Keywords

1 Introduction

Diabetes mellitus has long been known to be able to determinate consequences on the structure and function of the brain. Since the early twentieth century, it has been observed that diabetic patients frequently complained of poor memory and attention [1]. In 1922, Miles and Root [2] showed that people with diabetes performed poorly on cognitive tasks, namely, those involving memory and attention. The term “diabetic encephalopathy” was proposed in the 1950s to describe central nervous system-related complications of diabetes [3]. Other terms like “functional cerebral impairment” and “central neuropathy” have also been proposed to describe diabetes-related cognitive impairment, and the term “diabetes-associated cognitive decline” was proposed to describe diabetes-related mild to moderate reductions in cognitive functions [4].

Since the prevalence of diabetes mellitus is growing rapidly throughout the world, diabetes-related cognitive dysfunction could have challenging future public health implications [5]. In this chapter we will cover available data concerning how diabetes affects the central nervous system, in particular brain function and structure. In addition, we will also address pathophysiologic characteristics of diabetic autonomic disorders.

2 Cerebrovascular Structural Alterations

2.1 Atherosclerosis and Stroke

Atherosclerotic disease often involves the intracranial and extracranial arteries [6]. Age, hypertension, and diabetes mellitus are independent risk factors for intracranial as well as extracranial atherosclerosis [6], which can result in thromboembolism with or without hypoperfusion leading to transient or permanent cerebral ischemic events [7], thus possibly having functional consequences, including cognitive decline, vascular dementia, and even depression [6, 8].

Diabetes is also a well-established independent risk factor for stroke. In the INTERSTROKE study, a 22-nation case-control study, the presence of diabetes increased the risk of stroke by 36% [9]. In the Framingham Study, diabetic males who were in their fifth and sixth decades of life had a fourfold increase in the incidence of stroke, while females in the sixth decade had a fourfold increase and in the seventh decade a threefold increase [9]. In a large biracial population from the Cincinnati/Northern Kentucky area of the Unites States, there was a five- to 14-fold increased risk of stroke in diabetic subjects who were between the ages of 20 and 65 years [9]. A prospective Japanese study showed that for both male and female diabetic subjects, there was two- to fourfold higher rate of all types of ischemic stroke without an association with intraparenchymal or subarachnoid hemorrhage [9]. In type 1 diabetes mellitus (T1DM), the increase in the incidence of stroke is even greater than in the type 2 diabetes mellitus (T2DM). In the prospective Nurses’ Study, those with T2DM had a 2.3-fold increase in the incidence of stroke, whereas those with T1DM had a 6.3-fold increase when compared with nondiabetic individuals [9]. Unlike T2DM, T1DM was associated with a 3.8-fold increased risk of hemorrhagic stroke. The major source of extracranial embolism causing an ischemic stroke in the diabetic patient is the extracranial portion of the internal carotid artery. Furthermore, diffuse atherosclerotic disease (multiple atherosclerotic lesions in the coronary, carotid, and iliofemoral arteries) is more prevalent in those subjects with T2DM who have a stroke, especially when atherosclerosis is accompanied by hypertension [9].

2.2 Imaging Studies on Diabetes and Brain Structure

Type 1 diabetes Structural magnetic resonance imaging (MRI) techniques are commonly used to examine the possible consequences of diabetes on the brain structure, in particular on total and regional brain volumes [5]. Structural MRI studies have shown lower gray and white volumes in subject with T1DM compared to nondiabetic controls [5]. Diffusion tensor imaging (DTI) can identify white matter microstructural deficits by measuring the directionally restrained diffusion of water (anisotropy) within fiber tracts [5]. When fiber bundles are damaged, a reduction in fractional anisotropy (due to the loss of restriction of water movement) is to be expected. Kodl et al. [10] reported white matter microstructural deficits in the posterior corona radiata and the optic radiation in a DTI study in subjects who had diabetes for at least 15 years [9]; these changes correlated with lower performance in cognitive tests, probably as a consequence of an impairment of white matter function [5].

In vivo brain magnetic resonance spectroscopy may be used to noninvasively quantify concentration of various metabolites, and lower N-acetylaspartate (probably a marker of neuronal dysfunction) and glutamate concentration in gray matter-rich occipital lobe of patients with T1DM was observed [11].

Type 2 diabetes People with T2DM have also been shown to have brain atrophy [12] including lower total and regional white and gray matter volumes, as compared to nondiabetic controls [5]. Moran et al. [13] showed that subjects with T2DM had lower total gray, white, and hippocampal volumes; in the medial temporal, anterior cingulate, and medial frontal lobes, a loss of gray matter was clearly observed, while white matter loss was found mainly in the frontal and temporal regions [5, 13]. In this study it was also observed that brain volume loss was associated with poor performance in cognitive testing [13]. Other studies have suggested that atrophy may be particularly pronounced in the hippocampal region [14]. In people with long-standing, less strictly controlled type 2 diabetes, white matter hyperintensity volumes were associated with decreased processing speed [15]. This suggests that cerebral small vessel disease may be a mechanism underlying cognitive dysfunction in these individuals [15].

In a systematic review of DTI studies, the presence of brain microstructural abnormalities in T2DM was confirmed [16]. Twenty-nine studies have demonstrated widespread brain microstructural impairment and topological network disorganization in patients with T2DM; microstructural abnormalities were correlated with pathological derangements in the endocrine profile as well as deficits in cognitive performance in the domains of memory, information-processing speed, executive function, and attention [16]. Therefore, microvascular alterations and dysfunction may play a major role in the development of brain damage in diabetes mellitus and cardiometabolic disease [17, 18]. Also in T2DM altered brain metabolites were detected, to be possibly regarded as noninvasive biomarkers for diabetes-induced brain metabolic changes during progression of the disease [19].

3 Cognitive Function

3.1 Type 1 Diabetes

A meta-analysis by Brands et al. [20] examined the nature and extent of cognitive impairment in T1DM. Thirty-three studies were included; participants were mostly less than 50 years of age. Compared to nondiabetic controls, patients with T1DM had mild to moderate declines in multiple domains, including intelligence, speed of information processing, psychomotor efficiency, attention, cognitive flexibility, and visual perception [5, 20]. This lower cognitive performance appeared to be associated with the presence of microvascular complications but not with the occurrence of severe hypoglycemic episodes or with poor metabolic control [5, 20]. Also the pediatric setting was explored in this regard; in fact, Gaudieri et al. [21] preformed a meta-analysis including data from 19 studies in children with T1DM. A decrement in a broad range of domains was found; however the magnitude of decrement was greater in children with an early diagnosis of diabetes (less than 7 years of age) [5, 21]. Therefore, early age of onset may be an important variable of cognitive dysfunction in children with T1DM [5]. In the Diabetes Control and Complications Trial (DCCT) and its follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study, it was demonstrated that T1DM patients with worse metabolic control (glycated hemoglobin values >8.8%) showed moderate declines in motor speed and psychomotor efficiency, but this was not the case for those with better control (glycated hemoglobin <7.4%) [22]. Frequency of severe hypoglycemia was not associated with decline in any cognitive domain in this population [5]. Similar results were seen in the Stockholm Diabetes Intervention Study (SDIS), where at 10-year follow-up cognitive function was similar in both treatment groups and was not related to the number of severe hypoglycemic episodes [23].

In summary, T1DM seems to be associated with mild to modest decrements in cognitive function. Domains of psychomotor speed, mental flexibility, attention, and general intelligence are most commonly affected [5].

3.2 Type 2 Diabetes

Longitudinal and cross-sectional studies have consistently demonstrated an association between T2DM and mild to moderate cognitive dysfunction, but less is known about the strength of association between T2DM and dementia [5].

Dementia due to both Alzheimer’s disease and vascular disease has also been linked to T2DM in longitudinal studies. In the ARIC (Atherosclerosis Risk in Communities) study cohort, Rawkings and colleagues [24] observed that diabetes in midlife was associated with a 19% greater cognitive decline over 20 years. Cognitive decline was noted primarily in the domains of processing speed and executive function and was associated with duration of diabetes [5, 24]. In the Rotterdam Study, a prospective population-based cohort study of more than 6000 elderly subjects, T2DM almost doubled the risk of dementia [25].

Investigators have also performed systematic reviews and meta-analyses to address in more details the problem of the possible association between T2DM and dementia. Biessels et al. [1] reported that risk of dementia was increased by 50–100% in people with T2DM relative to people without diabetes. Processing speed, attention, memory, and cognitive flexibility were the most commonly effected domains in subjects with T2DM [26]. Palta et al. [27] in a meta-analyses of data from 24 studies found small to moderate reductions in the domains of motor function executive function, processing speed verbal memory, and visual memory in people with T2DM.

T2DM or insulin resistance frequently co-occurs with bipolar disorders and is associated with negative psychiatric clinical outcomes and compromised brain health [8, 28].

There are several pathophysiological mechanisms through which diabetes could influence the onset and progress of the various pathologies associated with dementia. Some of these are common to Alzheimer’s and vascular dementia, as well as the aging process. In some people with diabetes, vascular damage may be predominant leading to the development of a form of dementia that can be clinically classified as “pure vascular dementia”; in other patients, on the other hand, the mechanisms associated with the formation of beta amyloid plaques predominate, which will lead to the development of a clinical picture that can be classified as “pure Alzheimer’s”. The majority of patients, on the other hand, present an intermediate clinical picture between these two forms of dementia that can be classified as “mixed.”

In synthesis, both T1DM and T2DM have been associated with reduced performance on multiple domains of cognitive function and with evidence of abnormal structure and function of the brain [5, 29]. There are significant differences in the underlying pathophysiology of cognitive impairment between T1DM and T2DM. T1DM is usually diagnosed at an early age and may have effects on brain development [30]. Chronic hyperglycemia and microvascular complications [17, 18] are important risk factors common to both T1DM and T2DM. T2DM is usually diagnosed at an older age and is commonly associated with obesity, insulin resistance, hypertension, and dyslipidemia, all of which can have negative impact on the brain [18].

The pathophysiology underlying the cognitive decline and brain structural changes in subjects with diabetes is poorly understood [5]. Poor glycemic control, microvascular disease [31, 32], oxidative stress, genetic predisposition, insulin resistance, and amyloid disposition have been proposed as possible contributors [5, 33]. Also blood-brain barrier injuries [34, 35] and changes in brain metabolism [36] have been advocated as contributors to the development of brain functional and structural damage and cognitive alterations. Another pathogenetic factor that could be involved in determining the presence of cognitive deficits in diabetes mellitus is the hyperglycemia-related production of advanced glycosylation terminal products, which may induce vascular and endothelial damage, inflammatory reactions, and deposition of amyloid. The detrimental effects of cerebral microvascular dysfunction in this regard are described in Fig. 14.1 [8].

Fig. 14.1
The pictorial representation of microvascular dysfunction includes inflammatory cell, astrocyte, pericyte or smooth muscle cell, endothelial cell, and neurons. Their transition, phase diagram, and graph are illustrated.

Detrimental effects of cerebral microvascular dysfunction. (a) Type 2 diabetes-related microvascular dysfunction is related to increased oxidative stress, inflammatory and immune responses, and increased blood-brain barrier permeability, resulting in leakage of proteins and other plasma constituents into the perivascular space. (b) Microvascular dysfunction might lead to perfusion defects, hypoxia, and increased angiogenesis. Angiogenesis is associated with formation of capillaries that are leaky and poorly perfused and have reduced pericyte support. (c) Microvascular dysfunction might contribute to impaired neurovascular coupling, leading to compromised neuronal function. Neurovascular coupling is the mechanism that links transient local neural activity to the subsequent increase in blood flow. (d) Microvascular dysfunction might impair cerebral autoregulation, leading to greater vulnerability of brain tissue to the harmful effects of blood pressure changes. With impaired autoregulation, the normal autoregulation curve that shows the relation between cerebral blood flow and mean blood pressure (black curve) might become more linear and steeper, with perfusion becoming pressure dependent (red curve). From Ref. [8]

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Cognitive damage may also result from recurrent strokes or transient ischemic attacks that are, as previously mentioned, more frequent and with worse outcomes in the diabetic population [37]. Large longitudinal studies, especially in older people with diabetes, are however needed to better understand the impact, progression, and risk factors that drive the development of diabetes-related cognitive dysfunctions [5].

3.3 Depression

Observational studies strongly suggest that depression is more prevalent among adults with diabetes than among the general population. Patients with both T1DM and T2DM have a risk of developing a depressive disorder that is more than twice that that of the healthy control population [38]. About 20–30% of diabetic patients experience depression; individuals withT2DMs have a doubled risk for depression, and individuals with depression have a one to five times increased risk of presenting a T2DM [38]. The reasons for these high prevalence rates of depression in diabetic patients are not yet fully understood. The two dominant hypotheses are the following: depression may result from biochemical changes directly due to the illness or its treatment, or it may be explained by psychosocial demands or psychological factors related to the illness or its treatment [38]. This may contribute to explain the higher recurrence and longer duration of major depressive disorders and related symptoms. The link between diabetes and depression might also include shared risk factors (obesity, physical inactivity, or psychosocial stress related to any chronic disorder) and shared underlying mechanisms (inflammation, alterations in hypothalamic-pituitary-adrenal axis, vascular damage) [38]. The vascular depression hypothesis proposes that vascular damage in frontal and subcortical brain regions, which are involved in mood regulation, might lead to depression at least in some individuals [38]. Major depressive disorders in diabetic individuals represent, therefore, a multifaceted phenomenon, resulting from interactions between various biologic and psychosocial factors [38].

4 Dysautonomic Disorders

4.1 Definition

Diabetes mellitus represents the main cause of neuropathy [39, 40]. Being one of the major diabetic complications [41], it plays a relevant role in morbidity and mortality in diabetic patients. Diabetic neuropathy may be defined as “the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes” [42]. Sensory, motor, or autonomic nerves can be involved, even at the same time [40]. Generalized symmetric polyneuropathies and focal/multifocal neuropathies may be present [40, 43]; diabetic autonomic neuropathy (DAN) belongs to the first group. DAN was wrongly considered for a long time as a rare condition, while it should be regarded as a serious and often underestimated complication of diabetes, potentially affecting any part of the autonomic nervous system [40], and possibly leading to a significant increase in morbidity and mortality [40].

Early stages of DAN may be even asymptomatic, especially in young T1DM patients, and may represent, therefore, a diagnostic and therapeutic challenge. Subclinical DAN can occur within a year of diagnosis in T2DM and within 2 years in T1DM, while clinical symptoms may appear even after years [40].

4.2 Cardiovascular Autonomic Neuropathy

Cardiovascular autonomic neuropathy (the impairment of autonomic control of the cardiovascular system) [43] is the most common manifestation of DAN and may be associated with severe and even life-threatening complications (arrhythmias, silent myocardial ischemia, and sudden death) [40].

Cardiovascular autonomic neuropathy may be detected in the first years after diabetes onset mainly by means of cardiovascular reflex tests [44] supported recently by newer procedures [40].

Clinical indicators of cardiovascular autonomic neuropathy are reduced heart rate variability during deep breath, a prolongation of QT interval, temporally followed by resting tachycardia, an impaired exercise tolerance, and a decreased baroreflex sensitivity with consequent abnormal blood pressure regulation and orthostatic hypotension [40, 45].

Cardiovascular autonomic neuropathy prevalence tends progressively to increase; however, diabetes duration is not a good predictor of its severity [46]. Initially, there is a relative increase of the sympathetic tone, since diabetic neuropathy firstly impairs longest fibers as those of the parasympathetic system (e.g., vagal fibers) [40]; the following stage is represented by sympathetic denervation [45].

4.3 Other Clinical Manifestations of DAN

DAN may affect the central control of breathing and the sympathetic bronchial innervation. Peripheral and central chemosensitivity to hypoxia may be altered, as well as the bronchomotor tone in the lung [40]. Sleep apnea syndrome is highly prevalent in diabetic patient [47], with consequent decrease in quality of life and to an increased risk of sudden death [48].

Also the enteric nervous system may be affected, with loss in inhibitory and increase in excitatory enteric neurons, and, therefore, gastrointestinal symptoms may appear, such as gastroparesis, esophageal dysmotility, constipation, diarrhea, fecal incontinence, or gallbladder atony [40, 49]. Gastroparesis correlates weakly with upper gastrointestinal autonomic symptoms (nausea, vomiting, early satiety, postprandial fullness, bloating, and abdominal pain) which are common in T1DM and T2DM patients [40]. However, alterations in gastric motility may have an impact in acute glycemic control by delaying glucose absorption [50].

Sacral parasympathetic fibers may be damaged even in early stages of diabetes; thus genitourinary dysfunction may occur (impaired bladder sensation with increase in urine retention to dysuria, nicturia, incomplete bladder emptying, and urgency up to overflow incontinence due to the progressive involvement of motor sympathetic and somatic nerves) [40, 43]. Bladder dysfunction may predispose to recurrent urinary tract infections. Also the sexual sphere may be affected: diabetic autonomic neuropathy together with other concomitant conditions including vascular alterations, connective tissue damage, and psychological, endocrine, nutritional, and pharmacological factors may cause erectile dysfunction, retrograde ejaculation, and decreased sexual desire in female, dyspareunia, or inadequate lubrication [40].

DAN may have consequence on the eye: sympathetic predominance in pupil control decreases its diameter at rest [51]. A preserved pupil miotic reaction to accommodation convergence without the miotic reaction to light is named “Argyll Robertson pupil,” which is a clinical sign shared with neurosyphilis (40). Sudomotor function may be also affected: sweat gland denervation may result in skin dryness, which is a risk factor for the development of foot ulcerations [40, 52].

The prevalence of DAN is highly dependent on the criteria used to define autonomic dysfunction (type of tests performed, application of age-related normative values, presence or absence of clinical signs and symptoms, different patient cohorts studied) [40]. A meta-analysis of adult patients including 15 studies from 1966 to 2001 reported prevalence rates of cardiovascular autonomic neuropathy ranging from 1 to 90% [40, 53]. Similarly, Dimitropoulos reported prevalences between 1 and 90% in patients with T1DM and 20–70% in patients with T2DM [54]. In a community-based population study, the prevalence of autonomic neuropathy, as defined by the presence of one or more abnormal heart rate variability test, was around 17% [40, 55].

Using other definitions, Ziegler et al. reported prevalences of cardiovascular autonomic neuropathy in T1DM and T2DM patients of 25.3 and 34.3%, respectively [40, 56]. Finally, using more conservative criteria (alterations of at least three of six autonomic function tests), the prevalence of cardiovascular autonomic neuropathy was 16.8% in T1DM and 22.1% in T2DM [40, 53].

Dealing with the time of onset of DAN, it should be remarked that cardiovascular autonomic neuropathy may be detected in about 7% of both T1DM and T2DM at the time of diagnosis [40], and the yearly increase in its prevalence has been reported to be around 6% in T2DM and 2% in T1DM [40]. The incidence of the single symptoms related to DAN is highly variable, and indicative values are the following: delayed esophageal transit, 50%; gastroparesis, 40%; disordered small and large intestinal motility with diarrhea, 20% or constipation, 25% [40, 53]; erectile dysfunction, 35–90%; and retrograde ejaculation, 32% [40, 53]; bladder dysfunction may be present in 43–85% of patients with T1DM and in 25% of T2DM [40, 53].

Glycemic control and longer diabetes duration may be among the predictors of autonomic test abnormalities in young people [51]; however, only few studies have addressed the possible associations between DAN and other microvascular complications, although some association with retinopathy and nephropathy seems to be present [51].

4.4 Pathogenesis

The genesis of DAN is probably multifactorial (Fig. 14.2). A key role is played by hyperglycemia, oxidative stress, and insulin resistance [40, 57]. In addition, the role of inflammation in the pathogenesis of DAN has increasingly been highlighted (Fig. 14.2) [40]. With reference to T1DM, the possible role of autoimmunity has also been postulated. Autoantibodies against sympathetic ganglia vagus nerve and adrenal medulla were found in T1DM patients [58]. Also nerve growth factors may be involved in the pathogenesis of DAN: insulin-like growth factor-1 and neurotrophin-3 have been demonstrated, in an animal model, to be able to reverse diabetic neuropathy [59]. The role of hyperglycemia in the pathogenesis of diabetic autonomic neuropathy as the cause of inflammation and oxidative stress is described in Fig. 14.2 [40].

Fig. 14.2
An illustrated flow has hyperglycemia encircled by dyslipidemia, insulin signaling, genetics, puberty, and C-peptide deficiency. They further connect the R O N S cyclic diagram and then branches as inflammation and oxidation stress.

Pathogenesis of diabetic autonomic neuropathy: the role of hyperglycemia as the cause of inflammation and oxidative stress. RONS Reactive oxygen and nitrogen species (mitochondrial overproduction), AGE Advanced glycation end products, RAGE AGE receptors, IL Interleukin, TNF Tumor necrosis factor, NF Nuclear factor, PKC Protein kinase C, TLR Toll-like receptors, PARP Poly-ADP ribose polymerase. From Ref. [40]

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4.5 Prevention and Treatment

Intensive glycemic control seems to be the most effective way to prevent or delay the onset and slow the progression of autonomic dysfunction in patients with T1DM [40, 53, 54]. Once DAN becomes clinically evident, there is no specific treatment which was proved to be able to stop or reverse it. The most recent studies confirmed the efficacy of intensive insulin therapy in slowing the progression of both diabetic peripheral neuropathy [60] and DAN [61].

5 Conclusions

According to existing scientific evidence, both T1DM and T2DM are associated with mild to modest decrements in cognitive function [5]. Domains of psychomotor speed, mental flexibility, attention, and general intelligence are those most frequently affected [5]. Hypoglycemia is not usually risk factor for cognitive decline; however, this may not be true for children with young age at onset of diabetes [5]. Relevant risk factors for the development of cognitive decline are an early age of onset and the presence of microvascular complications. Since age and duration of diabetes are important contributors to the changes in cognitive function, we need longitudinal studies looking at cognitive function, especially in elderly subject with T1DM. In addition, more information is needed in order to better understand the clinical implications of these mild-moderate decrements in cognitive function, also in terms of impact on daily lives and habits. In addition, the underlying mechanism and the risk factors that may lead to the development of more severe cognitive dysfunction like dementia in some, but not all diabetic patients are not clear [5].

DAN represents a particular aspect of diabetic neuropathy, which may lead impairment of several organs, including the heart, both in T1DM and in T2DM patients. The pathogenesis of DAN is not entirely clear, but metabolic, genetic, and hormonal factors may be involved; however, the final pathway probably involves oxidative stress and inflammation caused by hyperglycemia [40]. Since no therapy was demonstrated to effectively reverse DAN, prevention with close glycemic control, multifactorial intervention, and lifestyle modification remain crucial [40].