microvascular complications in the brain. Future research will determine whether the putative causal factors resulting in microvascular complications in the body (e.g., insulin resistance, hypertension, oxidative stress, and AGEs) mediate the observed associations between T2DM and brain microvascular abnormalities. Understanding the causes ofmicrovascular disease in the brain associated with T2DM will provide targets for preventing cognitive decline and dementia in patients with T2DM.