*Commentary* **Exploring My Life Path by Asking 600 People What They Love about Theirs**

**Fionn Crombie Angus \* and Jonathan Angus**

Fionnathan Productions, 5 School Lane, Mountshannon, V94 D8FT Clare, Ireland

**\*** Correspondence<EMAIL_ADDRESS>
**Abstract:** A young man with Down syndrome and an early adopter of self-managed supports wanted to have a great life, but he needed to be sure what a great life was for him. He decided to ask successful people, "What do you love about your life?", which he felt was a question that gets right to the heart of the matter. In this paper the young man and his father will outline their journey as co-researchers in collecting/filming 600 stories across ten countries, with some interviews prearranged but many occurring spontaneously at music, film, and arts festivals. The initial findings of "what people loved about their lives" fall into the following categories: Family, Work, Home, Travel, Health, Pets, and Life Itself. Positive side effects for the young man covered: self-confidence, ability to connect with people, opportunities, working relationships, and ongoing friendship. The implications of taking a social journalism approach to collecting stories will be discussed in line with the question "What makes for good inclusive research"? The journey of the co-researchers speaks to the outcome that it is worthwhile to research your life path, accessing elders' wisdom. The tools of inclusive research are powerful when applied to a citizen's life questions. Each person values their life in unique ways, yet there are many commonalities.

**Keywords:** down syndrome; qualitative research; quality of life; self-advocacy; happiness

**Introduction**

Fionn is a young man with Down syndrome who rents an apartment in Galway. Jonathan, his father, supports him to live independently. Together they follow Fionn's dreams: they travel to experience unique landscapes and natural phenomena; and they meet communities and individuals, by offering workshops and talks, and by performing music. They weave all these together into amazing adventures.

Fionn is one of the first in Ireland to adopt self-managed supports. He wants to have a great life, but he needs to be sure what a great life is for him. Gathering information about what is a great life for others was a way to gain clarity on his question: to determine his life path. And through the process of meeting, greeting and interviewing many people, a great life is happening along the way.

There has been much written about the value of inclusive research in line with its principles of ensuring that the research questions are relevant to the life of the person involved in collecting information (Johnson and Walmsley 2003). Their reflection will demonstrate how such data collection has been life-giving for Fionn, leading him to widen his circle of contacts as well as provide him with "an adaptable way to a sustainable and meaningful career" (Angus 2022, p. 1).

#### **How They Went about This Reflection**

As a team of two co-researchers they discussed what they would like to share about their inclusive research journey and how it had impacted Fionn's life journey. They had several discussion sessions following which Jonathan would draft the ideas into a script that Fionn would listen to and then agree or suggest additions and/or modifications. The

**Citation:** Crombie Angus, Fionn, and Jonathan Angus. 2022. Exploring My Life Path by Asking 600 People What They Love about Theirs. *Social Sciences* 11: 551. https://doi.org/ 10.3390/socsci11120551

Academic Editor: Patricia O'Brien

Received: 25 August 2022 Accepted: 16 November 2022 Published: 27 November 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

reflection is a joint effort using Jonathan's strength as a writer and Fionn's strength of contributing to discussion and interpreting ideas from his own perspective of being an inclusive researcher. The reflection is written in the third person which allowed for some details being personalised to either Jonathan or Fionn versus the plural use of "we". For the purpose of the reflection there are a number of what the authors have described as Spin Offs for Fionn arising from doing inclusive research.

#### **The Happiness Project**

In this commentary the authors have chosen to reflect on what they have learned from their Happiness Project which they have developed and which is an ongoing citizen research project containing more than 600 open-ended interviews filmed in ten countries over seven years. Initially they met only with people with Down syndrome. This project began in the summer of 2013, when Fionn was a teenager. It arose from the desire to share insight into the lives of a small group of people with Down syndrome from the west of Ireland. It was decided to make a video to be shown on the first night of 600 km charitable cycling tour for the benefit of people with Down syndrome. Jonathan asked Fionn to decide on a single interview question they could ask all of the participants in the film, and Fionn suggested: What do you love about your life?

For Jonathan, the question initially sounded a bit awkward, a bit too naked or naïve. The more he ruminated with it, the more the simple brilliance shone, a profound question that could be asked a dozen times of the same person and could elicit a dozen responses, one that could lead toward greater appreciation of one another's lives. It illustrated well the core principle of inclusive research that research question/s need to be owned by the person with the lived experience of disability (Johnson and Walmsley 2003).

For the Happiness project it was important to film a variety of people with Down syndrome, including those who, through communication challenges, could not be expected to speak on camera. The method settled upon for this latter group was to query a loved one, usually a family member, and film the person doing the activity they love. This way the project was far less language dependent. All interviewees both verbal and non-verbal were videoed doing things they love: ocean swimming, surfing, racing greyhounds, baking cakes, dancing, playing with pets, and driving a car.

An edit of the video was made (with Fionn playing fiddle for the soundtrack) and it was warmly received when screened at the end of the first day of the race for the tired cycle riders. A subsequent article in the local paper caught the eye of a national TV chat show, and they were invited to show clips and talk about it as guests on the show.

For the purpose of the commentary there are a number of what the authors have described as Lessons Learned for Fionn arising from working on inclusive research projects. These are now explored below.

### **Lesson Learned: Doing the Pilot Happiness Inclusive Research Project Enabled Fionn to Speak to the Media as an Agent of Attitude Change for People with Disability**

The end of the cycle race could have been the end of Fionn's search to understand what people loved about their lives however Jonathan was still grappling with how to help him settle on something fulfilling, where his gifts could be shared. They both agreed that it would be foolish to rush into a career decision and determined to continue the Happiness Project, extending their focus to include people with a range of different interests and accomplishments. By broadening the group and learning what was most important to a larger group of individuals, Fionn believed that he might gain insight into areas of life that he had not thought about in relation to his own life. At the same time both agreed that the project was a way of developing their father /son relationship as one built on shared experience of doing research together.

#### **Recruiting People to Answer Fionn's Question**

Fionn's network of contacts reflected how, with Jonathan's support, he had built a start-up career that included his interests in music, art, and education. His wide network came from his busking on the Galway traditional music scene playing the fiddle, from exhibiting his artwork both in Ireland and beyond and doing inclusive research as a member of the Inclusive Research Network of Ireland (http://www.fedvol.ie/Inclusive\_ Research\_Network\_IRN/Default.241.html, Available Online: 26 November 2022) and Citizen Network (https://citizen-network.org/map/fionnathan-productions, Available Online: 26 November 2022). The fluidity of Fionn's world led him to decide on approaching people for interviews on meeting them at the range of events he and Jonathan attended together. This covered concerts to gallery exhibitions, from lectures to movie premiers. Such an approach was not unlike street interviews done by journalists (Gubrium and Holstein 2001). This decision coincided with Fionn and Jonathan gaining free access to these types of events as journalists.

### **Lesson Learned: Doing Inclusive Research Led to Fionn to Be Recognised in Other Valued Roles Both as Interviewer and Event Journalist**

As part of the flexible approach to recruitment potential participants were asked for their verbal consent to film them answering the single question put to them by Fionn., What do you love about your life? It was explained by Fionn supported by Jonathan how these videos were recorded to learn about the person's life, so Fionn could gain insight into how other people lived and how this might help him to decide what he wanted to do with his life. They shared with each interviewee how they would post the interview online, providing them with the link and contact details if they wished to have the video deleted. As their interviewing continued their video making skills also grew. They became adept in using professional film making equipment, including digital cameras, tripods, microphones, and lights. They found that a smartphone often worked best, as people were more at ease and appeared to speak more freely. They agreed with Wolfensberger (2013) that their new roles of interviewer and journalist added value to their lives.

#### **Lesson Learned: Doing Inclusive Research for Fionn Gave Him Experience in Learning New Skills on the Job**

### • *Doing the Interviews*

The interviews were posted on Fionn's YouTube channel, titled Fionnathan Presents The Happiness Project: What Do You Love? (https://www.youtube.com/channel/UCEUi8 gOAbuMUXdZRE5Yw0PQ, Available Online: 26 November 2022). Here the date of the interview, location, a description of the events surrounding events, a biographical sketch and links to the interviewee's online profile are available. They were then cross promoted on social media such as Facebook and Twitter. Some of the videos were linked through to Fionn's website, www.fionnathan.com, Available Online: 26 November 2022. Interviews about the project were done with traditional media (TV, radio, and newspapers) as well as podcasts and blogs.

The methods used by Fionn, with Jonathan's support, to hear and record what people loved about their life, supports the issue raised by (Milner and Frawley 2019) who have called for action in inclusive research to provide space for researchers with the lived experience of disability to select how they collect data without being reined in by traditional research methods. For data collection to work for Fionn and Jonathan as two co-researchers, one with an intellectual disability and the other as a supporter, the data collection needed to fit with the spontaneity of the event where they meet potential interviewees. Also, they did it together challenging the traditional belief of a potential conflict of interest between them as father and son. Their view in response to such potential criticism was that doing research together reflected their respective roles as partners in a company that they had set up called, Fionnathan Productions as a social enterprise that aims:

Making media productions, doing research, and promoting inclusion provided them with an opportunity that moved beyond vested interests to developing sustainable interests that became life enhancing for Fionn.

Looking back to the beginning of the pilot, there was a moment when the Happiness Project might have never started. "On the first day", Jonathan reminisced, "as we travelled out to collect stories, Fionn spoke from the passenger seat, saying, 'I think maybe you should ask the question, and I'll hold the camera,' to which I responded, 'How about you try it out. And more than a few, so you know what it's like past the start'". Fionn agreed, leading to Jonathan's viewpoint that he has grown to exude self-confidence. He is surprisingly capable, and his good cheer is disarming, cutting through social barriers and calling up honest reflection. People feel safe opening up to Fionn, it seems, intuitively recognising a lack of guile. Perhaps surprisingly, as meeting people with Down syndrome is a relatively rare occurrence for many in society, those we interview seem to find Fionn immediately relatable.

### **Lesson Learned: Doing Inclusive Research for Fionn in a Space That Is Not Bounded by Traditional Methods Allowed Him to Collect Information in a Doable Way That Built His Confidence as an Interviewer**

• *What Was Learned about What People Loved about Their Lives?*

The interview collection now numbers over 600 stories. More than 100 participants are famous enough to have Wikipedia pages about them. Interviewees' ages cross the adult lifespan, from teenagers to people in their 10th decade. Many of the people they have collaborated with have intellectual or physical disabilities with important things to say.

The technique that was used in the pilot project to interview subjects with all levels of speaking ability served to support them in engaging with a very diverse body of participants. They shared thoughts with a deaf interviewee through a translator who spoke and signed. With non-English speakers, they used a combination of gestures, smiles, and smartphone apps.

This fluidity of approach allowed the interview style to change to fit the circumstance. Interviews with the touring troupe from Shakespeare's Globe Theatre presupposed their love of acting. Fionn instead asked a rhyming couplet: "Which line, from this play, is your favourite to say?"

Many people find being asked by Fionn, "What do you love about your life?" quite a moving experience. Dozens say, "that's a wonderful question," or sometimes "what a beautiful question," or even "you probably have asked me the most important question you could ask anybody."  Generally, though, even such respondents warm to the theme.

Once, a touring musician from America settling in for the interview asked about the origin of Fionn's name. Briefly the Irish myth of the third-born son, a simple man who gained all wisdom from the Salmon of Knowledge unintentionally, while serving others was shared. In the ensuing interview, the participant referred to this story to describe her creative process, saying, "You can't be like a king. One has to be like a servant, one needs to be 'broken enough'".

Each person interviewed valued their life in unique ways, yet there are many commonalities covering the following eight areas: Family & Friends; Work; Travel; Home; Nature; Health and Well Being; Hobbies and Education.

Here are some direct quotes selected by Fionn that relate to these categories as ones that he found that were meaningful to him. He pointed out that all the quotes come from a place where people were living lives doing things that made them happy. What both Fionn and Jonathan found amazing was that there were no negative answers. They wondered if their own excitement to ask this question led people to only think positively. The power of positive thinking was at work.

#### **Family & Friends**

"The influence of my mother."

"My family, my friends, my grandchildren."

"I love my family. Because of them I able to keep grounded, and I remember that what I do, I'm doing for them"

#### **Work**

"I try to love almost everything, approaching our lives and our work like we're making art and music."

"I love making films. I get to do a job that I would pay to do—please don't tell Disney that."

"I am enjoying a number of opportunities to grow in my profession. I have been assisted by conservation colleagues not only in Zambia but in the Southern region."

#### **Travel**

"I enjoy traveling to strange and new places."

"I love traveling. I think that has really changed my life."

"I love being here in Dublin for my first time."

#### **Home**

"Home." ("And what do you love about home?") "Breakfast."

"I love going place, which only makes coming back home all the sweeter."

"I love living here on campus and having fun with all my frineds."

#### **Nature**

"I love nature."

"I really enjoy getting close to really wild animals, and big wild animals, at times. And then I like getting a chance to watch them for a long time."

#### **Health and Well Being**

"Gathering primary sources, and helping people use them."

"Interdependence, and being there for each other, is way more valuable than independence."

"I love that my live is surprising in the best and deepest ways."

#### **Hobbies**

"I love the fact that I discovered, by sheer chance, that I could play music."

"What I love about my life is I'm a teenager, and I listen to music."

"I love gardening."

#### **Education**

"Opportunities to never stop learning."

"Men like you, asking questions like that."

"My son taught me that pretty much everything the world values is of no value. That money isolates you from other people."

Responding to the question "What do you love about your life?" often leads to emotional responses where tears and laughter are shared, and Fionn has received many spontaneous hugs. Here is a favourite moment, when Fionn's interviewed a retired secondary school history teacher in a small village.

"That's a profound question, and it would take me a long time to do it justice. But I would say . . . I will just tell you that I have been blessed, in my studies, in my job, in my entire life, with good health, a good wife, a happy family, and what can I say? a great, great life, in every possible situation.

And I am thoroughly happy. I have so many blessings, and so many things to be grateful to.

And thank you for asking me a question that's so profound, so deep, and profound, and would take, actually, a long time to answer adequately. But it is a hugely important question.

Now, could I ask you a question?"

"Sure."

"The same question to you: What is most important to your life?"

"I suppose, this moment, interviewing you"

(Nearly overcome with emotion) "Bless you".

**Lesson Learned: Doing Inclusive Research Led to Fionn Being in Receipt of Positive Statements about His Role as Interviewer, Leading to him Feeling That He Was Appreciated**

• *What Was Learned by Fionn about His Life?*

Fionn and Jonathan agreed that the most enjoyable part of the research cycle was sharing what they had learned with others who are interested in the topic and receiving their responses. They have been asked to deliver talks to social science students on courses in thirty colleges and at multiple conferences, in cities such as Honolulu, Copenhagen, Amsterdam, Glasgow, Bristol, Sydney, Brisbane, Vancouver, Montreal, Detroit, Philadelphia, and Austin. On the surface their presentations may appear as purely educational, but they serve a deeper purpose for Fionn being recognised as a valued presenter arising from doing research in a manner that best suits his abilities and interests. This outcome was life enhancing for Fionn as it paved his life pathway with speaking opportunities that would often snowball into other invitations. For example, families would often refer Fionn to other family groups after gaining insight into his life as inspiration for their own family member with a disability. A further example of one presentation leading to another happened three years ago, when Fionn had an opportunity to interview Tim Shriver, Chairman of Special Olympics. He was profoundly impressed by the question, and during a dinner celebrating the launch of a UNESCO Chair, asked Fionn if he would partner to deliver the post dinner address. Fionn described his project to the gathering, and Tim invited all to reflect on what it was they loved about their lives, providing a minute of silence. Then, volunteers shared their responses to the question with Jonathan recording it all—six more interviews, in the bag.

What was also learned by Fionn was that celebrities, leaders, and other people of influence was open to being interviewed if the question is appealing and the approach flexible, and ideally instant. In getting to ask this one major question about what people love about their lives the outcome for Fionn has not been a chosen pathway emulating anyone person that he has interviewed but rather he has become more himself becoming not only an expert on what people love about their lives but also being open to becoming an Ambassador for a Global for Citizen Network (https://citizen-network.org/about/citizennetwork-research, Available Online: 26 November 2022), as well as founding officer of the National Down Syndrome Policy Group (NDSPG) UK (https://ndspg.org/who-we-are Available Online: 26 November 2022). Recently, he lobbied 107 MPs (probably a world

record for an Irishman) contributing to the recent passage of the Down Syndrome Act (2022). As a Research Officer for the NDSPG, he with support from Jonathan established an Advisory Group of people with Down syndrome from all around England. You can probably guess what the first focus group question was.

Perhaps the biggest honour of all: Fionn is Chair of the new Special Interest Inclusive Research Group for the International Association for the Scientific Study of Intellectual and Developmental Disabilities (IASSIDD) (https://iassidd.org/sirgs/inclusive-research/, Available Online: 26 November 2022) and the first Council Member with intellectual disability in the organisation's 58-year history.

**Lesson Learned: Asking People What They Love about Their Lives Has Enabled Fionn to Recognise That He Has Leadership Potential Becoming a Member of Both Inclusive Research and Advocacy Groups Which All Play a Part in Building Him a Sustainable Future**

#### **Conclusions**

Fionn and Jonathan have approached this reflective commentary as two co-researchers describing a body of work that has warmed hearts of 3 million others (latest YouTube count https://www.youtube.com/channel/UCEUi8gOAbuMUXdZRE5Yw0PQ/about, Available Online: 26 November 2022). They hope that this journey, attempting to discover a young man's life path, might stimulate interest in both professional academics and aficionados of knowledge to break (or at least bend) some of the rules and conventions of who can do research, and for what purposes.

Finally, it will come as no surprise that when Fionn was last asked about what he loved about this life his answer was "I love meeting people from all corners of society, and I love to hear their stories and share my stories with them. I want to make the world a place where everyone belongs, and I think that can happen when we listen to each other."

**Author Contributions:** Both authors worked jointly on all parts of this project, using third person perspective when referring to themselves. All authors have read and agreed to the published version of the manuscript.

**Funding:** The authors received no external funding for this project.

**Informed Consent Statement:** All participants were informed of the nature of the project, and how their likeness and words would be used. Consent was received by each.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


**3.7. Therapy outcome and test diagnostics: at the end of therapy (independent blind diagnostician)**

*SCID diagnostics* demonstrated a remission of the SAD and depressive episode. The patient showed a well understanding for the complexity of his symptomatology and confrontation with otherwise too much anxiety causing social interaction and performance situations. Safety and avoidance behavior was no longer seen. *Standard diagnostics*: The *Symptom Checklist (SCL-K-9)* showed the psychological symptom pressure on average (T = 57, D = −14, *p* < 0.05). The *Brief Symptom Checklist (BSCL)* also showed all values on average. *Disorder-specific diagnostics*: The *Liebowitz Social Anxiety Scale (LSAS-SR)* total score was at 42 (cutoff, 30; LSASprä = 105), the *Social Interaction Anxiety Scale (SIAS)* at 17 (cutoff, 35; SIASprä = 46), the *Social Phobia Scale (SPS)* at 11 (cutoff, 24; SPSprä = 29), and the *Beck Depression Inventory (BDI)* at 2 (no depression; BDIprä = 17).


**6. Clinical use of PDE-5 inhibitors in patients with heart failure**

Following years of basic research examining the cardioprotective effects of PDE-5 inhibitors against ischemia, a recent study by Guazzi et al. demonstrated that sildenafil improves LV diastolic function, cardiac geometry, and clinical status in patients with stable systolic heart

Phosphodiesterase-5 Inhibitors Improve Left Ventricular Function in Failing Hearts 111

compared with placebo (P<0.01). Additionally, diastolic measures of LV function demonstrated systematic and sustained improvement after both 6 months and 1 year of sildenafil treatment. The transmitral E/A ratio, isovolumic relaxation time, and both lateral and septal E/E′ decreased from baseline through 12 months (all P<0.01), which is indicative of an improvement in LV diastolic function and a decrease in LV filling pressure. Furthermore, septal T E-E′ was significantly reduced at 6 and 12 months of sildenafil treatment (P<0.01). All these changes were in agreement with the observed reverse remodeling on LAVI, which is viewed as morphological expression of LV end-diastolic pressure (Lester et al., 2008). Changes observed at 6 months and 1 year after sildenafil were

With the advancement in the management of patients with cardiovascular disease and improvement in survival following cardiovascular events, the incidence of heart failure, especially in patients of age 65 and older is increasing. Using state-of-the-art echocardiography, we and others have demonstrated that treatment with PDE-5 inhibitors improve LV function in various models of myocardial dysfunction and heart failure. These studies suggest that PDE-5 inhibitors are immensely promising for further development as novel drug therapies for myocardial infarction, LV hypertrophy and dysfunction, doxorubicin-induced cardiotoxicity, and heart failure. Clinical studies of sildenafil on heart failure patients have reported improved exercise capacity, coupled with reduced pulmonary vascular resistance and better endothelial function (Lewis et al., 2007; Guazzi et al., 2007). Sildenafil also preserved LV function in patients with heart failure due to various etiologies (Guazzi et al., 2011). Several other studies indicated that PDE-5 inhibition with sildenafil has a therapeutic promise for stroke, neurodegenerative diseases and potentially other circulatory disorders (reviewed in Kukreja et al., 2007; Kukreja et al., 2011a; Kukreja et al. 2011b). These drugs may not only delay or reduce the pathological damage or defects in various vital organs, but also improve the overall well-being and quality of life in patients.

This work was supported by grants from the National Institutes of Health (HL51045, HL79424 and HL93685) to Rakesh C. Kukreja and a National Scientist Development Grant

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**7. Concluding remarks**

**8. Acknowledgment**

**9. References**

failure (Guazzi et al., 2011). The study primarily focused on the effects of chronic PDE-5 inhibition on LV diastolic function and cardiac chamber remodeling, providing the first human evidence that PDE-5 inhibition can be beneficial for improving the diastolic and structural properties of the failing LV. Transthoracic echocardiography was performed using IE33, Philips ultrasound machine, equipped with a software for tissue Doppler (TD), using a 2.5- to 5.0-MHz probe (S5). Standard M-mode, 2D, and Doppler blood flow measurements were performed according to the current American Society of Echocardiography Guidelines (Quiñones et al., 2002). Chamber dimensions were obtained using standard procedures including left atrial volume index (LAVI) and LV mass index (LVMI) (Devereux & Reichek, 1977). Septal and posterior wall thickness, LA, and LV end-systolic and end-diastolic dimensions were obtained from the parasternal long-axis view. LVEF, end-diastolic volume index (LVEDVI), and end-systolic volume index were evaluated with the Simpson method.

Interestingly, E/E′, a variable repeatedly found related to LV filling pressures in a variety of left-sided cardiac disorders (Lester et al., 2008), significantly decreased at 6 months and 1 year of active treatment (Figure 9). Additional study findings that support the hypothesis that PDE-5 inhibition may represent a novel and viable therapeutic strategy for improving LV relaxation were the significant shortening in both lateral and septal T E-E′, a Dopplerderived index of LV relaxation performance validated against invasively measured negative dP/dT22, and the reverse remodeling effect on LV mass. Moreover, over 12 months, LAVI, LVEDV, and LVMI were unchanged in the placebo group and decreased in the active treatment group, which suggests reverse remodeling with sildenafil involving both the ventricle and the atrium. Over the same time period in the sildenafil group, there was a progressive increase in mean LVEF, from 29.5% at baseline to 34.9% and 36.3% at 6 and 12 months, respectively (P<0.01). Changes observed with sildenafil were significantly different

Fig. 9. Sildenafil significantly decreased E/E′ at 6 months and 1 year of active treatment in patients with stable systolic heart failure

compared with placebo (P<0.01). Additionally, diastolic measures of LV function demonstrated systematic and sustained improvement after both 6 months and 1 year of sildenafil treatment. The transmitral E/A ratio, isovolumic relaxation time, and both lateral and septal E/E′ decreased from baseline through 12 months (all P<0.01), which is indicative of an improvement in LV diastolic function and a decrease in LV filling pressure. Furthermore, septal T E-E′ was significantly reduced at 6 and 12 months of sildenafil treatment (P<0.01). All these changes were in agreement with the observed reverse remodeling on LAVI, which is viewed as morphological expression of LV end-diastolic pressure (Lester et al., 2008). Changes observed at 6 months and 1 year after sildenafil were significantly different compared with the placebo group (P<0.01).


**1. Introduction**

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Cerebral amyloid angiopathies (CAA) can be divided into sporadic and hereditary forms. This chapter is focused on the genetics of sporadic CAA, but will first consider hereditary forms in brief.

#### **1.1. Hereditary CAA**

Amyloid-β protein (Aβ), the commonest amyloid subunit implicated in sporadic forms of CAA, is also involved in certain hereditary forms. Several other proteins are also associated with rare familial diseases in which CAA is a characteristic morphological feature. [1] Missense mutations within or just outside the Aβ peptide coding region of the APP gene result in clinicopathological phenotypes of early onset Alzheimer's disease (AD) and are associated with a neuropathological phenotype which includes prominent CAA – for example hereditary cerebral haemorrhage with amyloidosis of Dutch type (HCHWA-D), or with Italian, Arctic, Iowa, Piedmont and Flemish mutations. Severe Aβ CAA has also been well documented in cases of familial AD due to mutations in the presenilin (PSEN1 and PSEN2) genes. Familial CAAs associated with other proteins include BRI2 gene-related dementias (familial British dementia and familial Danish dementia), cystatin C gene mutations in hereditary cerebral haemorrhage with amyloidosis of Icelandic type, TTR gene mutations in meningo-vascular amyloidosis, hereditary prion disease with premature stop codon mutations and mutated gelsolin gene in familial amyloidosis of Finnish type. [1]

### **1.2. Sporadic CAA**

Sporadic cerebral amyloid angiopathy is characterised by deposition of Aβ in leptomeningeal and cortical blood vessels. It has a prevalence in population-based autopsy studies of 20-40%

© 2014 The Author(s). Licensee InTech. 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.

in non-demented and 50-60% in demented elderly people. [2] Neuropathological case-control and cross-sectional studies, as well as the increased incidence of intracerebral haemorrhage (ICH) in patients with Alzheimer's disease, suggest that CAA causes lobar ICH. [3, 4] CAA is also associated with increasing age, dementia, lobar brain microbleeds, leukoaraiosis, small cortical infarcts and superficial siderosis. [3, 5-7]

It is unknown why only a few people with CAA pathology develop an ICH, but it seems likely to involve biological pathways additional to and distinct from those involved in vascular amyloid deposition. Cases of CAA with ICH not only have a greater proportion of amyloidladen blood vessels, [8] but also more often demonstrate severe CAA with associated vascul‐ opathy. [8-11]

Non APOE polymorphisms/ sporadic CAA

24 studies 4,703 participants

Studies with data for meta-analysis 5 studies 497 participants

**Figure 1.** Selection of included studies

Electronic database searches (2,445 publications)

Studies without data for meta-analysis 22 studies 3,125 participants

49 publications excluded because of overlapping participants

12 studies excluded because no. of participants <35

1,642 publications excluded on the basis of screening titles, abstracts ± full texts

702 duplicate publications

excluded

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53

Studies with data for meta-analysis 24 studies 3,520 participants

APOE/ severe CAA-associated vasculopathy

Publications screened (1,754 publications)

> Relevant studies (112 publications)

> > 8 studies ~557 participants

APOE/ severe CAA-associated vasculopathy 6 studies 543 participants

> Studies without data for meta-analysis 1 study 46 participants

2 studies excluded because no. of participants <10

APOE / sporadic CAA (107 publications)

Hand search and bibliography screening (11 publications)

> APOE/ presence vs absence of CAA

> > 58 studies 6,855 participants

APOE/ presence vs absence of CAA 46 studies 6,645 participants

Identifying genetic polymorphisms associated with the presence of histopathologically confirmed CAA in general, as well as with the severe form of CAA thought to cause vessel rupture and ICH, should increase our understanding of the mechanisms leading to CAA and associated diseases, including CAA associated ICH.

Polymorphisms in the apolipoprotein E gene (APOE) [12] are associated with ICH as well as with other conditions in which CAA may be involved, including subarachnoid haemorrhage, lobar brain microbleeds, and AD. [7, 13-18] In vitro studies have shown that APOE influences Aβ conformation, fibril formation and toxicity, [19, 20] while in vivo mouse studies have confirmed a critical role for apolipoprotein E in Aβ deposition, toxicity and possibly clearance. [21, 22] It therefore seems likely that APOE influences risk of developing histopathologically confirmed, sporadic CAA. Other genetic polymorphisms are also likely to contribute to development of sporadic CAA.

Below we present and summarise the evidence for associations of polymorphisms in APOE or any other gene with histopathologically confirmed, sporadic CAA in adult humans. We then go on to consider the evidence for associations of APOE with the severe form of CAA. The evidence presented is based mainly on our two recently published systematic reviews of all relevant published studies, both of which incorporated a comprehensive search strategy, a thorough assessment of study quality, a series of meta-analyses, and an evaluation of the robustness of any positive findings to small study and other methodological biases. [23, 24] Figure 1 summarises the strategy used for identifying relevant studies and the numbers of studies (and study participants) identified.

## **2. Genetic associations with histopathologically-confirmed, sporadic CAA**

While robust, large-scale evidence exists for an association of APOE with ICH attributed to CAA on the basis of clinical criteria, [15] studies assessing association of APOE with histopa‐ thologically confirmed CAA have had various methodological shortcomings (including small size), and reported results vary. Our systematic review of genetic associations with histopa‐ thologically confirmed, sporadic CAA sought all studies in which participants had been

**Figure 1.** Selection of included studies

in non-demented and 50-60% in demented elderly people. [2] Neuropathological case-control and cross-sectional studies, as well as the increased incidence of intracerebral haemorrhage (ICH) in patients with Alzheimer's disease, suggest that CAA causes lobar ICH. [3, 4] CAA is also associated with increasing age, dementia, lobar brain microbleeds, leukoaraiosis, small

It is unknown why only a few people with CAA pathology develop an ICH, but it seems likely to involve biological pathways additional to and distinct from those involved in vascular amyloid deposition. Cases of CAA with ICH not only have a greater proportion of amyloidladen blood vessels, [8] but also more often demonstrate severe CAA with associated vascul‐

Identifying genetic polymorphisms associated with the presence of histopathologically confirmed CAA in general, as well as with the severe form of CAA thought to cause vessel rupture and ICH, should increase our understanding of the mechanisms leading to CAA and

Polymorphisms in the apolipoprotein E gene (APOE) [12] are associated with ICH as well as with other conditions in which CAA may be involved, including subarachnoid haemorrhage, lobar brain microbleeds, and AD. [7, 13-18] In vitro studies have shown that APOE influences Aβ conformation, fibril formation and toxicity, [19, 20] while in vivo mouse studies have confirmed a critical role for apolipoprotein E in Aβ deposition, toxicity and possibly clearance. [21, 22] It therefore seems likely that APOE influences risk of developing histopathologically confirmed, sporadic CAA. Other genetic polymorphisms are also likely to contribute to

Below we present and summarise the evidence for associations of polymorphisms in APOE or any other gene with histopathologically confirmed, sporadic CAA in adult humans. We then go on to consider the evidence for associations of APOE with the severe form of CAA. The evidence presented is based mainly on our two recently published systematic reviews of all relevant published studies, both of which incorporated a comprehensive search strategy, a thorough assessment of study quality, a series of meta-analyses, and an evaluation of the robustness of any positive findings to small study and other methodological biases. [23, 24] Figure 1 summarises the strategy used for identifying relevant studies and the numbers of

**2. Genetic associations with histopathologically-confirmed, sporadic CAA**

While robust, large-scale evidence exists for an association of APOE with ICH attributed to CAA on the basis of clinical criteria, [15] studies assessing association of APOE with histopa‐ thologically confirmed CAA have had various methodological shortcomings (including small size), and reported results vary. Our systematic review of genetic associations with histopa‐ thologically confirmed, sporadic CAA sought all studies in which participants had been

cortical infarcts and superficial siderosis. [3, 5-7]

associated diseases, including CAA associated ICH.

development of sporadic CAA.

studies (and study participants) identified.

opathy. [8-11]

52 Intracerebral Hemorrhage

genotyped for any genetic polymorphism and had CAA assessed pathologically (using autopsy or biopsy). [23] Studies that had assessed genetic associations with CAA-associated ICH (CAAH) versus CAA-free controls were excluded, because these would not be able to distinguish a genetic association with the presence of CAA histopathology from an association with ICH.

#### **2.1. APOE ε2/ε3/ε4 polymorphism and sporadic CAA**

We identified 46 studies including 6645 participants with data about the APOE ε2/ε3/ε4 polymorphism and sporadic CAA (Figure 1). [25-70] These studies had used autopsy brains from clinical autopsy collections, a brain bank or a population-based prospective study. Participants' mean age was 70 to 85 years in most studies and about half were male. Almost 90% of participants were of European ancestry while around 10% were from Asian populations (all Japanese). About 30% of participants had clinical dementia (mainly AD), about 10% were known not to be demented and dementia status was not specified for the remainder. There was substantial variation in overall study quality. Genotyping reporting quality [71, 72] was generally limited and methods for pathological assessment were very variable. Larger studies tended to be of higher quality. [23]

#### *2.1.1. APOE ε4 and CAA*

Meta-analyses were possible of data from just over half of these studies (including just over half of the participants), and showed a significant association between ε4+ genotypes and presence of CAA (OR 2.67, 95% CI 2.31 to 3.08), although there was significant heterogeneity between the studies' results (Figure 2). There were no significant differences between sub‐ groups of studies based on dementia status, ethnicity or overall study quality score (Figures 2 and 3). Six studies (443 participants) made only a qualitative statement, [27, 30, 33, 37, 40, 42] reporting either no significant association or a trend towards association with APOE ε4, while 16 studies (2682 participants) provided no information about the association. [25, 28, 29, 31, 32, 34-36, 38, 39, 41, 43, 46, 47, 50, 57]

Failsafe N calculations [73] showed that a null study of >137, 000 participants would be re‐ quired to bring the association of ε4+ genotypes with CAA from the meta-analysis to a just statistically non-significant level. This makes it unlikely that there might plausibly be enough participants in unpublished, unreported or otherwise unretrieved null studies to make this significant result non-significant, and suggests that the association of APOE ε4+ genotypes with histopathologcally confirmed, sporadic CAA is real and robust. Meta-analy‐ sis of the association of APOE ε4 allele dose with CAA among 12 studies (1706 participants) providing quantitative data showed a significant increase in the odds of having CAA with increasing dose of the ε4 allele (Figure 4). Two further studies (117 participants) provided a qualitative statement about the association supported this result. [40, 64] Failsafe N calcula‐ tions showed that it would require a null study of >7000 participants to bring the stronger association with CAA of ε4 homozygous versus heterozygous genotypes to a just non-sig‐ nificant level, suggesting that the finding of a dose-response relationship between APOE ε4 and CAA is real and robust.

The squares represent study-specific odds ratios (ORs), with their size proportional to their statistical weight by the generic inverse variance method. Horizontal lines represent 95% confidence intervals (CIs). Diamonds represent

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Reproduced from "Genetics of cerebral amyloid angiopathy: systematic review and meta-analysis" Rannikmäe K, Sa‐ marasekera N, Martīnez-Gonzālez NA, Al-Shahi Salman R, Sudlow C. Journal of Neurology Neurosurgery and Psychia‐

**Figure 2.** Meta-analysis of association of APOE ε4+ vs ε4- genotypes with CAA by participants' dementia status

pooled ORs, and their width represents the 95% CI. Higher score represents better study quality.

try 2013;84(901-8), with permission from BMJ Publishing Group Ltd.

genotyped for any genetic polymorphism and had CAA assessed pathologically (using autopsy or biopsy). [23] Studies that had assessed genetic associations with CAA-associated ICH (CAAH) versus CAA-free controls were excluded, because these would not be able to distinguish a genetic association with the presence of CAA histopathology from an association

We identified 46 studies including 6645 participants with data about the APOE ε2/ε3/ε4 polymorphism and sporadic CAA (Figure 1). [25-70] These studies had used autopsy brains from clinical autopsy collections, a brain bank or a population-based prospective study. Participants' mean age was 70 to 85 years in most studies and about half were male. Almost 90% of participants were of European ancestry while around 10% were from Asian populations (all Japanese). About 30% of participants had clinical dementia (mainly AD), about 10% were known not to be demented and dementia status was not specified for the remainder. There was substantial variation in overall study quality. Genotyping reporting quality [71, 72] was generally limited and methods for pathological assessment were very variable. Larger studies

Meta-analyses were possible of data from just over half of these studies (including just over half of the participants), and showed a significant association between ε4+ genotypes and presence of CAA (OR 2.67, 95% CI 2.31 to 3.08), although there was significant heterogeneity between the studies' results (Figure 2). There were no significant differences between sub‐ groups of studies based on dementia status, ethnicity or overall study quality score (Figures 2 and 3). Six studies (443 participants) made only a qualitative statement, [27, 30, 33, 37, 40, 42] reporting either no significant association or a trend towards association with APOE ε4, while 16 studies (2682 participants) provided no information about the association. [25, 28, 29,

Failsafe N calculations [73] showed that a null study of >137, 000 participants would be re‐ quired to bring the association of ε4+ genotypes with CAA from the meta-analysis to a just statistically non-significant level. This makes it unlikely that there might plausibly be enough participants in unpublished, unreported or otherwise unretrieved null studies to make this significant result non-significant, and suggests that the association of APOE ε4+ genotypes with histopathologcally confirmed, sporadic CAA is real and robust. Meta-analy‐ sis of the association of APOE ε4 allele dose with CAA among 12 studies (1706 participants) providing quantitative data showed a significant increase in the odds of having CAA with increasing dose of the ε4 allele (Figure 4). Two further studies (117 participants) provided a qualitative statement about the association supported this result. [40, 64] Failsafe N calcula‐ tions showed that it would require a null study of >7000 participants to bring the stronger association with CAA of ε4 homozygous versus heterozygous genotypes to a just non-sig‐ nificant level, suggesting that the finding of a dose-response relationship between APOE ε4

**2.1. APOE ε2/ε3/ε4 polymorphism and sporadic CAA**

tended to be of higher quality. [23]

31, 32, 34-36, 38, 39, 41, 43, 46, 47, 50, 57]

and CAA is real and robust.

*2.1.1. APOE ε4 and CAA*

with ICH.

54 Intracerebral Hemorrhage

The squares represent study-specific odds ratios (ORs), with their size proportional to their statistical weight by the generic inverse variance method. Horizontal lines represent 95% confidence intervals (CIs). Diamonds represent pooled ORs, and their width represents the 95% CI. Higher score represents better study quality.

Reproduced from "Genetics of cerebral amyloid angiopathy: systematic review and meta-analysis" Rannikmäe K, Sa‐ marasekera N, Martīnez-Gonzālez NA, Al-Shahi Salman R, Sudlow C. Journal of Neurology Neurosurgery and Psychia‐ try 2013;84(901-8), with permission from BMJ Publishing Group Ltd.

**Figure 2.** Meta-analysis of association of APOE ε4+ vs ε4- genotypes with CAA by participants' dementia status

*2.1.3. Summary and discussion*

There is, therefore, robust evidence for a highly significant, dose-dependent association between APOE ε4 and pathologically proven CAA, which does not vary significantly with dementia status, ethnicity, or study quality. However, there is no clear overall association between APOE ε2 and histopathologically confirmed CAA. Lack of variation in the effect of APOE ε4 by study size and the very large failsafe N showed that this association could not plausibly be explained by publication, reporting or any other small study bias. It is important to note that the quality of studies included in our systematic review was generally limited when assessed against current reporting standards. [71, 72] However, there were - reassuringly

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The prevalence of CAA in Alzheimer's disease is over 70% but the relationship between CAA and AD is still poorly understood. Although the diagnostic criteria for dementia and the participant inclusion criteria varied between the studies in our systematic review (some excluding cases with severe dementia), the demonstration of a similar association in those with and without clinical dementia suggests that the association of APOE ε4 with CAA is inde‐

Pathological assessment in the included studies was very variable. Indeed, there is no widely accepted, standardized histopathological grading system for CAA, [74] and no comparative studies to determine the most accurate method for assessing CAA (although the suggested method is a combination of Thioflavin S/T or Congo Red with immunohistochemistry). [75] CAA assessment location also varied widely, possibly influencing the rate of CAA detection, since a greater burden of CAA is generally reported in the occipital or parietal lobes, albeit with a higher frequency of frontal lobe involvement reported in studies from China and Japan. [74] This is important because genetic associations may differ by CAA location and subtype. For example, there is preliminary evidence that APOEε4 may be associated with CAA type 1 (where CAA is found in cortical capillaries), and ε2 with CAA type 2 (where amyloid is deposited in leptomeningeal and cortical vessels with the exception of cortical capillaries). [26] In addition, since APOE effects on ICH may vary with ethnicity, there may also be ethnic variation in genetic associations with CAA, but these have not yet been widely enough studied

pendent of its known association with dementia (mainly Alzheimer's disease).

**2.2. Associations between other genetic polymorphisms and sporadic CAA**

In our systematic review, few polymorphisms other than APOE had been studied in more than a few hundred participants or in more than one study and there were not enough data for meta-analysis (Figure 1, Table 1). [39, 46, 50, 61, 63, 77-95] Thus, there were too few studies and participants to draw firm conclusions about the effect of other genetic polymorphisms. However, there were some suggestive positive associations with CAA. First, there was a consistent trend towards an association with CAA of a single nucleotoide polymorphism (SNP) in the transforming growth factor-β1 (TGF-β1) gene in two studies (449 participants). [82, 85] If real, this may occur through an influence of TGF-β1 on Aβ clearance and deposition through activation of astrocytes and microglia. Second, there were significant associations in one study (723 participants) of SNPs in the translocase of outer mitochondrial membrane 40 (TOMM40)

in non-white populations to assess this reliably. [76]

The squares represent pooled ORs and their width represents the 95% CI. Higher score represents better study quality. Reproduced from "Genetics of cerebral amyloid angiopathy: systematic review and meta-analysis" Rannikmäe K, Sa‐ marasekera N, Martīnez-Gonzālez NA, Al-Shahi Salman R, Sudlow C. Journal of Neurology Neurosurgery and Psychia‐ try 2013;84(901-8), with permission from BMJ Publishing Group Ltd. The squares represent pooled ORs and their width represents the 95% CI. Reproduced from "Genetics of cerebral amyloid angiopathy: systematic review and meta-

Figure 4. Meta-analysis of effects of APOE ε4 dose (ε4--/ε4+-/ε4++ genotypes) on presence

**Figure 3.** Subgroup analysis based on study quality scores. analysis" Rannikmäe K, Samarasekera N, Martīnez-Gonzālez NA, Al-Shahi Salman R, Sudlow C. Journal of Neurology Neurosurgery and Psychiatry 2013;84(901-8),

vs absence of

CAA

with permission from BMJ Publishing Group Ltd.

Generic inverse variance fixed effects method. \*Refers to number of participants included in the analysis.

The squares represent pooled ORs and their width represents the 95% CI. The squares represent pooled ORs and their width represents the 95% CI.

**Figure 4.** Meta-analysis of effects of APOE ε4 dose (ε4--/ε4+-/ε4++genotypes) on presence vs absence of CAA

#### *2.1.2. APOE ε2 and CAA*

Meta-analysis of the association of APOE ε2+ versus ε2- genotypes with CAA among 11 studies (1640 participants) showed borderline significant decreased odds of CAA with APOE ε2+ genotypes (OR 0.73, 95% CI 0.53 to 1.00, p=0.05). Two studies (213 participants) provided a qualitative statement; neither reported a significant association. [60, 64]

4

#### *2.1.3. Summary and discussion*

*2.1.2. APOE ε2 and CAA*

Meta-analysis of the association of APOE ε2+ versus ε2- genotypes with CAA among 11 studies (1640 participants) showed borderline significant decreased odds of CAA with APOE ε2+ genotypes (OR 0.73, 95% CI 0.53 to 1.00, p=0.05). Two studies (213 participants) provided a

**Figure 4.** Meta-analysis of effects of APOE ε4 dose (ε4--/ε4+-/ε4++genotypes) on presence vs absence of CAA

4

The squares represent pooled ORs and their width represents the 95% CI. Higher score represents better study quality. Reproduced from "Genetics of cerebral amyloid angiopathy: systematic review and meta-analysis" Rannikmäe K, Sa‐ marasekera N, Martīnez-Gonzālez NA, Al-Shahi Salman R, Sudlow C. Journal of Neurology Neurosurgery and Psychia‐

> Reproduced from "Genetics of cerebral amyloid angiopathy: systematic review and metaanalysis" Rannikmäe K, Samarasekera N, Martīnez-Gonzālez NA, Al-Shahi Salman R, Sudlow C. Journal of Neurology Neurosurgery and Psychiatry 2013;84(901-8),

> Figure 4. Meta-analysis of effects of APOE ε4 dose (ε4--/ε4+-/ε4++ genotypes) on presence

No.\* OR (95% CI)

ε4/x vs εx/x 1538 2.09 (1.69 to 2.58)

ε4/4 vs ε4/x 824 3.26 (2.24 to 4.74)

ε4/4 vs εx/x 1050 6.60 (4.47 to 9.75)

0.1 1 10 Presence of CAA decreased with ε4 allele Presence of CAA increased with ε4 allele

The squares represent pooled ORs and their width represents the 95% CI.

Figure 3. Subgroup analysis based on study quality scores.

try 2013;84(901-8), with permission from BMJ Publishing Group Ltd.

Generic inverse variance fixed effects method. \*Refers to number of participants included in the analysis.

with permission from BMJ Publishing Group Ltd.

**Figure 3.** Subgroup analysis based on study quality scores.

vs absence of

CAA

56 Intracerebral Hemorrhage

qualitative statement; neither reported a significant association. [60, 64]

The squares represent pooled ORs and their width represents the 95% CI. The squares represent pooled ORs and their width represents the 95% CI.

There is, therefore, robust evidence for a highly significant, dose-dependent association between APOE ε4 and pathologically proven CAA, which does not vary significantly with dementia status, ethnicity, or study quality. However, there is no clear overall association between APOE ε2 and histopathologically confirmed CAA. Lack of variation in the effect of APOE ε4 by study size and the very large failsafe N showed that this association could not plausibly be explained by publication, reporting or any other small study bias. It is important to note that the quality of studies included in our systematic review was generally limited when assessed against current reporting standards. [71, 72] However, there were - reassuringly - no significant subgroup differences by study quality score.

The prevalence of CAA in Alzheimer's disease is over 70% but the relationship between CAA and AD is still poorly understood. Although the diagnostic criteria for dementia and the participant inclusion criteria varied between the studies in our systematic review (some excluding cases with severe dementia), the demonstration of a similar association in those with and without clinical dementia suggests that the association of APOE ε4 with CAA is inde‐ pendent of its known association with dementia (mainly Alzheimer's disease).

Pathological assessment in the included studies was very variable. Indeed, there is no widely accepted, standardized histopathological grading system for CAA, [74] and no comparative studies to determine the most accurate method for assessing CAA (although the suggested method is a combination of Thioflavin S/T or Congo Red with immunohistochemistry). [75] CAA assessment location also varied widely, possibly influencing the rate of CAA detection, since a greater burden of CAA is generally reported in the occipital or parietal lobes, albeit with a higher frequency of frontal lobe involvement reported in studies from China and Japan. [74] This is important because genetic associations may differ by CAA location and subtype. For example, there is preliminary evidence that APOEε4 may be associated with CAA type 1 (where CAA is found in cortical capillaries), and ε2 with CAA type 2 (where amyloid is deposited in leptomeningeal and cortical vessels with the exception of cortical capillaries). [26] In addition, since APOE effects on ICH may vary with ethnicity, there may also be ethnic variation in genetic associations with CAA, but these have not yet been widely enough studied in non-white populations to assess this reliably. [76]

#### **2.2. Associations between other genetic polymorphisms and sporadic CAA**

In our systematic review, few polymorphisms other than APOE had been studied in more than a few hundred participants or in more than one study and there were not enough data for meta-analysis (Figure 1, Table 1). [39, 46, 50, 61, 63, 77-95] Thus, there were too few studies and participants to draw firm conclusions about the effect of other genetic polymorphisms. However, there were some suggestive positive associations with CAA. First, there was a consistent trend towards an association with CAA of a single nucleotoide polymorphism (SNP) in the transforming growth factor-β1 (TGF-β1) gene in two studies (449 participants). [82, 85] If real, this may occur through an influence of TGF-β1 on Aβ clearance and deposition through activation of astrocytes and microglia. Second, there were significant associations in one study (723 participants) of SNPs in the translocase of outer mitochondrial membrane 40 (TOMM40) gene with vascular amyloid burden but not with ICH attributed to CAA, [88] which could be through interaction of TOMM40 with APOE ε2 or through its effects on Aβ mitochondrial transport. Finally, one study (544 participants) found an association of a SNP in the comple‐ ment component receptor 1 (CR1) gene with both CAA severity and ICH attributed to CAA, possibly occurring via altered clearance of Aβ peptide. [96] Other studies found no overall significant associations, although some reported associations in particular subgroups (Table 1).

**3. APOE allele-specific associations with severe CAA-associated**

The systematic review and series of meta-analyses presented in the previous section confirmed an association between histopathologically diagnosed CAA and APOE ε4, but not APOE ε2. However a recent large scale genetic association study found that both ε2 and ε4 containing genotypes were associated with clinically diagnosed CAA, manifesting as lobar ICH attributed to CAA. [15] Furthermore, APOE ε2 has been found to predict initial haematoma volume, haematoma expansion, increased mortality and poor functional outcome after lobar ICH. [17, 97] The currently favoured popular explanation for these findings is, that APOE ε4 enhances deposition of amyloid-β in cerebral blood vessel walls, while ε2 promotes haemorrhage from amyloid-laden blood vessels by increasing specific CAA-related vasculopathic changes

Figure 5. Proposed theory and current state of evidence about associations between APOE

CAA

Adapted from Figure 1 in Acta Neuropathologica 2005;110: 345–359 "Sporadic cerebral amyloid angiopathy: pathology, clinical implications, and possible pathomechanisms", Johannes Attems, with kind permission from Springer Science and Business Media and Adapted from Figure 1 in Acta Neuropathologica 2005;110: 345–359 "Sporadic cerebral amyloid angiopathy: pathol‐ Professor Attems. ogy, clinical implications, and possible pathomechanisms", Johannes Attems, with kind permission from Springer Sci‐

**Figure 5.** Proposed theory and current state of evidence about associations between APOE and CAA phenotype

In a further recent systematic review, we reviewed the evidence for this hypothesis. [24] The main focus of this work was on assessing the potential influence of APOE genotypes on severe CAA preceding rupture. To avoid selection bias, we excluded studies with participants selected on the basis of having had a CAA-related ICH, since APOE ε2 and ε4 are already known to be associated with this phenotype, and severe CAA is commoner in such cases. This review sought all studies, which had conducted both APOE genotyping and histopathological assessment for CAA, including assessment for severe CAA with associated vasculopathic

Severe CAA vasculopathy

ε4 ε4? ε2 and ε4

ε4 ε2 ε2 and ε4

CAA related ICH

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No CAA Mild/Moderate

5

**vasculopathy**

(Figure 5). [8, 25, 98]

and CAA phenotype

Popular theory:

Current state of evidence:

ence and Business Media and Professor Attems.

\*Range of participant numbers in individual studies \*\*probably rs4943

Adapted by permission from BMJ Publishing Group Limited, from "Genetics of cerebral amyloid angiopathy: systematic review and meta-analysis" Rannikmäe K, Samarasekera N, Martīnez-Gonzālez NA, Al-Shahi Salman R, Sudlow C. Journal of Neurology Neurosurgery and Psychiatry 2013;84(901-8)

**Table 1.** Summary of studies of non-APOE polymorphisms and CAA


**About the Editor**

**Paul B. Tchounwou** is Associate Dean of Graduate and International Programs at the College of Science, Engineering and Technology. He is a Presidential Distinguished Professor who also serves as a Director of DoD-Center of Excellence in STEM Education, Director of NIH-Center for Environmental Health, and Director of Environmental Science PhD Program at Jackson State University (JSU), Jackson, MS. He also serves as Adjunct Professor at Tulane University Health Sciences Center, New Orleans, LA, and Life Member of the scientific faculty of the International Biographical Institute in Cambridge, England.

Dr. Tchounwou is nationally and internationally known for his biomedical research. His work on arsenic trioxide pharmacology and toxicology was recently highlighted in the Fall 2011 issue of *NCRR—Reporter Magazine at the National Institutes of Health*. Dr. Tchounwou has published 178 refereed papers in top-tiered journals and books. He is the Editor-in-Chief of two international journals, including the *International Journal of Environmental Research and Public Health* (MDPI, Basel, Switzerland), and *Environmental Toxicology—An International Journal* (John Wiley & Sons, New York, USA). He was one of the Section Editors of *Encyclopedia of Environmental Health*, published by Elsevier BV in 2011. He served as Guest Editor for the *International Journal of Molecular Sciences*; *Ethnicity and Diseases*; and *Journal of Health Care for the Poor and Underserved*. He is also on the Editorial Board of several other journals, including *Journal of Cancer Science and Therapy*, *Journal of Environmental Biology*, and *Reviews on Environmental Health.* Dr. Tchounwou has served as Session Chair of scientific meetings, and has given over 450 presentations at national and international conferences. This year, he has been selected to serve as Expert Subject Reviewer for the Fulbright Specialist Program.


*2.3. Surgical Procedure*

After placement of a Leksell stereotactic frame (Elekta, Stockholm, Sweden), a computed tomography (CT) scan of the head was performed. The CT-image was co-registered with a magnetic resonance imaging (MRI) that had been performed before surgery. Following target identification and trajectory planning, a burr hole was drilled, micro-electrodes (model 230766, Medizintechnik GmbH, Emmendingen, Germany) were implanted and recordings were performed. Visual and auditory confirmation of the target was performed by a neurophysiologist. Then, macrostimulation and neurological testing were carried out. The presence of good quality electrophysiological recordings and few or no side effects indicated the optimal contact point at which a quadripolar electrode (model 3387 or 3389; Medtronic, Minneapolis, USA) was placed. A postoperative CT scan was performed within 24 h in order to exclude intracerebral hemorrhages and to evaluate the final position of the electrodes.


3.3.2. Passive Damping–Additional Mass System

This passive system is based on the counteracting inertial force created by an additional mass allocated at the top of a building. There are two main categories of devices belonging to this group: Tuned mass dampers (TMD) and tuned liquid dampers (TLD). A TMD is an additional mass [22], usually in the order of two percent of the total weight of the building, which is attached to the structure by means of springs and dashpots. The inertia force of the mass damps the reaction of the building. However, TMDs are mostly effective only when they are excited by the resonant frequency for which they have been designed. Sometimes, spacing limitations do not permit a traditional TMD system, which requires the installation of alternative configurations such as pendulums, hydrostatic bearings or laminated rubber bearings. A TMD damper was used in Fukuoka Tower (Fukuoka, Japan), Higashimyama Sky Tower (Nagoya, Japan) and Huis Ten Bosch Domtoren (Nagasaki, Japan).

Another type of mass damping system is tuned liquid dampers (TLCD). This damping system uses the movement of liquids in special containers to absorb the energy of building vibrations. The vibration frequency of TLCDs can be controlled by the water depth and the size of the container. TLCDs are preferred because of their simplicity, low maintenance price and the possibility of including water for emergency fire protection. The TLCD system was used in the Rokko-Island P and G Building (Kobe, Japan), Crystal Tower (Osaka, Japan) and Sea Hawk Hotel and Resort (Fukuoka, Japan).

Different from passive systems that are tuned to work on some range of loading conditions, active system perform more efficiently over a wider range. The most prominent active devices are active mass dampers (AMD) and active variable stiffness devices (AVSD). Both devices rely on the same principles of mass and material based dissipation but their properties are adjusted from a computer control system. The AMD system was used in the Applause Tower (Osaka, Japan) and AVSD in ORC 200 Bay Tower (Osaka, Japan).


*Article* **0.6-V 1.65-**μ**W Second-Order** *Gm***-***C* **Bandpass Filter for Multi-Frequency Bioimpedance Analysis Based on a Bootstrapped Bulk-Driven Voltage Buffer**

**Juan M. Carrillo 1,\* and Carlos A. de la Cruz-Blas 2**

**Abstract:** A bootstrapping technique used to increase the intrinsic voltage gain of a bulk-driven MOS transistor is described in this paper. The proposed circuit incorporates a capacitor and a cutoff transistor to be connected to the gate terminal of a bulk-driven MOS device, thus achieving a quasifloating-gate structure. As a result, the contribution of the gate transconductance is cancelled out and the voltage gain of the device is correspondingly increased. The technique allows for implementing a voltage follower with a voltage gain much closer to unity as compared to the conventional bulk-driven case. This voltage buffer, along with a pseudo-resistor, is used to design a linearized transconductor. The proposed transconductance cell includes an economic continuous tuning mechanism that permits programming the effective transconductance in a range sufficiently wide to counteract the typical variations that process parameters suffer during fabrication. The transconductor has been used to implement a second-order *Gm*-*C* bandpass filter with a relatively high selectivity factor, suited for multi-frequency bioimpedance analysis in a very low-voltage environment. All the circuits have been designed in 180 nm CMOS technology to operate with a 0.6-V single-supply voltage. Simulated results show that the proposed technique allows for increasing the linearity and reducing the input-referred noise of the bootstrapped bulk-driven MOS transistor, which results in an improvement of the overall performance of the transconductor. The center frequency of the bandpass filter designed can be programmed in the frequency range from 6.5 kHz to 37.5 kHz with a power consumption ranging between 1.34 μW and 2.19 μW. The circuit presents an in-band integrated noise of 190.5 μV*rms* and is able to process signals of 110 mV*pp* with a THD below −40 dB, thus leading to a dynamic range of 47.4 dB.

**Keywords:** bandpass filter; bootstrapping; bulk-driven; linearized transconductor; quasi-floating gate; voltage follower


*Neuropsychology of Moyamoya Disease DOI: http://dx.doi.org/10.5772/intechopen.96558*

third evaluation revealed a fluctuating evolution. Executive function, PS, total I.Q., perceptual reasoning, and calculation were most consistently affected during the three assessments, which is consistent with the rest of the literature [39].

The impact on the quality of life of 30 children with MMD (with a median age of 13,5 years) was studied by Ball, Steinberg and Elbers using the Pediatric Quality of Life 4.0 Measurement Model [40]. The authors compared their quality of life to that of chronically ill children and children with stroke in order to better understand the impact of a diagnosis of MMD. The results showed that, even in the absence of stroke, children with moyamoya disease had a lower quality of life than healthy controls and a similar quality of life to chronically ill children and those with non–moyamoya disease stroke. The concluded that hildren with moyamoya disease would benefit from mental health support beyond what a mild physical presentation may indicate.

Assessment of neurological and neuropsychological outcome following revascularization, shows that surgical procedures are effective in halting the neurological progression and results in neuropsychological improvement in some patients [41]. For example, Nehra and Kaur in 2015 reported a male diagnosed with MMD at eight years old and, referred for neuropsychological evaluation at 12 years due to, impaired intellectual functioning with moderate retardation in adaptive social functioning. Two years after psychosocial intervention, the patient showed a remarkable upward trend in his adaptive social functioning and, a jump of 21 I.Q. points in his intellectual functioning [42]. In the same line, Cusin-Lamonica et al. reported the case of a girl of seven years old who suffered two episodes of stroke in the left and right temporal-parietal and left frontal areas that occurred until the age of six years and five months [43]. She presented signs of deterioration in oral and written language (syllabic-alphabetic), non-naming of all graphemes, low arithmetic and writing means, pre-first-grade reading skillsand psycholinguistic delay, and pre-school-level phonological processing skills. The psychological evaluation indicated a satisfactory intellectual level. Revascularization surgery and medication were prescribed.

Considering the infant's brain's developmental plasticity, extrinsic influences, such as psychological interventions for speech-language pathology, coupled with intrinsic influences, can alter the cortical organization and regenerate damaged connections, thus improving the compromised skills of children. A recent systematic review and metaanalysis of pMMD and aMMD, assessed the presence, severity, and nature of cognitive impairments in children and adults with MMD [44]. The authors revised data (collected between 1969 and 2016) pertaining to mean intelligence quotient and standardized z-scores of cognitive tests, and determined percentages of children and adults with cognitive deficits, before and after conservative or surgical treatment. In the case of pMMD, they included 11 studies reporting on a total of 281 children. In children, the median percentage with impaired cognition was 30% (range, 13% to 67%); the median I.Q. was 98 (rang: 71 to 107), and the median z-score was –0.39 for memory, and –0.43 for speed processing. The investigators concluded that many children (30%) with MMD suffer cognitive impairment, with modest to large deficits across various cognitive domains. Thus, extensive prospective studies with a standardized neuropsychological test battery are needed to determine the severity of cognitive impairment and the domains affected.

Recently, Kazumata et al. aimed to investigate cognitive function in the presurgical phase of pediatric patients with MMD with no apparent brain lesions in order to explore an association between cognitive function and cerebral blood flow [45]. They designed a prospective, observational, single-centre study, of 21 children (mean age 10 ± 3.0 years, range 5–14 years) diagnosed with MMD at Hokkaido

University Hospital between 2012 and 2018. A cross-sectional evaluation of intellectual ability was performed using the Wechsler Intelligence Scale for Children. rCBF was measured using [123I] N-isopropyl p-iodoamphetamine/SPECT. The associations among clinical factors, disease severity, regional cerebral blood flow (rCBF), and intelligence test scores were also examined. Results showed that the mean fullscale intelligence quotient (FIQ ) was 101.8 ± 12.5 (range 76–125) in children with no apparent brain lesions. A significant difference in the intelligence scale index score was observed most frequently (42.9%) between the working memory index (WMI) and verbal comprehension index. Regional CBF was significantly reduced both in the left and right medial frontal cortices compared to the cerebellum. There was a significant association of rCBF in the left dorsolateral prefrontal cortex (DLPFC) with FIQ, perceptual reasoning index, and processing speed index. Although average intellectual ability was not reduced in the children with MMD, the association of reduced rCBF in the left DLPFC and medial frontal cortex with FIQ, perceptual reasoning and processing speed suggests mild cognitive dysfunction due to cerebral hypoperfusion. Li et al. [46] studied the cognitive performance profile of twenty-one pMMD and its relationship with regional cerebral blood perfusion using arterial spin-labeling magnetic resonance and the Wechsler Intelligence Scale for Children. Results showed that six patients (28.6%) had no cognitive deficits in any index score, while 15 (71.4%) displayed cognitive deficits of varying severity. Nine (42.9%) patients showed overall cognitive impairment, and all cognitive index scores except for Verbal Comprehension Index were significantly lower than the mean scores of normative data than controls of the same age. Perceptual reasoning index was statistically lower in patients with radiologically confirmed cerebral infarction. The area of interest analysis revealed that the left temporal lobe's cerebral blood flow positively correlated with processing speed [46].

The causes of Moyamoya vasculopathy are still unknown, though it has been associated with various genetic conditions, including Neurofibromatosis type 1 (NF1). When moyamoya vasculopathy is present in the context of an associated condition, it is called "moyamoya syndrome," whereas moyamoya pathology in the absence of known associated risk factors is called "moyamoya disease" [47]. Studies have shown that a subset of patients with NF1 experience associated vascular conditions, with moyamoya syndrome representing one of the most common comorbidities. While NF1 and moyamoya syndrome are associated with neurocognitive deficits, very few neuropsychological data ara available for cases of comorbid NF1 and moyamoya syndrome, particularly pre- and post-re-vascularization surgery. To shed light on this topic, DeDios-Sterna and Ventura published in 2019 a single casestudy of a bilingual girl of Latin-American descendency with NF1 and moyamoya syndrome, who was assessed pre- (age five years, 9months) and post neurosurgery intervention (age six years, 1month). The pre-neurosurgical cognitive evaluation results documented significant deficits in sustained attention, daily executive functioning, and academic abilities, and the girl met ADHD-combined type criteria. Post- evaluation results revealed generally stable abilities with relative improvements in social, emotional, and behavioral functioning, but a relative decline in visuospatial skills, visual-spatial learning/memory, and executive functioning [48].

Existing literature supports attentional deficits in pMMD, but the clinical presentation of ADHD has rarely been reported. Due to chronic ischemic hypoxic insults to the cerebrum, these patients have poor working memory and experience difficulty sustaining attention, which is thought to be due tohypoperfusion of the frontal lobe. In this sense, Patra and Patnaik reported a clinical case of mental retardation and hyperactivity and inattention five years before the diagnosis of MMD. A definitive diagnosis was made at 11 years of age by means of digital subtraction angiography. The low intellectual functioning and ADHD might have


**4. Conclusion**

The results obtained in this research indicated that natural safiot clay was considered low cost, eco-friendly, and a promising alternative adsorbent for removing BB9 and BY28 dyes in single and binary systems from an aqueous solution. The percentage of dye removed increased with increasing adsorbent dosage, decreased with increasing initial dye concentration, and varied with dye solution pH. The rate of adsorption was found to obey pseudo-second-order kinetics model with a good correlation coefficient indicating toward chemisorption, and the Langmuir isotherm represented the equilibrium adsorption and shows monolayer homogeneous surface of adsorbent for single and binary mixture.

All the theoretical parameters of DFT calculations show that the two dyes can be adsorbed and that the BB9 molecule has the best percentage of elimination. From this calculation, we note that: The dye removal efficiency increases with the highest values of ω, ELUMO, μ, and S and the lowest values of ΔEgap, EHOMO and η. Another important conclusion that we can draw from these calculations is that the theoretical results from reactivity descriptors show that nitrogen, sulfur, carbon, and nitrogen atoms of BB9 and BY28 are the main adsorption sites, respectively. Finally, this study displays a good correlation between the theoretical and experimental data, which confirm the reliability of the quantum chemical methods to study the competitive adsorption of two cationic dyes onto NSC surfaces, in the single and binary system. DFT calculations, Monte Carlo method, and Molecular dynamics simulations support the experimental findings.