The role of statin therapy in the management of CAA and potential or recurrent ICH seems paradoxical given the current understanding of the role of statins in preventing vascular events. The SPARCL trial showed an increased incidence of ICH in the statin arm compared to placebo. Given these results, the trial investigators recommended that perhaps statins should be avoided in patients with a history of ICH [48]. In addition, retrospective analysis of patients with ICH treated with statins showed increased incidence of microbleeds, particularly in cortex and subcortex [49]. Current recommendations are to avoid statins in survivors of ICH [50], however, further investigations revealed that use of statins prior to ICH was associated with reduced mortality and disability at 90 days [51]. In addition, a meta-analysis showed no increase in ICH in patients taking a statin once they developed radiologic evidence of ICH [52].

#### **2. Familial amyloid polyneuropathy**

Familial amyloid polyneuropathy (FAP) represents a group of multisystem, lifethreatening disorders characterized by the deposition of amyloid protein in either the peripheral motor nervous system, the sensory system, or the autonomic nervous systems, or in a combination of these subsets of the nervous system. These disorders are hereditary forms of amyloidosis, which are typically inherited in an autosomal dominant manner [53]**.** FAP was first described by Andrade in north Portugal in 1952 [54], and subsequently was described in Japan [55] and Sweden [56]. To date, three main proteins are implicated in the pathogenesis of the majority of cases of FAP: transthyretin, apolipoprotein A-1, and gelsolin. The extent of neurological and non-neurologic organ system involvement is variable, depending on the precursor protein, making the diagnosis often quite challenging. Early and accurate diagnosis is necessary to guide further testing, and subsequent treatment options, and could also contribute to improved research strategies to augment understanding of the pathophysiology and improve therapy.

#### **2.1 ATTR amyloidosis**

The most common type of familial amyloid polyneuropathy is caused by the misfolding of transthyretin. Transthyretin, the gene for which is located on human chromosome 18 [57], is produced in the liver, and under normal physiologic conditions, it is responsible for the transport of thyroxin as well as binding of retinol. Due to the electrophoretic mobility of transthyretin, it was originally named prealbumin. While researchers have identified many mutations responsible for the development of amyloid secondary to transthyretin, the substitution for methionine for valine at position 30 of the transthyretin gene is the most common mutation [58]. However, despite the simple missense mutation, disease phenotype is widely variable in severity, symptomatology, and age of onset [59].

#### **2.2 Additional mutations causing FAP**

Mutations in the apolipoprotein A1 (APOA1), a protein that is synthesized mainly in the small intestine and liver, is also associated with FAP. It was first described by van Allen in Iowa [60]. While at least 16 mutations have been identified in the APOA1 gene that are associated with amyloidosis [61], neuropathic symptoms are only associated with the Gly26arg mutation [62]. Similar to FAP

#### *Non-Alzheimers Amyloidoses of the Neurological System: Cerebral Amyloid Angiopathy… DOI: http://dx.doi.org/10.5772/intechopen.101476*

caused by TTR, APOA1 amyloid also causes a length-dependent polyneuropathy; however, polyneuropathy is not the primary feature of this disease. Renal, hepatic, and gastrointestinal symptoms are the most frequently documented symptoms. Treatment is mainly supportive at present, and is geared toward relief of symptoms. Hepatorenal transplantation for end stage renal disease has been associated with a decrease in concentration of plasma amyloidogenic proteins along with improvement of neuropathic symptoms [63].

Gelsolin-related FAP was first described in Finland in 1969, and it is referred to as the Finish type of amyloidosis [64]. The gelsolin gene is located on chromosome 9, and is a protein that normally binds to actin, and regulates the assembly and disassembly of filaments. Mutations in the gene increase the rate of gelsolin cleavage and cause amyloidosis [65]. Gelsolin amyloid is characterized by the triad of cranial neuropathies, corneal lattice dystrophy, and cutis laxa [66]. Amyloid deposition in gelsolin-related FAP affects the upper branch of the facial nerve, leading to bilateral facial paresis and reduced facial expressions; there is also involvement of the hypoglossal, glossopharyngeal, and vagus nerves. Patients typically begin to complain initially of symptoms of sensory neuropathy around the 5th and 6th decade of life, in a distribution which affects the lower extremeties. In addition, there are reports of autonomic involvement in this variant of FAP [67]. Amyloid deposition can also affect the central nervous system in gelsolin-related FAP; gelsolin amyloid can cause an angiopathy leading to vascular malformations in the brain and spinal cord [68]. To date, no specific treatment has been developed for gelsolin amyloidosis. Management is currently focused on proper ophthalmologic care, and plastic surgery for facial laxity [69].

#### **2.3 Signs and symptoms**

One of the key features of FAP that distinguishes it from other neuropathy presentations is that it typically involves multiple areas of the nervous system, with focal neuropathies, sensorimotor polyneuropathies, and autonomic neuropathies. The most recognized manifestation of focal neuropathy is carpal tunnel syndrome, which occurs secondary to endoneurial amyloid deposits of the median nerve [70]. Similar to idiopathic carpal tunnel syndrome, patients usually experience paresthesias in the thumbs and the second and third digits of the hands, along with significant wrist pain. The symptoms experienced with FAP are usually significantly more severe than in idiopathic carpal tunnel syndrome [70]. The sensorimotor neuropathy of FAP is a length dependent neuropathy that affects the small myelinated and unmyelinated fibers first [71]. Patients will initially describe symptoms of foot discomfort, characterized as numbness, paresthesias, and allodynia. On neurologic exam, patients will have decreased pin prick and impaired thermal sensation. With disease onset, light touch, proprioception, motor strength and reflex will be primarily preserved, however, as the disease progresses and affects larger sensory and motor nerve fibers, patients will begin to note deficit changes in these areas as well. Patients will, over time, exhibit significant weakness in their hands and feet, decreased or absent ankle reflexes, and diminished vibration and proprioception in the distal distributions of the nerves. The disease will continue to travel proximally, involving the proximal lower extremities, truck, and the upper extremities. Patients then will begin to have difficulty with ambulation, secondary to their loss of muscle strength and proprioception. Patients will then often start to develop joint deformities (e.g. Charcot joints) as well as plantar ulcers, because of the lack of sensation in their feet [58].

Patients with FAP show significant autonomic dysfunctions as well, particularly with the early age onset form. Typical sequelae of autonomic dysfunction affecting the cardiovascular, genitourinary, and gastrointestinal systems will be present.

Patients will exhibit signs and symptoms of orthostatic hypotension, including light headedness, dizziness, fatigue, and blurry vision upon standing. Patients often develop postprandial diarrhea and/or constipation, as well as post-prandial vomiting due to gastroparesis. In particular, the autonomic control of the cardiovascular, genitourinary, and gastrointestinal systems are affected. With regard to the genitourinary system, symptoms may include urinary retention and incontinence, as well as sexual dysfunction. However, it is important to note that FAP is not associated with central nervous system involvement [58].

#### **2.4 Pathophysiology**

The key pathologic step in the development of FAP is the misfolding of the transthyretin protein, which leads to pathologic deposition within the nervous system. Under normal physiologic conditions, TTR is a tetrameric protein with surface receptors that bind retinol and thyroxine, and then carries these in the circulation [72]. TTR is mainly produced in the liver, but also in the retinal pigment epithelium of the eyes and choroid plexus [73]. There are also reports of TTR synthesis in the neurons [74] and peripheral nerve Schwann cells [75]. Upon pathologic misfolding, ATTR deposits unevenly throughout the nervous system. As the ATTR accumulates, it causes pathology through damage to the nerves by mechanical compression, blood vessel invasion, and the toxicity of fibrils to normal cellular and organ structures [58]. Although many mutations have been identified in the TTR gene in patients with ATTR amyloidosis, there are also many cases with so-called wild-type ATTR amyloidosis. In these latter cases, there is abnormal folding of the TTR peptides, but no mutation identified. The molecular pathophysiology in these cases remains to be fully elucidated.

#### **2.5 Diagnosis**

The diagnosis of FAP can be elusive, considering the relatively low incidence and the non-specific constellation of symptoms. In fact, the differential diagnosis of polyneuropathy is quite wide (see **Table 1**). As always, a thorough history can potentially help tease out the diagnosis. In endemic areas, a family history can help make the diagnosis more straightforward, when taken together with the constellation of clinical involvement by signs and symptoms. Molecular diagnostics—that is, DNA sequencing, either by rapid allele specific oligonucleotide nucleic acid amplification, or by actual sequencing, will help secure the diagnosis. However, the diagnosis can be quite challenging in patients without a family history of FAP. In sporadic cases, keys to the proper diagnosis include the progressive nature of the disease affecting autonomic, sensory, and motor components of the nervous system, in addition to involvement of other organs affected by amyloid deposition (e.g. cardiac involvement, carpal tunnel syndrome). Since neuropathy is often one of the initial presenting symptoms, it is important that clinicians rule out some of the more common causes of neuropathy first. A useful adjunct to diagnosis, typically done prior to molecular diagnostic studies, is Nerve Conduction Velocity (NCV) studies and electromyography, which will document the specific areas of and electrical features of the neuropathy. Formal autonomic nervous system, including Quantitative Sudomotor Axon Reflex Testing (QSART) will document the extent of dysautonomia. These are typically not specific for FAP, however. Biopsy of a peripheral nerve may demonstrate amyloid, and analysis of the amyloid material in the biopsy by High Performance Liquid Chromatography and Mass Spectroscopy may confirm the amyloid as being composed of ATTR. This is definitive for a diagnosis of FAP, and in such a case, molecular diagnostics are an adjunct that will

*Non-Alzheimers Amyloidoses of the Neurological System: Cerebral Amyloid Angiopathy… DOI: http://dx.doi.org/10.5772/intechopen.101476*

#### **Table 1.**

*Differential diagnosis of familial amyloid polyneuropathy.*

allow testing of family members. However, nerve biopsy is invasive, and does carry the risk of causing neurologic damage itself.

#### **2.6 Treatment**

The treatment of FAP has progressed significantly over the years since the first cases were reported. The changes in disease therapy are a reflection of developments in the understanding of the disease pathobiology, as well as the advancements in medical treatment overall. The approach to treatment is divided into interventions for symptomatic relief, on the one hand, and disease modifying agents on the other hand. Common anticonvulsants such a gabapentin and pregabalin [76] are used to ameliorate symptoms, as well as antidepressants such as the tricyclic antidepressants (TCAs) [77] and serotonin-norepinephrine reuptake inhibitors (SNRI) [78]. TCAs are particularly helpful in patients who have significant night-time symptoms, given their sedatives properties; however, considerably attention is warranted for exacerbation of autonomic dysfunction. Duloxetine is the most widely used, and studied, SNRI for the treatment of FAP.

#### *2.6.1 Liver transplantation*

Liver transplantation has been a treatment option for management of FAP for several decades, based on the understanding that replacing a liver producing defective TTR with a liver that makes normal TTR protein will improve the long-term outcome. As an example of the results of liver transplantation in this setting, Yamashita and colleagues from Kumamoto University hospital reported on a cohort 80 patients with FAP due to the mutation Val30Met, managed between January 1990 and December 2010. The transplant group consisted of 37 patients who had a partial hepatic graft via living donor transplantation in Japan or who underwent liver transplantation in Sweden, Australia, or the United States. The non-transplant group consisted of 43 patients with FAP. The transplant group had prolonged survival (p < 0.001) compared with the non-transplant group. The estimated probability of survival at 10 years was 56.1% for the non-transplant group vs. 100% for the transplant group [79].

#### *2.6.2 Disease modifying agents*

The first development in disease modifying agents for FAP occurred with the repurposing of the non-steroidal anti-inflammatory medicine diflusinil. Although liver transplantation has proved to be a successful treatment option, there are many barriers to its use, including availability of technical expertise, availability of a donor, co-morbidities in the patient, and cost. Pre-clinical investigation showed that diflusinil can bind to the thyroxine binding site of the TTR tetramer, and stabilize TTR in the tetramer form, thus preventing the TTR protein subunits from misfolding and being deposited as amyloid. A multicenter, prospective, randomized, double-blind, placebo-controlled clinical trial demonstrated that the use of diflunisal reduces the rate of progression of neurologic impairment [80].

Tafamidis, a thyroxine analogue, is a disease-modifying agent approved for use in the treatment of FAP. Just as diflusinil can stabilize TTR tetramers, it was hypothesized that a synthetic thyroxine analogue may be able to bind to the thyroxin-binding sites on the TTR protein and stabilize the TTR tetramers, similarly preventing them from disassociating, misfolding, and forming amyloid fibrils [81]. A phase III clinical trial in patients with Val30Met ATTR amyloidosis documented delayed progression of neuropathic symptoms with use of Tafamidis, as compared to placebo [82]. An extension study also showed slowing of neuropathy progression [83]. Interestingly, in addition to slowing down the progression of amyloid neuropathy, Tafamidis has also proved effective in improving outcome in ATTR amyloid cardiomyopathy [84].

#### *2.6.3 Gene expression modifying therapy*

While stabilization of the TTR tetramer has proved to be somewhat effective in slowing progression of disease, there has, in recent decades, been an active effort to develop genetic modifying therapy in ATTR amyloidosis. Two gene-silencing treatments, Patisiran and Inotersen have been developed and are FDA approved. Patisiran, a small interfering RNA molecule, is delivered parenterally and reduces TTR production [85]. A phase III trial tested Patisiran against placebo; all endpoints were met, including a decrease in neuropathic symptoms and increase in quality of life [86]. Inotersen, an antisense oligonucleotide, was also designed to reduce the production of TTR. A randomized phase III clinical trial in ATTR amyloidosis patients demonstrated a statistically significant decrease in neuropathic impairment [87]. True gene therapy remains to be established for ATTR amyloidosis.

#### **3. Conclusion**

Given the constellation of non-specific symptoms, the diagnosis of Cerebral Amyloid Angiopathy and Familial Amyloid Polyneuropathy remains challenging, *Non-Alzheimers Amyloidoses of the Neurological System: Cerebral Amyloid Angiopathy… DOI: http://dx.doi.org/10.5772/intechopen.101476*

even to the most adept physician. Despite these challenges, the medical and scientific community's understanding of the diseases has grown considerably since the diseases were first identified and continues to grow, reflected by the increasing number of articles published on the topics. As our knowledge base continues to expand, not only has our ability to make more accurate and timely diagnoses grown stronger, but our treatment and management options have increased as well. It is the authors' hope that the reader has gained a deeper appreciation for the role of amyloid in pathology of the neurologic system and that it will help improve the lives of their patients.

#### **4. Methodology**

The information presented in each of the former sections was culled from a literature search using the National Library of Medicine, PubMed website, using key search terms. This involved the search terms amyloidosis, cerebral amyloid angiopathy, and familial amyloid polyneuropathy. From the articles culled, those published in peer reviewed journals were selected for inclusion, most prominently describing initial observations and key clinical trials that advanced therapies.

#### **Author details**

Gilad A. Muth1 \*, Jonathan S. Harrison2 and Rohan Arora3

1 Prime Health Care Consortium, Denville, New Jersey, USA

2 Rutgers University, Newark, New Jersey, USA

3 Zucker School of Medicine at Hofstra/Northwell, Great Neck, NY, United States

\*Address all correspondence to<EMAIL_ADDRESS>
© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[79] Yamashita T, Ando Y, Okamoto S, et al. Long-term survival after liver transplantation in patients with familial amyloid polyneuropathy. Neurology. 2012;**78**:637-643

[80] Berk JL, Suhr OB, Obici L, et al. Repurposing diflunisal for familal amyloid polyneuropathy. JAMA. 2013;**310**:2658-2667

[81] Obici L, Adams D. Acquired and inherited amyloidosis: Knowledge driving patients' care. Journal of the Peripheral Nervous System. 2020;**25**:85-101

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[83] Barroso FA, Judge DP, Ebede B, et al. Long-term safety and efficacy of tafamidis for the treatment of hereditary transthyretin amyloid polyneuropathy: Results up to 6 years. Amyloid. 2017;**24**:194-204

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## *Edited by Jonathan S. Harrison*

This volume presents a comprehensive overview of amyloidosis, beginning with a general historical overview and proceeding to a discussion of the subtypes of amyloidosis encountered in clinical medicine. The unifying feature common to all amyloidoses, that of misfolded proteins, is explored in some detail, and the pathobiology and manifestations are delineated for major disease entities. Both inherited and acquired amyloidosis are examined, and a discussion of current treatment approaches are included for many of these subsets. It is hoped that the volume will be useful to readers who approach the topic from a wide variety of disciplines.

Published in London, UK © 2022 IntechOpen © toeytoey2530 / iStock

Amyloidosis - History and Perspectives

Amyloidosis

History and Perspectives

*Edited by Jonathan S. Harrison*


**1. Introduction**

Zimbabwe is one of the Southern African countries that attained its independence from the British colony through a very vicious and protracted liberation struggle [1]. According to Zimbabwe National Statistics Agency ([2], p. 18), Zimbabwe has an estimated population of 13 million people with approximately three to four million currently living in foreign countries due to the socio-economic and political challenges that have rocked the country from the early 2000s to date unabated. The population composition of the Zimbabwean population comprises 98% Africans (Shona 82%, Ndebele 14%, and others 2%), Asian 1% and Whites less than 1% ([2], p. 19). Zimbabwe's socio-economic glory was celebrated in the first

10 years of its attainment of independence, despite the tribal-ethnic war between the Ndebele and the Korean-trained Fifth Brigade Mugabe military wing, which ruthlessly claimed the lives of more than 20000 civilians in the Matabeleland province of Zimbabwe ([1], p. 1). The foregoing genocidal incidence, compounded with other socio-economic and politically motivated policies and events which were subsequently introduced to extricate the colonial legacy tainted the image of the political leaders of Zimbabwe at the international level.

According to Makina [1], a typical example of some of the socio-economic incidence that fast-tracked the deterioration or collapse of the once-celebrated economy of Zimbabwe include the Black Friday of 14 November 1997. This is the day when Mugabe the former president of Zimbabwe unilaterally declared that the Reserve Bank of Zimbabwe gives all the war veterans \$50,000 each as compensation for their involvement in the liberation struggle. This was followed 2 years later by a gross infringement of the rule of law in 2000 precipitated by the state-sanctioned White farm invasion, which saw most of the Whites people brutally killed whiles others left the country. These unfortunate events coupled with the 2008 electorate malpractice, human rights violations, succession battles in the ruling Zimbabwe African National Union-Patriotic Front (ZANU-PF) political part, which culminated in the November 2017 coup that removed Mugabe from power, global pandemics such as HIV/AIDS ushered Zimbabwe in an unprecedented socio-economic melt-down. As such, these events affected more the rural communities and the vulnerable people than the urban communities and the working class in Zimbabwe.

In the past three decades, Zimbabwe, like other developing countries, has been severely affected by the HIV and AIDS pandemic which has exceeded wars in terms of cumulative deaths, morbidity, and social disintegration of families at the household level [3]. Statistically, the number of children in Zimbabwe has been estimated to be approximately 5.6 million, of which 1.3 million are orphans ([4], p. 2). The National AIDS Council ([4], p. 1) further estimated that there are approximately 48,000 child-headed households in Zimbabwe, housing approximately 100,000 children. In addition to the foregoing statistics, UNAIDS [5] indicates that there is approximately 165 'orphans' and 'vulnerable' children living with HIV and AIDS in Zimbabwe which aggravate the challenges of the caregivers to cope with the 'orphans' and 'vulnerable' children's problems at the household level. The studies carried out recently in Zimbabwe on the care and support of 'orphans' and 'vulnerable' children by Mugumbate & Chereni [6] and Ringson [3] show that whilst there are several residential care centres in Zimbabwe, the rural communities are predominantly espousing the extended safety nets and other traditional 'orphans' and 'vulnerable' children care and support systems.

Zimbabwe as a signatory to the United Nations Convention on the Rights of the Child (UNCRC) and the African Charter on the Rights and Welfare of the Child (ACRWC) promulgated governing policies and blueprints for child care and support which include the Zimbabwe Orphan Care Policy, the Zimbabwe National AIDS Strategic Policy, National Action Plan for Orphans and Vulnerable Children (NAP for OVC) and National Gender Policy (NGP) to mitigate the challenges of 'orphans' and 'vulnerable' children. However, despite the presence of these governing policies of childcare and support, there remains a gap regarding the capacitating and empowerment of caregivers at the household level. Chizororo [7] argues that the government policies are putting more emphasis on 'orphans' and 'vulnerable' children relegating the caregivers who are also vulnerable due to the increased number of 'orphans' and 'vulnerable' children. The government of Zimbabwe in partnership with non-governmental organisations is directing extensive resources towards the care and upbringing of 'orphans' and 'vulnerable' children and not towards the economic empowerment of the caregivers. The same effort is not being

#### *The Caregivers' Perspective in Coping with the Challenges Faced by Orphans and Vulnerable… DOI: http://dx.doi.org/10.5772/intechopen.101232*

made towards capacitating caregivers of 'orphans' and 'vulnerable' children at the household level, especially in rural areas.

The absence of these socio-economic empowerment programmes for the caregivers, not only in Zimbabwe but around the world, has contributed to the complexities found in 'orphans' and 'vulnerable' children care and support [6]. The studies conducted by Chizororo [7], Hove [8] and Ringson [9] revealed that the economic meltdown and unemployment in Zimbabwe have significantly contributed to the caregivers' burden of 'orphans' and 'vulnerable' children needing care and support in the rural communities. Although, these studies were carried out at different times, there is convergency of the findings that unemployment and the socio-economic exclusion of the rural communities have posed serious challenges to the caregivers in their endeavour to support 'orphans' and 'vulnerable' children in Zimbabwe. Premised in the foregoing, this study seeks to examine the challenges faced by the caregivers in coping with the challenges concerning 'orphans' and 'vulnerable' children at the household level with special emphasis on caregivers in the Gutu District of Zimbabwe.

Gutu District was consciously considered for this study because it is one of the marginalised rural communities that has been affected by HIV/AIDS and political polarisation. The Gutu District is a tribal-based community predominantly with people of the same dynasty except for the minority that migrated based on different socio-economic and political factors. A study conducted by Ringson in 2017 showed that the Gutu District is one of the most poverty and HIV/AIDS-stricken rural community [9]. This finding was predominantly evidenced with several child-headed households, rampant OVC under the guardian of their relatives and grandparents. The study, therefore, focuses only on the household level. In this context, the household level refers to a family or social unit of people living together as relatives. These households of families absorb their deceased's relatives' orphans according to their cultural values that upon the demise of the family member, the remaining relatives took over the custodianship of their relative's children. Similarly, these households also absorb their incapacitated relative's vulnerable children due to chronic illness, disability and living in abject poverty. Thus, the vulnerable children can either be children of the caregivers deceased relative (s) or of their incapacitated relatives. This study focuses on the vulnerable children within the purposively sampled household and not those outside the households. Within that context, this study was guided by the following two objectives:

The paper commences with the context of the study, and the conceptualization of orphans and vulnerable children based on traditional and contemporary understanding. The study also examines the conceptualization of caregivers within the context of the 'orphans' and 'vulnerable' children in the rural communities of Zimbabwe. Subsequently, a thorough review of the ubuntu child-care model and the ACRWC and its dichotomous conflicting mandate stipulates that child have independence rights as well as emphasising that these rights must be executed in respect of the African culture and tradition. These fundamental stages were followed by the methodology, presentation, and discussion of findings, concluding with the implications of the study for social work and the recommendations.


**Meet the editor**

Dr. Benjamin Valdez is the director of the Institute of Engineering at the University of Baja California, a member of the Mexican Academy of Sciences and the National System of Researchers of Mexico. He was granted a BS degree in Chemical Engineering, MS degree in Chemistry, and a PhD in Chemistry by the Autonomous University of Guadalajara. He has been Guest Editor for

several special issues in scholarly journals, and a member of the editorial boards of Corrosion Reviews, Corrosion Engineering Science and Technology, and Revista Metalurgia. He is a full professor at the University of Baja California, participating in activities of basic research, technological development, and teaching in the postgraduate program. His activities include research on the following topics: corrosion and materials, electrochemical and industrial processes, chemical processing of agricultural and natural products, and consultancy in corrosion control in industrial plants and environments.

Contents

**Preface IX**

**Part 1 Physical and Chemical Features 1**

Chapter 1 **Physical and Chemical Characteristics**

Chapter 2 **Hydrocolloids in Food Industry 17**  Jafar Milani and Gisoo Maleki

**of Tropical and Non-Conventional Fruits 3**

Chapter 3 **Emulsifying Properties of Hydrolized Sunflower**

Chapter 4 **Photodecomposition Behaviors of Pesticides**

Seiichi Ishikawa, Bunko Cho, Shin Li, Yuji Okumura, Yoshikazu Iida, Teiji Tanizaki and Masayuki Higuchi

Lai Teng Ling and U.D. Palanisamy

Chapter 6 **Acid-Induced Aggregation and Gelation of Bovine**

Jorge R. Wagner and Patricia H. Risso

Chapter 7 **Electrochemical Behaviour of AISI 304 Stainless Steel Immersed in Mixtures Consisting by Biocide and Fungal Suspensions 97**

**in the Source for Water Supply Using an**

Chapter 5 **Review: Potential Antioxidants from Tropical Plants 63**

Ítalo Herbert Lucena Cavalcante, Lourival Ferreira Cavalcante, João Marcos de Sousa Miranda and Antonio Baldo Geraldo Martins

**Lecithins by Phospholipases A2 of Different Sources 39**  D. M. Cabezas, R. Madoery, B. W. K. Diehl and M. C. Tomás

**Alumina Carrier-Titanium Dioxide Photocatalyst 51**

**Sodium Caseinate-Carboxymethylcellulose Mixtures 75**  María Eugenia Hidalgo, Bibiana D. Riquelme, Estela M. Alvarez,

Maricica Stoica, Petru Alexe, Rodica Dinica and Geta Cârâc


**1. Introduction**

The high-frequency surface wave radar (HFSWR), also known as the HF surface over-the-horizon radar, operates in the 3–30 MHz frequency band at wavelengths between 100 m and 10 m, respectively. The HFSWR can provide additional information on maritime traffic because it can detect targets over the horizon, has continuous temporal coverage, and can estimate vessel velocity based on Doppler data [1,2]. Currently, most HFSWR systems operate in a monostatic mode that requires the collocation of the transmitter and the receiver. This raises practical issues in terms of the coastal space required for installation of both the transmitting and the receiving antenna arrays, as well as the problem of mutual interference between antennas. These issues can be overcome by resorting to a bistatic radar system in which the transmitter and the receiver are located some distance apart [3–5]. In a bistatic HFSWR system, the receiver has robust anti-active directional jamming and anti-destruction characteristics because of the physical separation of the transmitter and the receiver, giving it unique advantages and potential regarding anti-electronic interference. A shipborne HFSWR system has the

advantage of flexibility and it can increase the radar detection range beyond that of an onshore HFSWR. A system in which one of the transmitting or receiving stations is installed on the coast and the other is placed on a ship forms a coast–ship bistatic HFSWR system. Such systems can be classified either as a coast-transmit ship-receive (CTSR) bistatic HFSWR or as a ship-transmit coast-receive (STCR) bistatic HFSWR depending on whether the receiving station is placed on the ship or the coast, respectively.

A CTSR bistatic HFSWR has the advantages of anti-stealth, anti–interference, and no onboard electromagnetic radiation because the ship carrying the receiver can move to areas far from the coast. Compared with STCR systems, CTSR systems can exploit fully the flexibility of a shipborne platform and further expand the radar detection range by adjusting the attitude of the shipborne platform and changing the radar system configuration, e.g., adjusting the radar spindle angle. However, the azimuth resolution of such systems is reduced because shipboard platforms are limited by the size of the platform and thus the radar receiving station aperture is typically limited to ≤100 m. In an STCR bistatic HFSWR system, the shipborne equipment comprises only the transmitter, and there is no need to consider the deployment of a receiver, signal processor, or other equipment. In addition, the antenna aperture of the radar system is not limited by the size of the ship, which means that a large aperture-receiving antenna array could be installed onshore to improve azimuthal resolution. However, the fixed nature of the coast-based receiving station means that the receiving array spindle angle cannot be changed, which limits the detection range of the radar system to a certain extent. In addition, a transmitter/receiver–receiver radar system could be formed by adding a second coast-based/shipborne transmitter–receiver monostatic radar on the same basis as the coast–ship bistatic radar. Then, the detection performance and positioning accuracy of the marine target could be improved through fusion of the results of the two systems.

In their research into onshore and shipborne bistatic HFSWR systems, Gill and Walsh derived analysis relevant to onshore bistatic HFSWRs [6,7] based on the equation for the first-order radar echo spectrum derived by Barrick and by Lipa and Barrick for an onshore multistatic HFSWR [8,9]. Based on the space–time distribution of the first-order radar echo spectrum of an onshore bistatic HFSWR system, Xie et al. proposed and verified a spreading model through simulation and experiment [10]. In research of shipborne HFSWRs, both Walsh et al. and Khoury and Guinvarch derived the first-order ocean surface cross section of a monostatic HFSWR system on a moving platform [11–13]. In addition, Xie et al. studied the first-order ocean surface cross-section for a shipborne HFSWR both theoretically and through experiment [14,15]. In research of coast–ship bistatic HFSWRs, Li et al., Chen et al., and Liu et al. all presented the first-order sea clutter based on system configuration and analyzed the mechanism of broadening [16–19]. It is worth noting that the HFSWR system used in their research employed multichannel transmitting arrays mounted on the coast and only one receiving antenna mounted on a ship, whereas the HFSWR system of consideration in the present study employed one transmitting antenna and multichannel receiving arrays. Zhu et al. analyzed the influence of bistatic angle and shipborne platform motion on the characteristics of the broadened sea clutter spectrum [20]. Most previous research on coast–ship bistatic HFSWR systems focused on simulation analysis, with few reports on experimental verification.

The main characteristic of the coast–ship bistatic HFSWR is that it combines the advantages (and disadvantages) of monostatic coast-based and shipborne HFSWR systems. The radar spectrum of the coast–ship bistatic radar, including the first-order sea clutter and moving target echoes, will change with variation of the motion of the shipborne platform and the existence of the bistatic angle. A frequency shift of the first-order sea clutter spectrum will lead to expansion of the first-order sea clutter, and the blind area, due to the broadening of the first-order sea clutter spectrum, could cause difficulty in detecting targets within it, significantly reducing the overall detection performance. Therefore, it is necessary to investigate the mechanism of broadening of the first-order sea clutter spectrum and its influence on target detection. A comprehensive understanding of the bistatic spreading mechanism of the first-order sea clutter spectrum is essential for study of bistatic clutter suppression in target monitoring.

The remainder of this paper is organized as follows. In Section 2, the theoretical formulas of the first-order sea clutter scattering cross-section and the Doppler frequency shift of moving ship targets for the two types of coast–ship bistatic radar system are derived. In Section 3, simulation results of the first-order sea clutter spectrum under different operating conditions are presented and the influence on target detection is analyzed. In Section 4, the coast–ship bistatic HFSWR experiment is introduced and the derived results interpreted. Finally, brief conclusions are outlined in Section 5.