Nanomedicine-Based Approaches for the Treatment of Dementia

By Umesh Gupta

Nanomedicine-Based Approaches for the Treatment of Dementia explores a wide range of promising approaches for the diagnosis and treatment of dementia. The book begins with introductory sections on dementia and brain ailments that are followed by further chapters that discuss detailed information about challenges of drug delivery across the blood-brain barrier as well as the current status. This book helps readers design and develop novel drug delivery systems and devices for the treatment of dementia that take advantage of recent advances in nanomedical technologies.

Numerous drug delivery systems have been developed recently for dementia. Unfortunately, most of them are ineffective since dementia is not a single disease. It is an umbrella term for several neurodegenerative conditions which alter brain functions. Due to this, there is an urgent need for innovative technologies/nano drug delivery systems to improve the targeting and delivery of therapeutic as well as diagnostic agents specifically for treating dementia.

• Explores promising approaches for the diagnosis and treatment of dementia
• Discusses advances in cutting-edge nanomedical technologies
• Focuses on the design, synthesis and application of nanocarriers in drug delivery

• Language: English
• Publisher: Academic Press
• Release date: Oct 11, 2022
• ISBN: 9780323859066

Book preview

Preface

Nanotechnology is progressively gaining interest of scientific fraternity mainly in biological applications for healthcare. However, still there are niche areas, where nanotechnology has limited applicability. The role of nanocarriers in the delivery of drugs has proven to be meritorious than the conventional ways of drug delivery. Particularly in diseases like cancer, diabetes, etc. nanocarriers have resulted into excellent outcome. However, brain disorders like Alzheimer's, Parkinsonism, etc. pose an entirely different challenge as per as drug delivery is concerned. The access of drugs and other bioactives to brain is still a major challenge to deal with. Dementia is a syndrome in which cognitive behavior of a person deteriorates which is difficult to predict beyond aging. This can affect the daily tasks performed by that person including language, learning capacity, memory, comprehension, and ability to carry out simple tasks including judgment. More than 45 million people are affected by dementia worldwide. This chronic disease is reported in almost 10 million new cases every year and hence needs solid treatment strategies. Dementia is the result of several brain disorders which directly or indirectly affects the brain function such as Alzheimer's, brain stroke, etc.

This book entitled Nanomedicine-based Approaches for the Treatment of Dementia is a fair attempt to report the capability of different nanocarriers such as polymeric nanoparticles, solid lipid nanoparticles (SLNs), dendrimers, liposomes, noninvasive nanocarriers, micelles in treating dementia, and other brain disorders. The complex nature of dementia necessitates the requirement of some of the carrier-mediated drug delivery approaches to mimic the physiological processes of human body for better results. The book is written in context to make readers understand the etiology, possible targets, receptors, and different approaches for the treatment of dementia. Initial chapters of the book emphasize on the understanding of dementia and the remaining chapters deliver the role of the different nanocarriers in treating dementia. Though there are very few products based on nanocarriers, which are there in the market for treating brain ailments; however, this book is also an attempt to accelerate the research in the area of brain targeting of drugs.

The book is comprised of eleven chapters including; Dementia and Neurodegenerative Disorders: An Introduction; Dementia: Etiology, Types, Causes and Prevention; Receptor Attacking Ligands for Active Targeting to Brain; Dendrimer Based Drug Delivery for Dementia; Polymeric Nanoparticles-Based Drug Delivery for Dementia; Solid Lipid Nanoparticles (SLN) Based Drug Delivery for Dementia; Liposome: A Potential Drug delivery Vector To Treat Dementia; Micelles based Drug Delivery for Dementia; Biologics for the Management Of Dementia; Nanocarrier Based Noninvasive Approaches for Dementia; Futuristic Aspect of Nanocarriers on Targeted Delivery for Dementia. The book is of special interest for the undergraduate, postgraduate, and doctoral students working in the area of dementia and related research. The book can be beneficial to the readers for the understanding the role of nanotechnology in dementia and its critical attributes. Individual chapters are dedicated to one nanocarrier so that the concept and role of each nanocarrier can be understood in more detail. As a final note we believe that the book will be helpful to a reader who is interested or working in the area of treatment of brain disorders including neurodegenerative disorders.

Umesh Gupta and Prashant Kesharwani

Chapter 1

Dementia and neurodegenerative disorder: An introduction

Swapnali Vasant Birajdar#, Manisha Mulchandani#, Farhan Mazahir#, Awesh K. Yadav

Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Lucknow, Uttar Pradesh, India

#Authors contributed equally.

1.1 Introduction

Neurodegenerative disorders are caused due to cognitive decline which leads to neuronal damage in the brain. Impairment in the nerve tissues is the main reason behind these neurological disorders. As neurons cannot reproduce or regenerate. These disorders are incurable and lead to progressive degeneration. Neurons are the cells of the nervous system which helps to perform every function of the body such as moving, thinking, talking, remembering, and thus when the neurons get damage there will be a miscommunication between the nerve cells and results in impairment in these normal functions of the body [1,2]. In the United States, an estimated rate close to 6.2 million or more in peoples who are of age 65 years and elders are standing with dementia nowadays, which is caused due to Alzheimer’s disease (AD) and additional neurodegenerative disorders. This number strength raises to a value around 13.8 million people through the year 2060 including the advancement of medical developments to prevent, slowdown, or treatment of AD and thus reducing the risk of dementia. AD is a progressed neurodegenerative disease mainly accountable for around 60–80% of all dementia cases. In the current year (2021) for which the numbers have been reported and making the AD more prominent to dementia. In the year 2019 around 121,499 death rates were documented to AD which is subsequent toward dementia.

In the United States, it is the sixth principal cause of death as reported in the United States which is covering the fifth principal cause for death and it is observed particularly with patients those who are in the stage of 65 years and elders. In between the year 2000 to the year of 2019, the numerous deaths from heart disease, stroke as well as HIV discovered to be reduced, whereas the reported deaths from AD contributing to dementia were found to be amplified further around 45%. The current COVID-19 pandemic situation in the year 2020 strengthens the rate of deaths from AD proceeding to dementia. In addition, the number adjacent to 11 million households besides other voluntary governesses specified a value of 15.3 billion hours of support and care to the peoples who are misery with AD or additional dementias in 2020 [3].

The brain is the composite organ of the body. It is composed of blood–brain barrier (BBB) Which controls the entry of drugs across the membrane and serves as a guard in the brain. Large molecular weight drugs, hydrophilic drugs cannot cross the BBB. Most 100% of molecules which are larger cannot enter the BBB and the 98% of molecules smaller in size cannot pass easily through the BBB. It does not allow the entry of proteins because the proteins are damaging to the nerve tissues and cause apoptosis. Plasma proteins such as albumin, prothrombin, plasminogen, etc. Their concentration in plasma is higher than the cerebrospinal fluid. This barrier protects the brain from neurotoxins which may be endogenous metabolites of drugs or some supplementary substances which are ingested in the diet [4].

1.2 Dementia

Dementia is neurodegenerative disarray as in this the nerve cells (neurons) mainly get affected and damaged. This leads to loss of neuronal signaling between the nerve cells and creates difficulty in the performance of the daily task, normal routine activities, and functioning of the body. Dementia is a disorder which gets worsens with time and the problem rises more and more as damage to neurons is triggered. The signs and symptoms of dementia are depending on the fact that which part of the brain is mainly affected, if the frontal lobe is affected it will create a problem with the judgment capabilities, intellectual ability of a person, and behavioral changes can occur. If the portion of the temporal lobe of the brain is being affected then it results in memory degeneration. If the parietal lobe gets affected it will distress the language of a person [5,6].

Dementia is chronic, incurable but in some cases, it is reversible such as psychometric disorders, folate deficiency, hypothyroidism, an unpleasant state of mind, abnormal metabolic activities are responsible for such conditions. Dementia is an illness that is characterized by cognitive impairment which leads to disturbance in functions like memory, orientation, language, learning capability but the conscious is not affected in this disease [5,6]. Dementia is the result of rather an interruption to nerve cells primes to improper functioning of the brain, death of brain cells. Symptoms of dementia depend on the location and severity of the damage. Dementia is classified as young-onset before the age of 65 and late-onset which occurs after the age of 65 years. There are several conditions that source to dementia as the main cause of dementia in older people is AD which is responsible for almost 60–70% of all cases and cerebrovascular diseases account for almost 15–20%. In adult’s frontotemporal dementia mainly occurs, in this type of dementia the frontal and temporal lobes become shrink and leads to alteration in behavior and problems with language but the memory remains intact. The other causes of dementia are Huntington’s disease (HD), Parkinson’s disease (PD), Creutzfeldt–Jakob disease is also a cause of progressive dementia. Cerebral contusions in the tissue of the brain can also lead to the loss of cognitive functions which will be another reason for the cause of dementia. Other causes of dementia furthermost to neurodegenerative disorders, which consequences in the polymerization of proteins or mutation in the gene. Alcohol consumption, multiple sclerosis, hypothyroidism, Wilson’s disease are correspondingly leading to dementia. There are approximately more than 55 illnesses that are accountable for dementia [5-7].

1.3 Etiology intended for dementia

● Alzheimer’s disease (AD)

● Cerebrovascular disease

● Huntington’s disease (HD)

● Parkinson’s disease (PD)

● Creutzfeldt–Jakob disease (CJD)

● Cerebral contusion

● Hippocampal sclerosis (HS)

● Lewy bodies

● Miscellaneous: alcohol consumption, multiple sclerosis, hypothyroidism, Wilson’s disease, etc.

1.3.1 Alzheimer’s disease

The worldwide incidence of dementia has been reported approximately across 45 million people. AD stands as the most popular reason intended for dementia, which is responsible for 60–80% of all dementia instances [8]. AD remains a proceeded neurodegenerative disorder that primarily leads to spare one-half of entirely dementia belongings. The AD is clinically acknowledged with an indication of loss of memory functions and other minor symptoms include cognitive deterioration, poor judgment, distress in decision making, language disorders, temporal loss and it has been correspondingly linked with mood disorders.

AD is escalating relentless neurologic disorder and it is the main cause of dementia and the reason behind the AD is the deposition of abnormal protein in the brain. Amyloid beta (Aβ) is the protein that has 36–43 amino acids in it and this is the main element of the plaques in people with this disease. This mainly occurs in the elderly distinguish between normal aging and AD is usually difficult. In some cases, AD is often misguided as some other mental diseases [8,9].

1.3.2 Cerebrovascular disease

It is mainly consequences when the supply of blood to the brain is affected and this is also a reason to loss of memory and cognitive impairment mainly in elderly patients, which is the main reason for dementia with cerebrovascular disease. The cerebrovascular disease mainly observed in patients who are suffering from AD [10].

1.3.3 Huntington’s disease

It is a type of neurological disorder that results in involuntary moments, the escalating loss of memory, and psychological disorders. Loss of memory and impairment in daily activity is the first feature that is seen in this disease. Hence this disease is also contributing to dementia [11,12].

1.3.4 Parkinson’s disease

PD results in the damage of nerve cells (neurons) and there is a decrease in the level of dopamine in the brain. The exact cause of this disease is not known but genes and several environmental factors can lead to PD and can cause tremor, slurred speech, rigidity in muscles. Lewy bodies are an important factor when we talk about Parkinson-induced dementia. In this, there is an abnormal deposition of protein which initiates the changes in the brain such as memory loss, cognitive impairment, behavioral and thinking problems [13].

1.3.5 Creutzfeldt–Jakob disease

It is a fatal disease mainly a person can die within the 1 year of onset of the disease. The reason behind this disease is the infection caused by a prion. There is a deposition of prion protein in the brain. This can result in loss of memory, abnormal activities in daily functioning, and results in neuronal damage [14,15].

1.3.6 Cerebral contusion

It is another reason behind dementia as there is damage in the tissues in the cerebrum which is permanent that will increase the amount of anomalous protein in the brain which is responsible for causing AD which will ultimately lead to loss of memory [16].

The rate of dementia depends on various factors:

● Genetic effects

● Age

● Physical activity

● Comorbidity

● Drugs

1.4 Genetic effects

It has a relation with dementia as they can increase the APOE (apolipoprotein-E) gene and this gene is responsible for AD which results in the development of dementia [17].

1.5 Age

It is the major responsible factor for causing dementia as age increases the chances of neuronal damage increase as the various diseases related to the brain which cause degeneration of the brain and this degeneration will lead to cognitive impairment causing dementia [17].

1.6 Physical activity

As we know that a person who has a sedentary lifestyle is more prone to diseases be it any disorder or diseases so physical activities always have a beneficial impact on a person’s lifestyle there will be the improvement in cognitive function and the risk of dementia is lower in people those who follow a healthy lifestyle and involve in physical activities [17]

1.7 Comorbidity

As we already discussed the diseases which cause dementia. Hence, we can say that comorbidities can have a great effect on dementia even they can worsen the condition [17].

1.8 Drugs

There are several drugs available in the market and these drugs can cause dementia. Drugs such as benzodiazepines, statins, anti-Parkinson’s drugs can lead to dementia[18]. Dementia has a great impact on a person’s physical illness and social life. As when we talk about the physical illness, people with dementia will usually suffer a disturbance in their normal routine activities as sleep disturbance, loss of appetite, their attention toward their care is decreased, weight loss thus we can say that people who are suffering from dementia they have to increase the chance of physical illness [18].

Social behavior is also affected due to dementia as difficulty in doing normal activities can bring a person’s confidence down thus the person will become socially less active [18]. People with dementia have shown difficulty in managing personal care this can be a severe cause of comorbid conditions as they lose personal care there will be poor hygiene such as poor oral hygiene which is responsible for conditions such as malnutrition [18].

1.9 Psychometric symptoms

These are major types of symptoms in people with dementia this can lead to suicidal thoughts, withdrawal of treatment, mercy killing the chances of depression and delirium increase, and ultimately a person loses the hope to live [19].

● Apathy: A behavioral and psychological change that is occurred because of dementia in this lack of enthusiasm. A person loses interest in daily activities [19].

● Agitation: It is a type of aggression that can occur in people with dementia as they become irritated with their lifestyle [19].

● Depression: It is another symptom that can be observed in people with dementia, it cannot be diagnosed accurately because the memory functions got impaired [19]. In this way, all we can say is dementia has a great impact on a person’s life. People with dementia are prone to certain diseases, comorbidities, suicidal thoughts, psychometric disorders, and all of such leads to a physical, social, and economic imbalance in life [19].

1.10 Pathophysiology of neurodegenerative disorder; AD

1.10.1 Amyloid beta peptide

The fabrication of Aβ peptides is mainly responsible for AD, these amyloid plaques are localized extracellular (Fig. 1.1) and as the Aβ production has been enhanced whereas their clearance rate is reduced, it starts to deposit in the brain region involving the orbitofrontal cortex and later developed to the region of the neocortex, hippocampus, basal ganglia, diencephalon as well as amygdala of the brain. The amyloid precursor proteins (APPs) are cleaved by either β-secretase or γ-secretase, resulting in the generation of Aβ peptides, which consequences in the notorious insoluble Aβ fibrils. The APP that has been processed by the α-secretase result in the formation of soluble β-amyloid peptides in the healthy adult, which plays a direct role in neuronal plasticity or its survival, which is found to be protective against excitotoxicity, also it is very significant for the primary development of the central nervous system (CNS). It has been revealed to be vital to uphold synapse formation and transmitting neuronal signals [20].

Fig. 1.1 The pathology of Alzheimer’s disease (AD) which involved the deposition of neurofibrillary tangles (NFT) comprised of hyperphosphorylated tau proteins in the neurons and extracellular accumulation of amyloid beta (Aβ) plaques.

The amyloid plaques (Aβ) encompass the formation and accumulation of misfolded Aβ tabloids extracellularly. These Aβ tabloid sheets composed of 40–42 amino acids in its misfolded Aβ sheets (Aβ40 and Aβ42). These two Aβ40 and Aβ42 are the main types of Aβ peptides that play a straight, significant role in the pathology of AD. The Aβ40 or Aβ42 sheets then oligomerize, and it relocated to the synaptic clefts, which also hinders the neuronal signaling in the synaptic cleft. These Aβ-peptide sheets further oligomerize toward insoluble Aβ fibrils and these result in the formation of aggregates of Aβ plaques [21,22]. The Aβ40 and Aβ42 responsible for the aggregation of these Aβ peptides and consequently it is central to the development of disorientated plaques. Aβ40 and Aβ42 are two main by-product metabolites of APP. The Aβ42 form is more toxic isoforms of the Aβ finding compared to the Aβ40 isoform.

The existence of Aβ42 in the cerebrospinal fluid certifies the incidence of AD in its preclinical stage, so the Aβ42 peptide is considered to be one of the most frequently accepted biomarkers of AD, which confirm AD over additional neurodegenerative disorders. It is found that the concentration of Aβ40 is 10 times higher than Aβ42 in CSF [23]. The Aβ42 and Aβ40 proportion is generally used as its ratio remains comparable throughout the disease, the ratio of Aβ42:Aβ40 is a potential biomarker in the development of AD, which specifies the Aβ accumulation, fibrillogenesis, and neurotoxicity, as it is consequential to cause dementia. The APP gene is positioned over 21q21 was revealed to be the first contributing gene for AD. The developments in the genetic investigation have been recognized into two different types of ADs which include:

1. Familial Alzheimer’s disease (FAD)

2. Sporadic Alzheimer’s disease (SAD)

The significant developments in the year of 1990s and early year of 2000s, it is discovered that the familial Alzheimer’s disease (FAD) is the consequence of the mutations of autosomal dominant genes in the APP (Fig. 1.2), PSEN-1, and PSEN-2, these are correspondingly positioned over 1, 14, and 21 of chromosomes [24,25]. The genes PSEN-1 and PSEN-2 containing an essential amino acid that breaks the active site through which it catalyzes the γ-secretase enzyme. These alterations triggered to the APP, PSEN-1, and PSEN-2 genes lead to increased production of Aβ peptides that indicate the process of neurodegeneration. The risk involved in the genetic factors for sporadic Alzheimer’s disease (SAD) was recognized as APOE gene which is a type e4 allele on chromosome number-19 and it is a transporter of low-density lipoproteins. In AD, the gene APOE exists around 50–60% in all cases of AD suffering patients. Whereas the gene APOE in a healthy adult is contributing about only 20–30% as compared to that of AD patients [8,25].

Fig. 1.2 The amyloid beta (Aβ) cascade; tau proteins hypothesis; AD; leading to dementia.

The following genes have been reported to be involved in the pathogenesis of AD [22]

1. Amyloid precursor protein (APP)

2. Complement receptor-1 (CR-1)

3. Apolipoprotein-E (APOE)

4. PSEN-1/PSEN-2 gene

5. Presenile genes

6. Phospholipids linked with clathrin protein

7. Sterol O-acetyltransferase

8. Prostaglandins endoperoxide synthase-2

9. SLC26A38 gene

10. Angiotensin-converting enzyme (ACE)

1.10.2 Tau proteins

The accumulation of these Aβ peptides stimulates the development of neurofibrillary tangles (NFT). These NFT principally involved the hyperphosphorylated tau protein. The accumulation of these hyperphosphorylated tau proteins is also a prominent marker for AD protruding toward dementia. In the normal brain, the three microtubule associated proteins (MAPs) that are MAP-Tau, MAP1A-Tau/MAP1B-Tau, and MAP2-Tau accomplish the analogous functions, that is, the advancement of microtubule assembly and the stabilization of microtubule. These three MAPs are originating in the normal matured neuron. The biological activity of tau which involved in the promoting assembly and stabilization of microtubules primarily in a neuronal protein is regulated by three main features which are turn out to be decreased by the hyperphosphorylation of tau proteins [26-28]. These are:

● The process of hyperphosphorylation

● Stabilization of microtubule assembly

● Its binding competency to the