Molecular Mechanisms of Dementia: Biomarkers, Neurochemistry, and Therapy

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Chapter 1

Neurochemical Aspects of Dementia

Abstract

Dementia is becoming increasingly prevalent among the elderly population. In 2001, ~24 million people worldwide were afflicted with dementia, and that number is estimated to double to an estimated prevalence of 42 million by 2020 and 81 million by 2040. Dementia is challenging from a medical care perspective since it is both progressive and irreversible. Additionally, dementia is a leading cause of admission to long-term care facilities and a major risk factor for hospitalization. AD is the most common form of dementia, and it constitutes approximately two-thirds of all cases. It is currently hypothesized that the pathophysiology of AD involves the accumulation of amyloid beta proteins and the hyperphosphorylation of tau proteins, which leads to neurofibrillary tangles and neuronal loss in the brain. However, AD pathogenesis is multifactorial, whereby both genetic susceptibility and environmental factors contribute to neurodegeneration.

Keywords

Aging; cognition; risk factors; dementia; behavioral changes; psychological symptoms

Introduction

Due to the increase in life expectancy, the number of elderly across the globe is increasing at a constant rate and it is estimated that the number of seniors will increase to approximate 2.1 billion by the year 2050 worldwide (United Nations, 2015; WHO, 2016). In the United States, the number of seniors is predicted to increase from approximately 45 million currently to 70 million by the year 2030 (Ortman et al., 2014); similarly, in the European Union the number of seniors over the age of 80 is expected to grow from 5% to 12% of the population (The 2015 Ageing Report, 2015). In 2016, Canada had more persons over the age of 65 (16.9%) than under the age of 15 (16.6%) (Government of Canada, Statistics Canada, 2016). This global trend is driven largely by the baby boom generation, born between 1946 and 1964, which began entering their senior years in 2011. Increase in life expectancy is a major risk factor for cognitive deterioration. Dementia is a Latin word which means madness or mindlessness (De means without and ment means mind). In a medical context, dementia is not a name for a particular disease, but a progressive neurodegenerative syndrome, which is characterized by impairment in memory and activities of daily living, altered behavior, personality, and other cognitive dysfunctions (Sosa-Ortiz et al., 2012). Dementia mainly affects older people: only 2% of cases start before the age of 65 years. After this, the prevalence doubles with every 5-year increment in age. Dementia is one of the major causes of disability in later life. In 2010, there were 35.6 million people suffering from dementia worldwide and this number is projected to double over the subsequent 20 years (Prince et al., 2013a). Dementia not only results in deterioration in cognitive function (i.e., the ability to process thought) beyond what might be expected from normal aging, but also affects memory, thinking, orientation, comprehension, calculation, learning capacity, language, and judgment. The prevalence rate for dementia increases with advancing age (Sosa-Ortiz et al., 2012). Thus, persons above 60 years of age show 0.43% prevalence whereas persons aged above 65 years show 2.44% prevalence. The prevalence rate rises to 54.8% in individuals above 95 years of age (Vas et al., 2001). The impairment in cognitive function is commonly accompanied, and occasionally preceded, by deterioration in emotional control, social behavior, or motivation. Importantly, 75% of people with dementia manifest some, but not all, symptoms of dementia at a given time (Lyketsos et al., 2002). According to World Health Organization estimates 35.6 million people live with dementia, a number that is anticipated to triple by 2050 (World Health Organization, 2012).

Mild cognitive impairment (MCI) is form of predementia, which is characterized by objective impairment in cognition that is not severe enough to require help with usual activities of daily living. MCI leads to general forgetfulness in many people as they age. However, only a few MCI patients develop dementia. The mild dementia involves memory loss, confusion, personality changes, getting lost, and difficulty in planning and carrying out tasks. In moderate dementia daily life becomes more challenging, and the patient may require help in performing daily life activities. Symptoms are similar to mild dementia along with significant changes in personality (Sosa-Ortiz et al., 2012; Rizzi et al., 2014). Severe dementia involves all the symptoms of moderate dementia and the loss of the ability to communicate. The patient may need full-time care. Simple tasks, such as sitting and holding one’s head up become impossible along with the loss of bladder control. According to the World Health Organization (2012) most of the increase in dementia patients will occur in low- and middle-income countries. Thus, currently 62% of all people with dementia live in such regions. This proportion may increase to 66% in 2030 and 71% in 2050. The fastest growth in the elderly population is taking place in China, India, and their south Asian and western Pacific neighbors (Dong et al., 2007; Llibre Rodriguez et al., 2008; Plassman et al., 2007). Although recent studies suggest a decline in prevalence (Matthews et al., 2013), dementia remains a devastating and costly disease. In the United States the cost of dementia has already surpassed that of cancer and heart diseases (Hurd et al., 2013). The realization of its paramount public health impact has led nations, including the United States, to develop national plans to cope with dementia and attempt to reduce its devastating effects (National Alzheimer’s Project Act; Public Law 111-375).

As stated above, dementia syndrome not only results in deterioration in cognitive function (i.e., the ability to process thought) beyond what may be expected from normal aging, but also affects memory, thinking, orientation, comprehension, calculation, learning capacity, language, and judgment. A gradual age-related cognitive dysfunction, particularly in executive function and mental speed, is evident even in nondemented oldest-old. Hearing and vision losses, which are also prevalent in the oldest-old and found in some cases to precede/predict cognitive decline, may mechanically interfere in neuropsychological evaluations. As stated above, the prevalence rate for dementia increases essentially with advancing age (Savva et al., 2009). Thus, persons above 60 years of age show 0.43% prevalence, whereas persons aged above 65 years show 2.44% prevalence. The prevalence rate rises to 54.8% in individuals above 95 years of age (Vas et al., 2001; Cerejeira et al., 2012). It is stated that impairment in cognitive function in dementia is commonly accompanied, and occasionally preceded, by deterioration in emotional control, social behavior, or motivation. These processes may result in memory loss, and cognitive impairment. Among humans, the impact of dementia can be felt at three interrelated levels: the individual (patients with dementia), their family and friends, and wider society. While dementia does shorten the lives of those affected, its greatest impact is upon quality of life, both for individuals living with dementia, and for their family and carers. The total estimated worldwide costs of managing dementia were US$ 604 billion in 2010, equivalent to 1% of the world’s gross domestic product (Prince et al., 2013a,b). Low-income countries accounted for just less than 1% of total worldwide costs (but 14% of the prevalence of dementia), middle-income countries for 10% of the costs (but 40% of the prevalence of dementia) and high-income countries for 89% of the costs (but 46% of the prevalence of dementia). About 70% of the global costs occurred in just two regions: Western Europe and North America. These discrepancies are accounted for by the much lower costs per person in lower income countries – US$ 868 in low-income countries, US$ 3109 in lower-middle-income, US$ 6827 in upper-middle-income, and US$ 32,865 in high-income countries (Wimo et al., 2017).

Classification of Dementias

Several types of dementia have been reported to occur in the human population including Alzheimer’s type of dementia (30%), vascular dementia (VaD; 26%), mixed dementia (21%), Lewy body dementia (LBD; 11%), frontotemporal dementia (FTD)/degeneration (7%), and infective dementia (5%) (Fig. 1.1). Secondary causes of dementia include vascular, CNS infections, trauma, metabolic derangements, and other reversible/treatable causes such as type 2 diabetes, stroke, AIDS, or multiple sclerosis (Kabasakalian and Finney, 2009; Ironside and Bell, 2007). Sometimes dementia-mediated changes become reversible. This is called pseudodementia. Pseudodementia is caused by depression, malnourishment (vitamin deficiency), dehydration, medications, sleep deprivation, metabolic problems, excessive drinking, smoking, and infections. Symptoms of dementia are underrecognized. The understanding of behavioral and psychological symptoms of dementia (BPSD) would be helpful for an early diagnosis and better management so as to improve the patients’ quality of life (Levy and Chelune, 2007; Cerejeira et al., 2012; Kales et al., 2015).

Figure 1.1 Proportions of various types of dementia found in the human population. AD, Alzheimer’s type of dementia; FTD, frontotemporal dementia; ID, infective dementia; LBD, Lewy body dementia; MD, mixed dementia; VD, vascular dementia.

Alzheimer’s disease (AD) type of dementia is the most common cause of dementia (30%) and is rare before 60 years of age. AD type of dementia is characterized clinically by progressive memory and orientation loss and other cognitive deficits, including impaired judgment and decision-making, apraxia, and language disturbances. AD type of dementia is accompanied by the accumulation of Aβ peptide in the form of senile plaques (Farooqui, 2017). These Aβ plaques are thought to be one of the major contributors to dementia caused by AD (Villemagne et al., 2013). In addition to senile plaques, AD also appears to be related to tangles in the brain, which are structural abnormalities due to defective or deficient tau proteins; tau proteins support microtubules, which help provide cell structure and movement. AD is typically diagnosed by biomarkers, such as Aβ in cerebrospinal fluid (CSF), tau proteins, and regional brain volumes; these measurable substances can be used to predict AD progression in patients with MCI. In addition, ischemic, cerebral small vessel disease, and neurodegenerative diseases have a profound impact on the onset and expression of the dementia, supporting the view that there may be reciprocal interactions between ischemia and neurodegeneration (Shi and Wardlaw, 2016). Ischemic injury results in a number of small, focal cerebral infarcts (small strokes) that may go unnoticed individually but have an additive detrimental effect as more and more small areas of the brain are destroyed by ischemic events; however, there are also a number of other causal subtypes of cerebrovascular disease (Nagata et al., 2007). The second most frequent type is VaD and the third is LBD. These are then followed by FTD.

VaD is the second most common type of dementia following AD-type dementia. The onset of VaD occurs when the blood supply to the brain is reduced by various cerebrovascular pathologies, such as hypoperfusions or hemorrhages causing disruption of the blood–brain barrier (BBB) and neurovascular units (NVUs), usually in hemispheric white matter (Román et al., 2002; Iadecola, 2013), leading to a progressive decline in memory and cognitive function. Pathological features of VaD are diffuse myelin pallor, astrocytic gliosis, and the loss of oligodendrocytes leading to rarefaction, vacuolization, and the loss of myelin and axons without definite necrosis, ultimately culminating in white matter lesions and lacunes (Román et al., 2002). The hardening of cerebral arteries in VaD leads to a reduction in blood flow, a major contributor of cognitive decline.

Changes in dementia involve the decrease in blood flow causing low perfusion pressure and hypoperfusion in several brain regions including hippocampus (American Psychiatric Association, 2013). Sustained cerebral hypoperfusion in dementia syndrome may cause white matter attenuation, a key feature common to both AD and dementia associated with cerebral small vessel disease. Under conditions of chronic hypoperfusion, white matter rarefaction, glial activation, and axon damage can promote diffused ischemic-neuronal loss (Hachinski et al., 1974; Libon et al., 2006). It is proposed that cerebral hypoperfusion is the common pathophysiological mechanism which contributes to cognitive decline and degenerative processes leading to VaD and cerebral small vessel disease. White matter changes are also closely associated with increased risk for stroke, dementia, and disability (Duncombe et al., 2017). Based on the above description, converging evidence suggests that pathological features of VaD are diffuse myelin pallor, astrocytic gliosis, and the loss of oligodendrocytes leading to rarefaction, vacuolization, and the loss of myelin and axons without definite necrosis, ultimately culminating in white matter lesions and lacunes (Román et al., 2002). These findings are supported by structural neuroimaging studies (Risacher and Saykin, 2013; Valkanova and Ebmeier, 2014). The onset of dementia syndrome may occur in several stages including MCI, mild dementia, moderate dementia, and severe dementia (Sosa-Ortiz et al., 2012; Rizzi et al., 2014).

Progressive accumulation of α-synuclein (α-syn) in selected regions of the brain contributes to the pathogenesis of Parkinson’s disease (PD) and LBD (Hashimoto and Masliah, 1999). In these disorders, the abnormal accumulation of α-syn is not limited to the striatonigral system but also affects the limbic areas, the insula, frontal cortex, and subcortical nuclei (Hurtig et al., 2000; Marui et al., 2002). The FTDs are a group of heterogeneous neurodegenerative disorders characterized by progressive deterioration of behavior or language and associated pathology in the frontal or temporal lobes. Six clinical subtypes of FTD have been described in the literature. They are: (1) behavioral variant of FTD; (2) semantic variant primary progressive aphasia; (3) nonfluent agrammatic variant primary progressive aphasia; (4) corticobasal syndrome; (5) progressive supranuclear palsy; and (6) FTD associated with motor neuron disease (Finger, 2016; Olney et al., 2017). Some FTD related disorders include FTD with motor neuron disease, progressive supranuclear palsy syndrome, and corticobasal syndrome.

The abovementioned information on dementia subtypes are highly variable among countries with more variation being observed in developing countries as compared to developed countries due to factors such as cultural and socioeconomic variability and a lack of methodological uniformity (Rizzi et al., 2014). Many studies have indicated that type 2 diabetes increases risk of AD type of dementia in the elderly. Multiple possible mechanisms have been proposed to explain this association. These mechanisms include direct effects of hyperglycemia, insulin resistance, and insulin-induced Aβ amyloidosis in brain, as well as indirect ischemic effects of type 2 diabetes-promoted cerebrovascular disease (Niures et al., 2015). Among these mechanisms, induction of insulin resistance contributes to increased risk of cognitive decline and increased rates of brain atrophy with dementia (Rasgon et al., 2010; Yaffe et al., 2004).

It is well known that normal brain function is dependent on receiving 20% of the cardiac output of oxygenated blood, and both higher and lower blood pressure may reduce this cerebral blood flow (Stukas et al., 2014). Another factor, which contributes to a reduction in regional cerebral blood flow is the decrease of endothelial nitric oxide (NO) synthesis in elderly subjects. NO is synthesized by the endothelial nitric oxide synthase (eNOS). NO is not only important for cardiovascular homeostasis, but also acts as a vasodilator controlling vasomotor function and local blood flow (Katusic and Austin, 2014). Thus, vascular risk factors play an important role in the pathogenesis of dementia and AD. This suggestion is supported by recent findings on the involvement of NVU, an entity, which is composed of astrocytes, mural vascular smooth muscle cells and pericytes, and endothelia. NVU regulates blood flow, controls the exchange across the BBB, contributes to immune surveillance in the brain, and provides trophic support to brain cells in the pathogenesis of poststroke dementia (Nelson et al., 2016). The BBB plays a critical role in maintaining CNS homeostasis and its dysfunction contributes to multiple neurological disorders. The BBB dysfunctions include (1) BBB disruption, which results in leakage of circulating substances, which may be neurotoxic, into the brain; (2) transporter dysfunction, which has consequences such as inadequate nutrient supply, build-up of toxic substances in the brain, and increased entry of compounds that are normally extruded; and (3) alterations in protein expression and secretions by endothelial cells and other cell types of the NVU that can promote inflammatory reactions and oxidative stress leading to neuronal damage. Aging is an important factor, which modulates the integrity of the NVU. The age-related physiological or pathological changes in the cellular components of the NVU increase the vulnerability of the NVU to ischemia/reperfusion injury leading to brain damage (Cai et al., 2017). Aging impairs cerebral blood flow triggered by alterations in NVU, a critical entity, which modulates and matches oxygen and nutrient delivery to the increased demands in active brain regions (Tarantini et al., 2017). These findings support the view that aging, consumption of a Western diet (meat, sweets, and high-fat dairy products), physical inactivity, and environmental factors may contribute to the pathogenesis of dementia. These factors decrease cerebral blood flow, induce brain hypofunction, and induce an onset of neuroglial crisis leading to MCI, which all ultimately contribute to dementia (Fig. 1.2).

Figure 1.2 Factors contributing to the onset of dementia.

Diagnosing VaD is not a simple matter. Currently, there is a lack of validated criteria for establishing a diagnosis of VaD, and many of the various pathologies that reduce the brain’s blood supply are complex (Jellinger, 2008). Although cerebrovascular lesions can be seen using brain imaging techniques, the diagnosis of VaD remains difficult, since such lesions may or may not be contributing to dementia symptoms, and this can lead to overdiagnosis of VaD as the cause of dementia (Niemantsverdriet et al., 2015). Collective evidence suggests that age-related cerebromicrovascular dysfunction and microcirculatory damage play critical roles in the pathogenesis of many types of dementia in the elderly, including AD. Understanding and targeting of the age-related molecular mechanisms, which underlie vascular dysfunction-mediated alterations in dementia, play a major role in preserving brain health in older subjects. Maintenance of normal cerebral perfusion, protecting the microcirculation from hypertension-induced damage, and moment-to-moment adjustment of regional oxygen and nutrient supply to changes in demand are prerequisites for the prevention of cerebral ischemia and neuronal dysfunction. Aging is also accompanied by a marked deficiency in circulating insulin-like growth factor-1 (IGF-1), which has been shown to contribute to age-related cognitive decline. Impairment of moment-to-moment adjustment of cerebral blood flow via neurovascular coupling is thought to play a critical role in the genesis of age-related cognitive impairment (Toth et al., 2015, 2017). In contrast to AD type and LBD dementias, VaD is defined as loss of cognitive function resulting from ischemic or hemorrhagic brain lesions due to cerebrovascular disease or cardiovascular pathology. Diagnosis of VaD requires cognitive loss, often predominantly subcortical; vascular brain lesions identified by neuroimaging; a temporal link between stroke and dementia; and exclusion of other causes of dementia. Dementia syndrome is not only accompanied by the deterioration in cognitive function beyond what may be expected from normal aging, but also affects memory, thinking, orientation, comprehension, calculation, learning capacity, language, and judgment.

Risk Factors for Dementias

Major risk factors for dementia include advancing age, low body mass index (BMI), long-term consumption of a Western diet, physical and cognitive inactivity, and epigenetic and environmental factors (Fig. 1.2) (Farooqui, 2017). Other risk factors for dementia include (1) cardiovascular (e.g., hypertension, atrial fibrillation, diabetes, sleep apnea, insulin resistance, and obesity) and cerebrovascular problems (e.g., stroke); (2) excessive alcohol consumption; (3) social isolation; (4) traumatic brain injury (TBI); (5) hearing loss; and (6) having one or two copies of the APOEε4 genetic variant (Farooqui, 2017). A combination of all these factors is known to contribute to the pathogenesis and development of the dementia syndrome, but information on underlying molecular mechanisms contributing to dementia remains speculative and controversial. In addition, other modifiable risk factors include smoking, hypertension, lower literacy rate, nutritional status, and metabolic and cardiovascular factors (Baumgart et al., 2015). Secondary causes of dementia are associated with vascular, CNS infections, trauma, hearing loss, metabolic derangements, and other reversible/treatable causes (Kabasakalian and Finney, 2009; Lin et al., 2013; Gurgel et al., 2014).

Among these causes, hearing loss is independently associated with accelerated cognitive decline and incident cognitive impairment in community-dwelling older adults (Lin et al., 2013). A number of mechanisms have been implicated in explaining the involvement of hearing loss and cognition dysfunction in dementia. Poor verbal communication associated with hearing loss may confound cognitive testing, or vice versa may indicate that there may be an overdiagnosis of hearing loss in individuals with subclinical cognitive impairment (Gordon-Salant, 2005).

The mechanistic basis of association between hearing loss and cognitive decline in dementia is not known. However, it is proposed that hearing loss may contribute to an overall cycle of multimorbidity and frailty or synergistically interact with other known risk factors for dementia (Daviglus et al., 2011; Plassman et al., 2010), both of which may be associated with cognitive decline in older adults. However, the underlying pathway contributing to hearing loss and cognition may not mutually exclusive, and hence, multiple pathways (e.g., shared neuropathology, cognitive load, increased loneliness) may coexist and synergistically contribute to accelerated cognitive decline in demented subjects with hearing loss (Daviglus et al., 2011; Plassman et al., 2010). Another limitation of our study is that hearing loss was only measured at baseline, and information was not available on the trajectory or the possible etiology of the hearing loss.

In vitro studies have shown that inhaled anesthetic agents can promote dementia (Chen et al., 2013; Jiang et al., 2017). Very little is known on the biochemical consequences of anesthetic agent injections on pathogenesis of dementia. It is reported that regardless of the anesthetic agent used, anesthesia induces rapid and massive hyperphosphorylation of tau, rapid and prolonged hypothermia, inhibition of Ser/Thr PP2A (protein phosphatase 2A), but no changes in APP metabolism or Aβ (beta-amyloid peptide) accumulation (Chen et al., 2013; Jiang et al., 2017). Reestablishment of normothermia during anesthesia completely prevents tau phosphorylation. Detailed investigations have indicated that changes in tau phosphorylation are not a result of anesthesia per se, but a consequence of anesthesia-induced hypothermia, which led to inhibition of phosphatase activity and subsequent hyperphosphorylation of tau (Planel et al., 2007). In contrast, other animal studies have provided evidence that exposure to anesthetic agents can impair not only memory and induce caspase-3 activation, but also can increase levels of Aβ (Planel et al., 2007; Xie et al., 2008). The prevalence of dementia is consistently higher among women. This may be due to longer life expectancy in women. Lower educational levels have been found associated with higher prevalence of dementia. Within the United States, prevalence has been reported as elevated in African American and Latino populations; some authors have attributed these findings to lower education and higher cardiovascular morbidity in those populations (Graham, 2014).

Symptoms of Dementias

Neurochemical mechanisms of dementia start years before it is diagnosed clinically—the preclinical period of the disease, when neuronal degeneration has begun, but cellular and biochemical damage is not yet sufficient for symptoms to manifest (Mosconi, 2005). The symptoms of dementia in patients are heterogeneous and largely unpredictable. These symptoms include agitation, depression, apathy, repetitive questioning, psychosis, aggression, sleep disturbances, wandering, and a variety of inappropriate behaviors. Importantly, 75% of people with dementia manifest some, but not all symptoms of dementia at a given time (Fig. 1.3) (Lyketsos et al., 2002). These symptoms are among the most complex, stressful, and costly aspects of dementia care. They are accompanied by a 40% or greater loss of neocortical synapses as compared with normal adults. These symptoms may lead not only to poor neurotransmission in dementia patients, but may also contribute to healthcare problems, and income loss for family care givers (Van Den Wijngaart et al., 2007). The prevalence rate for dementia increases essentially with advancing age. Persons above 60 years of age show 0.43% prevalence whereas persons aged above 65 years show 2.44% prevalence. The prevalence rate rises to 54.8% in individuals above 95 years of age. The impairment in cognitive function is commonly accompanied, and occasionally preceded, by deterioration in emotional control, social behavior, or motivation. The first step in recognizing the clinical manifestations of dementia is to appropriately understand the psychopathology and molecular mechanisms contributing to the symptoms of various types of dementias. This can be a very challenging issue because there is considerable overlap in pathogenic mechanisms among various types of dementias. Secondly, it is useful to evaluate whether specific symptoms occur in association with various types of neurodegenerative diseases (Lyketsos et al., 2002; Kabasakalian and Finney, 2009; Ostling et al., 2009). It is proposed that symptoms of dementia can be delayed by enhancing and encouraging cognitive and physical activity, social engagement, smoking cessation, and healthy diet, including alcohol reduction. Comorbid depression is common in older people with dementia and treating this can improve cognition. Dementia is typically diagnosed by a doctor in a clinical setting, when acquired cognitive impairment has become severe enough to compromise social and/or occupational functioning (Buntinx et al., 2011). Positron-emission tomography (PET) and single-photon emission computed tomography (SPECT) are both brain imaging methods that are most commonly used to make a dementia diagnosis by examining the physical condition of the brain (Bamford et al., 2016). However, even with these tools, the difficulties of recognizing and diagnosing dementia are apparent, and approximately half of dementia cases are currently undiagnosed (Savva and Arthur,