*2.7.3 Arrhythmias*

The most common arrhythmia in DCM is AF, which increases the risk of thromboembolic complications, impairs cardiac function and worsening HF symptoms. Therefore, evaluation of rate control and anticoagulation in order to preserve LV-function and prevent thromboembolic events is crucial. In the acute setting betablockers, digoxin and their combination may be used to control ventricular rate. In the chronic stage, rhythm control has been shown to be superior to rate control alone in reducing mortality [85]. Because of the commonly reduced left ventricular function, the only therapeutic option is type III antiarrhythmic drug such as amiodarone. Alternatively, electrical cardioversion can be performed. Recently, the CASTLE-AF study demonstrated the superiority of AF catheter ablation in certain patients with HF as compared to medical therapy. The ablation was associated with a significantly lower rate of death and hospitalization for worsening HF [86]. DCM patients may suffer from ventricular arrhythmias (VA), which are mainly caused by myocardial damage, fibrosis and/or loss of cell-to-cell conjunctions, that are described by three mechanisms: reentry, trigger activity, and automatism [87]. Monomorphic ventricular tachycardias (VTs) are frequently induced by macro-reentry mechanism, which is best treated by ablation. The main trigger mechanisms are electrolyte imbalance, mostly secondary to diuretic treatment, antiarrhythmic drugs, and bradycardia. The therapeutic options are a combination of antiarrhythmic drugs like betablockers and type III antiarrhythmics and/or implantation of an implantable cardioverter defibrillator (ICD). The indications for ICD treatment are described later [4].

#### **2.8 Prognosis and risk stratification**

Although there has been a significant improvement in prognosis of DCM patients over the last decades, mortality is still high. The prognosis is mainly influenced by HF symptoms and more relevant by the appearance of VTs. Survival data of adults with DCM have shown a one-year mortality of 25–30% and a 50% survival at 5 years. Sustained VT or VF presents the main cause for SCD, which occurs in up to 12% of DCM patients [4, 88]. In general, the prevalence of sustained VT (monomorphic or polymorphic) is estimated as less than 5% [89]. Recently, the Pediatric Cardiomyopathy Registry presented a 5-year incidence rate of SCD in children with DCM of 3% [90]. An age at diagnosis below 14 years, LV dilation, and posterior wall thinning were identified as the most important risk factors. In contrast, the mortality in adults is mostly associated with age and male gender, reduced New York Heart Association (NYHA) functional class, impaired LVEF, and the presence of specific cardiac biomarkers as well as myocardial fibrosis in CMR [91–94]. Furthermore,

**53**

*Current Pathophysiological and Genetic Aspects of Dilated Cardiomyopathy*

genetic aspects play an important role for detection of high-risk patients. Most commonly the pathogenic mutation in the lamin A/C (LMNA) gene is associated with atrial and ventricular arrhythmias. LMNA mutation has been identified as the most malignant and penetrant condition with worse outcomes compared to other forms of DCM [95]. Beside risk models such as the Seattle Heart Failure Model for the prediction of prognosis in the general population of HF patients, there exist no specific risk tools for DCM patients [96]. For the identification of high-risk DCM patients, a personalized and precise approach is required (**Table 3**). This should include the personal and familial history, measurement of LVEF, detailed search for VA and proof of fibrosis using CMR. Other promising approaches are expected to be helpful in decision-making in high-risk DCM patients, determination of microvolt T-wave alternans analysis and detection of autonomic dysfunction using nuclear imaging. In addition, detection of LMNA gene mutation has been described to identify the high-risk DCM population. However, all these approaches need

The most effective therapy of malignant VTs and thus prevention of SCD in DCM patients is the implantation of an ICD. Current ESC guidelines recommend the implantation of a defibrillator in patients who experienced VT or VF (secondary prevention of sudden cardiac death), as well as in high risk patients for primary prevention. The latter are patients with symptomatic HF NYHA class II–III and LVEF ≤35% after ≥3 months of optimal medical therapy who are expected to survive for at least 1 year [97]. Similarly, the American College of Cardiology and American Heart Association guidelines recommend ICD therapy in patients with LVEF ≤35% due to prior myocardial infarction (MI), at least 40 days post-MI, or non-ischemic DCM and NYHA class II or III [98]. However, existing guidelines lack sensitivity and specificity for the selection of patients with DCM for primary prevention ICD implantation. A recently presented meta-analysis by Golwala et al. has demonstrated a 23% reduction in all-cause mortality with ICD therapy compared with optimal medical therapy alone (HR, 0.77; 95% CI, 0.64–0.91) [99]. Although ICD implantation seems to be the best possible option for SCD prevention in DCM, there remain potential complications. Inappropriate shocks, risk of infection, device or lead replacement have to be considered and discussed in detail

DCM includes a heterogeneous group of myocardial and systemic conditions

causing left ventricular dilatation and dysfunction. DCM is one of the most common cardiomyopathies worldwide. Yet, the real prevalence is unknown. The etiology contains non-genetic (e.g. myocarditis, peripartum, toxics, arrhythmia, infiltrative etiologies, endocrine, nutritional, and neuromuscular) and genetic causes. Literature on genetic mutations being responsible for DCM has increased exponentially. Today, up to 30% of the DCM cases are described to be caused by a gene mutation, the majority of which occur in autosomal genes that encode for a wide range of proteins of the cardiomyocyte's structural elements. Mutations in genes encoding sarcomeric, cytoskeletal, desmosomal, nuclear membrane, mitochondrial, and RNA-binding proteins have all been linked to DCM. However, the most common mutations occur in genes encoding sarcomeric proteins and in genes related to the nuclear envelope and the

*DOI: http://dx.doi.org/10.5772/intechopen.83567*

**2.9 Prevention of sudden cardiac death**

further research.

before an ICD is implanted.

**3. Conclusion**

*Current Pathophysiological and Genetic Aspects of Dilated Cardiomyopathy DOI: http://dx.doi.org/10.5772/intechopen.83567*

genetic aspects play an important role for detection of high-risk patients. Most commonly the pathogenic mutation in the lamin A/C (LMNA) gene is associated with atrial and ventricular arrhythmias. LMNA mutation has been identified as the most malignant and penetrant condition with worse outcomes compared to other forms of DCM [95]. Beside risk models such as the Seattle Heart Failure Model for the prediction of prognosis in the general population of HF patients, there exist no specific risk tools for DCM patients [96]. For the identification of high-risk DCM patients, a personalized and precise approach is required (**Table 3**). This should include the personal and familial history, measurement of LVEF, detailed search for VA and proof of fibrosis using CMR. Other promising approaches are expected to be helpful in decision-making in high-risk DCM patients, determination of microvolt T-wave alternans analysis and detection of autonomic dysfunction using nuclear imaging. In addition, detection of LMNA gene mutation has been described to identify the high-risk DCM population. However, all these approaches need further research.

#### **2.9 Prevention of sudden cardiac death**

The most effective therapy of malignant VTs and thus prevention of SCD in DCM patients is the implantation of an ICD. Current ESC guidelines recommend the implantation of a defibrillator in patients who experienced VT or VF (secondary prevention of sudden cardiac death), as well as in high risk patients for primary prevention. The latter are patients with symptomatic HF NYHA class II–III and LVEF ≤35% after ≥3 months of optimal medical therapy who are expected to survive for at least 1 year [97]. Similarly, the American College of Cardiology and American Heart Association guidelines recommend ICD therapy in patients with LVEF ≤35% due to prior myocardial infarction (MI), at least 40 days post-MI, or non-ischemic DCM and NYHA class II or III [98]. However, existing guidelines lack sensitivity and specificity for the selection of patients with DCM for primary prevention ICD implantation. A recently presented meta-analysis by Golwala et al. has demonstrated a 23% reduction in all-cause mortality with ICD therapy compared with optimal medical therapy alone (HR, 0.77; 95% CI, 0.64–0.91) [99]. Although ICD implantation seems to be the best possible option for SCD prevention in DCM, there remain potential complications. Inappropriate shocks, risk of infection, device or lead replacement have to be considered and discussed in detail before an ICD is implanted.


**3. Efforts on the in-built possession of the catalyst materials to enhance the bifunctional activity**

After the detailed discussion of the fundamental electrochemical parameters, it is now essential to highlight the significance of in-built possessions of the materials, which decide the properties of the catalyst materials. As stated earlier, a reputable candidate for electrochemical reaction must be recognized with certain properties such as intrinsic activity, density of active sites, conductivity, surface area, wettability (hydrophilicity) and stability. But all these properties are decided by their appropriate association with in-built possessions like phase, morphology, particle size, defects and *A Perspective on the Recent Amelioration of Co3O4 and MnO2 Bifunctional… DOI: http://dx.doi.org/10.5772/intechopen.109922*

strain. A slight change in these in-built possessions leads to the huge impact on the properties of catalyst materials. In addition, practically, there is no catalyst material with an adequate quantity of all these mentioned properties. To resolve this inadequateness, many efforts have been devoted on catalyst materials. A catalyst with optimum quantity of all the aforementioned properties can be attained only by a systematic fine-tuning of its in-built possessions such as phase, morphology, crystal facets, particle size, defects and strain. Therefore, to understand the linear thread connection between the in-built possessions, inherent properties and outperforming activity of the electrocatalyst, all these possessions have been discussed in more detail in this section.

#### **3.1 Phase engineering**

The smallest repeating domain containing identical (in both distance and space) arrangement of atoms is called a crystal lattice. The extent of a single or a group of crystal lattice can be defined as a phase, a key factor in deciding the properties of the materials. Each phase has its own property and the variation in phases causes dramatic changes in the properties especially in the intrinsic activity, density of active sites, conductivity, wettability and stability, thus having more impact on the bifunctional activity. Controlling materials with desirable phases is an art associated with synthetic methodology. Hence, it is recommended to choose a suitable methodology to prepare the materials with desirable phase selectivity, so that the extent of the activity can be attained [24]. Therefore, it has been concluded that the phase of the material is the primary in-built possession deciding almost all inherent properties, and hence, by choosing the appropriate methodology, the selectively particular phase can be attained.

#### **3.2 Morphology engineering**

An inherent property, surface area is often morphology dependent since different morphologies have different surface areas even for identical phases [25]. The electrochemical reaction takes place only at the interface, where surface atoms are in contact with electrolytes rather than interior atoms. Although all surface atoms are in contact with the electrolyte, only their certain portions are capable of catalyzing bifunctional reactions called active sites. The morphology with the exposure of the maximum number of active sites is the most opted for better bifunctional catalysis.

#### **3.3 Defect engineering**

Defect engineering is another way to tune the properties of the catalyst material for enhancing the catalytic activity; due to this reason, it is intentionally introduced into the lattice of the materials although it drags the stability of the catalyst materials. The introduction of defects on the lattice can tailor the intrinsic property, especially the electronic configuration, conductivity, chemical reactivity and stability by adjusting electron distribution on the lattice. Defects also lead to the formation of unsaturated atoms on the surface of the catalyst, which are capable of intensively catalyzing the reaction and hence are highly desirable to promote the oxygen electrode reactions [26]. Defects can exist in many forms, namely, structure distortion, oxygen vacancy, cation vacancy, anion vacancy and lattice defects. All the forms of defects lead to the enhancement of the catalytic activity somehow, mainly impacting the

conductivity and density of active sites of the catalyst materials [27]. Caution must be taken while improving the activity of the catalyst by defect engineering since a larger extent of defect density leads to a fall in stability due to the increase in the number of dangling bonds in the material. And it is recommended to adopt an effective and feasible way to create defects, rather than following tedious processes and harsh conditions so as to retain the other properties of the catalysts.


**3. Chromosomal and molecular abnormalities associated with ALL-B**

60–80% of patients with ALL have abnormalities in chromosome number or structural rearrangements (translocations), whereas the remaining 20–40% have normal karyotype [9, 10]. Besides those with a normal karyotype, t(9;22)(q34,q11); BCR/ABL (BCR-ABL1), t(12;21)(p13;q22);TEL/AML1 (ETV6-RUNX1), t(4;11) (q21;q23); MLL/AF4 (KMT2A/AFF1), t(1;19)(q23;p13); E2A/PBX1 (TCF3-PBX1), are the most common cytogenetic subtypes in ALL [10–12].


**3. Classification**

The classification of PIDs is generally based on the defects of the major components of human immunity, such as innate/adaptive immunodeficiencies, phagocytic deficiencies, complement deficiencies, and immune dysregulation. The classification has evolved over time with more phenotypic and genetic defects identified [4, 11].

#### **Table 2.**

*The 2017 IUIS phenotypic categorization of PIDs [6, 11].*

The International Union of Immunological Societies (IUIS) expert committee, currently named as Inborn Errors of Immunity Committee, has been responsible for issuing the classification of PIDs every other year from 1970. The complete catalog of classification has now been widely used as a reference by clinicians and researchers. From 2013, IUIS published more user-friendly phenotypic classification in two formats: one is a pdf file, namely clinically oriented phenotype categorization in the Journal of Clinical Immunology, and the other is a csv file containing a comprehensive list of various disorders that can be downloaded from http://www. iuisonline.org [6, 11]. The phenotypic categorization published in the journal has been well designed for clinical use, while the online list contains the most updated information demonstrated in a digital friendly excel format that can be sorted by phenotypic and genetic features, which are very useful for designing sequencing panels, disease code lists, and diagnostic algorithms.

The major category and subcategory of PIDs from the revised 2017 IUIS phenotypic classification are summarized in **Table 2**.


*Article* **Genome-Wide Identification and Analysis of** *MYB* **Transcription Factor Family in** *Hibiscus hamabo*

**Dina Liu 1,2,†, Chunsun Gu 1,2,3,†, Zekai Fu 1,2 and Zhiquan Wang 1,3,\***

† These authors contributed equally to this work.

**Abstract:** MYB transcription factors constitute one of the largest gene families in plants and play essential roles in the regulation of plant growth, responses to stress, and a wide variety of physiological and biochemical processes. In this study, 204 MYB proteins (HhMYBs) were identified in the *Hibiscus hamabo* Sieb. et Zucc (*H. hamabo*) genome and systematically analyzed based on their genomic sequence and transcriptomic data. The candidate HhMYB proteins and MYBs of *Arabidopsis thaliana* were divided into 28 subfamilies based on the analysis of their phylogenetic relationships and their motif patterns. Expression analysis using RNA-seq and quantitative real-time PCR (qRT-PCR) indicated that most *HhMYB*s are differentially regulated under drought and salt stresses. qRT-PCR analysis of seven selected *HhMYB*s suggested that the HhMYB family may have regulatory roles in the responses to stress and hormones. This study provides a framework for a more comprehensive analysis of the role of MYBs in the response to abiotic stress in *H. hamabo*.

**Keywords:** MYB family; transcription factors; abiotic stress; semi-mangrove plant; *Hibiscus hamabo*


**4. Neurological conditions with ocular manifestations**

#### **4.1 Multiple sclerosis (MS)**

Multiple sclerosis (MS) is a neurodegenerative disease characterized by demyelination in CNS due to autoimmune-mediated inflammatory processes. Recently, vascular and metabolic factors are increasingly being recognized to play important roles in the neuroinflammatory mechanism of MS [4]. The optic nerve is commonly injured in MS with or without optic neuritis (ON). Optic neuritis (ON) is unilateral or bilateral inflammation of the optic nerve due to many causes, including multiple sclerosis (MS), optic neuritis associated with neuromyelitis optica (NMO), infectious, or isolated. In patients with MS, ON is the presenting symptom in 25% and occurs in 75% of cases during the disease course [3].

According to post-mortem studies, demyelinating plaques can be seen in the optic nerves of up to 99% of MS patients, making optic nerve involvement a common aspect *Optical Coherence Tomography Angiography (OCT-A): Emerging Landscapes in Neuro… DOI: http://dx.doi.org/10.5772/intechopen.110810*

#### **Figure 6.**

*Optical coherence tomography angiography (OCT-A) of the optic nerve head (ONH) in a representative Multiple Sclerosis (MS) patient. Split-spectrum amplitude decorrelation angiography (SSADA) results (N = nasal,T = temporal) show that, in comparison to (c) a healthy control example, (a) MS eyes with a history of ON (MSON) and (b) MS eyes without a history of ON (MSNON) both exhibit an apparent qualitative reduction of the ONH microvascular density in the peripapillary area (between circles), mostly in the temporal region. (c). Bar = 0.5 mm (Reprinted from ref. [5]).*

of the disease process [5]. The parafoveal and ONH (**Figure 6**) flow index, a representation of relative blood flow velocity in the vasculature, was determined to be significantly lower in MS eyes with a history of ON (MSON) in comparison to eyes without a history of ON (MSNON), compared to healthy controls [5, 24, 25].

On the other hand, in the largest study of OCT-A on MS so far, Murphy *et al.* [26] showed retinal SVP densities measured by OCT-A are reduced in MS eyes in both MSON and MSNON [26]. They also found that reduced SVP densities correlate with reduced visual function, longer disease duration, and higher levels of global disability in expanded disability status scale (EDSS) and multiple sclerosis functional composite (MSFC) assessments. The group suggested that OCT-A may have additive value as a biomarker in MS, in addition to routine OCT evaluation. The suggestion is coherent with a previous study by Spain *et al.* [25] where they investigated 68 eyes from MS patients and 55 healthy eyes with OCT and OCT-A to assess the structural and vascular change in the peripapillary area. The results showed that MS patients, regardless of whether they had a history of optic neuritis (ON), had a lower ONH flow index and reduced thickness of the retinal nerve fiber layer compared to healthy control eyes. The differences were even more pronounced in MS patients with a history of ON. In comparison to their previous study with a smaller sample size, this study showed that MS patients without a history of ON had a 5.5% decrease in the ONH flow index compared to healthy controls, while MS patients with ON showed a 14.7% decrease compared to healthy controls [25].

Kleerekooper *et al.* summarized the current state of development of OCT-A in MS and some other neuroinflammatory disorders (e.g., neuromyelitis optica spectrum disorder (NMOSD)) and interested readers may refer to it [4]. Although, OCT-A gives new insight into various neuroinflammatory disorders using qualitative features of the retinal microvasculature. Prior to OCT-A being fully implemented into clinical practice, however, concerns with image quality and the creation of standardization must be resolved.

#### **4.2 Alzheimer's disease (AD)**

The neuropathology of Alzheimer's disease (AD) involves the buildup of betaamyloid plaques and neurofibrillary tangles, which cause inflammation and neurodegeneration [8]. It is now recognized that changes in vascular remodeling also play a role in AD, dementia, and mild cognitive impairment (MCI). Due to their similar anatomic, embryonic, and physiologic characteristics, there has been evidence that the retinal vascular network is a surrogate marker of small cerebral microvascular changes [6, 8, 15, 27]. As the retinal vascular network can be observed directly in AD by OCT-A, there has been evidence of decreased retinal vascular density in AD [8, 15]. In a recently conducted systematic review by Katsimpris *et al.* summarized the OCT-A metrics in AD [6]. They found whole and parafoveal superficial venous plexus (SVP) vessel density were inversely associated with AD. This conclusion was coherent with the systematic review of Rifai *et al.* where the authors reported a significant increase in the foveal avascular zone (FAZ) area and a significant decrease in parafoveal SVP and whole SVP density in AD [27]. However, a possible limitation of OCT-A in AD is less suitable for advanced AD patients. Advanced AD patients are easily fatigued by imaging and are more prone to fixation errors [8]. OCT-A may not be useful in subjects with advanced dementia and may be most useful for patients with a new-onset or milder form of the disease. Nevertheless, though recent advances in biomedical imaging modalities like positron emission tomography (PET) have revolutionized the visualization of amyloid-β plagues presence *in vivo* in cognitively healthy individuals, it is not yet feasible as a large-scale screening procedure due to its expensive nature [6]. Compared to this, quantitative OCT-A measurements might provide cost-effective useful biomarkers for assessing the course of AD-related neurodegeneration. From a clinical perspective, it would be really beneficial if a cost-effective retinal OCT-A screening can make an early diagnosis of AD and its disease progression even before severe brain degeneration. Though it requires further study, OCT-A shows promise to develop early retinal biomarkers for pre-clinical AD pathology and its progression from dementia.

Apart from these, there has been growing interest in OCT-A-based screening for cerebral small vessel diseases (CSVD). Lee *et al.* [28] conducted a prospective crosssectional study in the eyes of 69 (138 eyes) cognitively impaired patients to evaluate radial peripapillary capillary (RPC) network density through OCT-A and retinal nerve fiber layer (RNFL) thickness and determine their association with brain imaging markers. Among the 29 patients with amyloid-positive Alzheimer's disease-related cognitive impairment (ADCI), 25 patients with subcortical vascular cognitive impairment (SVCI), and 15 amyloid-negative cognitively normal (CN) subjects were enrolled in the study. The authors found the microvasculature of the RPC network was related to the CSVD burden. However, the RNFL thickness did not reflect cerebral neurodegeneration (**Figure 7** and **Table 4**).

#### **4.3 Stroke**

Stroke may be defined as a neurological deficit attributed to an acute focal injury of the central nervous system (CNS) by a vascular cause, including cerebral infarction, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH), and is a major cause of disability and death worldwide [29]. Of the two types of strokes: ischemic and hemorrhagic, ischemic stroke accounts for 80% of stroke cases and is characterized as an episode of neurological dysfunctions caused by focal cerebral, spinal, or retinal infarction [29, 30]. Lacunar infarctions, which are tiny infarctions (3–15 mm in diameter) in the deep perforating artery region, account for around 25% of ischemic strokes [31]. The causes of lacunar infarction and whether it differs from cortical stroke are still up for debate despite the fact that it has been acknowledged as a recognized subtype of stroke for more than 50 years. OCT-A allows the understanding of the pathophysiological processes underlying lacunar infarction in other vascular *Optical Coherence Tomography Angiography (OCT-A): Emerging Landscapes in Neuro… DOI: http://dx.doi.org/10.5772/intechopen.110810*

#### **Figure 7.**

*Representative images according to diagnostic groups.  Images demonstrate the subcortical vascular cognitive impairment (SVCI), the Alzheimer's disease-related cognitive impairment (ADCI), and the superficial radial peripapillary capillary network (upper row) and axial T2 fluid-attenuated inversion recovery (bottom row) of patients. The patient with SVCI has severe subcortical white matter hyperintensity and decreased peripapillary capillary network density in the temporal quadrant (arrows). (arrowheads). (Reprinted from ref. [28].)*

beds, such as the retina, where small vessels can be visualized easily. Very recently, Duan *et al.* conducted the first OCT-A study and compared its metrics in lacunar and non-lacunar strokes [31]. They found retinal microvascular changes using OCT-A several years after the diagnosis of ischemic stroke. Though OCT-A is not yet established for the diagnosis of acute stroke, the modality can increase our understanding of different stroke sub-types and cerebrovascular diseases. They detected that increased FAZ axis ratio (FAR) of the deep capillary plexus (DCP) and decreased FAZ circularity (FC) of the DCP were associated with ischemic stroke. Also, decreased vascular orientation distribution (VOD) of the superficial capillary plexus (SCP) is associated with lacunar infarction compared with non-lacunar infarction.

Moreover, in a very recent study, Pachade *et al.* demonstrated that microvasculature density features from OCT-A images have the potential to be used to diagnose acute cerebral stroke from the retina. They found decreased microvasculature density, signifying a sparser vessel network, was associated with acute stroke in their study group. Using a self-supervised learning of OCT-A and fundus imaging, their diagnostic system may have a future role in relatively lower cost acute stroke diagnosis and warrants further research [7].

Apart from it, Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), a rare autosomal dominant disease, is the leading cause of hereditary ischemic strokes. The vessel wall of the brain's vasculature thickens as a result of a mutation in the Notch-3 gene, leading to lumen stenosis [15]. OCT-A changes in CADASIL were found to be significantly reduced vessel density in the DCP in the macular region. When compared to the control group, there were no differences in any other macular or optic nerve head OCT-A parameters.

#### **Table 4.**

*Comparisons of capillary density in the radial peripapillary capillary (RPC) network and retinal nerve fiber layer (RNFL) thickness among the three groups.*

Finally, in addition to improving our understanding of CSVD as stated in the previous section, OCT-A vascular parameters may shed light on the progression of ongoing microvascular vascular events (e.g., in hypertension, stroke, endothelial dysfunction, and inflammation) in patients.

#### **4.4 Parkinson's disease (PD)**

Previous research on the retina in Parkinson's disease (PD) patients relied solely on structural OCT scans [9]. Although OCT allows for the analysis of morphological changes in various neurological conditions, the addition of OCT-A will significantly enhance the diagnostic capabilities by enabling a closer examination of the functional and vascular components. Now, it has been established that retinal microvasculature density is associated with PD progression (**Figure 8**) [9, 32]. It was first demonstrated by Kwapong et al. [33] that OCT-A revealed decreased retinal microvascular density in early PD patients, which was later confirmed by Robbins et al. [34] too [33, 34]. In an advanced approach by Zou et al. showed combination of OCT and OCT-A in PD had better diagnostic ability than either alone, and may provide an additional biomarker for disease progression [8].

However, the limitation of OCT-A in PD is that motion artifacts increase in advanced PD patients. The possible cause is PD's cardinal motor symptoms such as tremors, bradykinesia, and rigidity, as well as neuropsychiatric symptoms like reduced attention control and bradyphrenia. The motor symptoms worsen as the disease progresses and that is why motion artifacts also increase with the duration of PD, making it difficult to obtain artifact-free OCT-A recordings, especially in the advanced stages of the disease [9]. An interesting study by Lauermann *et al.* found that motion artifacts in OCT-A images are equally common in both medicated PD patients and healthy controls [9]. However, more advanced stages of PD, indicated by longer disease duration and more severe motor symptoms, were associated with

*Optical Coherence Tomography Angiography (OCT-A): Emerging Landscapes in Neuro… DOI: http://dx.doi.org/10.5772/intechopen.110810*

#### **Figure 8.**

*Representative Optical Coherence Tomography Angiography (OCT-A) Images in PD vs control. OCT-A image and measurement of the density analysis of the superficial retinal capillary plexus (SCP). (A,B) Map of macular and peripapillary area. The inner and outer rings were divided into four quadrants: superior (SO & SI), nasal (NO & NI), inferior (IO & II), and temporal (TO & TI). (C,D) Foveal avascular zone (FAZ) area was significantly decreased in patients with Parkinson's disease (PD) (D) compared to healthy controls (HC) (C). (Reprinted from ref. [32].)*

higher levels of motion artifacts. Thus, caution and expertise are necessary when evaluating the quality and interpreting the results of OCT-A images, particularly in the advanced stages of PD. More importantly, the authors suggest that as like as MRI scans are evaluated by specialized radiologists or neuroradiologists to ensure accurate results for clinical interpretation by other departments. Specialized eye clinics should create and assess OCT-A recordings and then provide the revised results to nonspecialist colleagues for clinical use to mitigate such caveats. Nevertheless, OCT-A has opened a new avenue of research in early diagnosis, and disease progression from micro-perfusion changes in PD patients.

### **5. Conclusion**

Optical Coherence Tomography Angiography (OCT-A) has emerged as a powerful tool in imaging microvasculature in different neuro-ophthalmological and central nervous system disorders. With its unique capability to provide detailed

microvascular architecture, it has contributed to the diagnosis, monitoring progression, and prognosis of various conditions such as optic neuropathies, papilledema, glaucoma, multiple sclerosis, Alzheimer's disease, Parkinson's disease, different cerebral small vessel diseases, and stroke. Despite the current limitations, the future of OCT-A in neuro-ophthalmology and neurology is promising, as ongoing research continues to explore its potential applications, overcome its challenges, and further advance its capabilities.


*4.1. Metatheatre-1*

Although both Seurat and George manage stages (Seurat poses people and shows his work to Jules, a rival artist; George publicly introduces his Chromolume and cajoles patrons at the reception), neither directly breaks the fourth wall like Wilder's Stage Manager (though they may carry scenery such as cut-outs). The two Georges remain in their fictive worlds, except for the play's first lines, where Seurat is in lecture mode: "White. A blank page or canvas. The challenge: bring order to the whole" (p. 21). Then he intones a litany of aesthetic principles—from design to light and harmony—and with each word, the park's trees, sky, landscape, and water appear. A perennial conundrum in aesthetic epistemology is whether artists *find* new worlds or *create* them, or find them through creation. Are Seurat's aesthetic principles eternal forms beyond the mind or Kantian a priori that live within? The question goes to Tracy's distinguishing limit-of from limit-to—that is, the inferred ontological ultimate from the experienced, ontic boundary. *Sunday in the Park* will not resolve this question but keeps returning to it as it articulates and crosses metatheatrical edges and limits.

Musicals break the wall with their 'numbers,' listed by title and character in the program. Even when integrated with the plot, numbers can be showstoppers, necessarily sung to *us* as well as to other characters. Numbers are as much commentary as story, establishing themes and ranges of emotion. As if to say to us, "We are *at* a musical" and indeed we are *in* it, for our applause affects the show's momentum. All this is true in Sondheim: people burst into song and tell you how they feel and what is going on. Yet the boundaries of his numbers are harder to demarcate, especially on the printed page where, in *Sunday in the Park,* they read smoothly together with the unsung dialogue.46 In this way, Sondheim's numbers *are* like Wilder's Stage Manager, who talks to us and to various characters.

Dot, however, frequently does speak retrospectively to us in Act I, and so is more a metatheatre-1 presence than Seurat. Her first number, "Sunday in the Park with George," comments on the world the song establishes and values: "there are worse things" than posing in the summer for your artist-lover "On an island in the river on a Sunday" (p. 30). By the first act's end, her appreciative complaint has become "Sunday," hymn-like in emotion and which articulates Seurat's method of color juxtaposition. Colors mix not on the canvas but "in the eye." And despite the stasis of these figures 'living' forever in a painting, the song suggests liminal passage toward a verticality within but not of the limits of 'ordinary' time.47

Sunday,/By the blue/Purple yellow red water On the green/Purple yellow red grass, Let us pass through our perfect park [. . .], Through arrangements of shadows Toward the verticals of trees/Forever . . . [. . .] On an ordinary Sunday . . . (pp. 127, 128)

Then, at the play's finale, before the stage becomes a blank canvas and George says, "So many possibilities," "Sunday" reprises as he reads Dot's note in the grammar book about *her* George, "So much love in his words . . . forever with his colors . . . how George looks . . . he can look forever . . . what does he see?" (p. 201). "Sunday" frames the simultaneity Dot and the two Georges share with each other and with Marie. And the song frames us in the limit dimensions of the play, 'beyond,' 'at,' and 'within' its world (especially if we happen to be enjoying a Sunday matinee).

46 See Sondheim 2011, *Look, I Made a Hat*, pp. 6, 17.

47 The play's Sundays are during summer. Gillespie and I wonder if Sondheim and Lapine were alert to the Christian liturgical meaning of 'ordinary time' after Pentecost in the spring.