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Johns Hopkins University researchers have identified more than 200 types of misfolded proteins in rats that could be associated with age-related cognitive decline.

The findings could lead the way to finding new therapeutic targets and treatments in humans that could provide relief for the millions of people over 65 who suffer from Alzheimer’s, dementia, or other diseases that rob them of their memories and independence as they age.

“Amyloids are the buildup of misshapen proteins. They’re big and ugly and easy to see under the microscope, so it makes sense that they catch our attention. But we’re seeing hundreds of proteins misfolding in ways that don’t clump together in an amyloid and yet still seem to impact how the brain functions,” said Stephen Fried, an assistant professor of chemistry and protein scientist who studies how molecules in the brain change during aging. “Our research is showing that amyloids are just the tip of the iceberg.”

The results were published on July 11 in Science Advances.

To understand the molecular differences between older brains that are mentally sharp and those that are experiencing decline, Fried and his team studied 17 2-year-old rats that grew up in the same colony. Seven rats performed poorly on memory and problem-solving tests and were considered cognitively impaired, while 10 performed as well as 6-month-old rats.

The researchers then measured more than 2,500 types of protein in the hippocampus, the part of the brain associated with spatial learning and memory. For the first time, scientists were able to determine for a large number of proteins whether individual proteins were misshapen or folded incorrectly, allowing the researchers to work out which proteins misfold for all the rats and are associated with aging in general versus which proteins specifically misfold in cognitively impaired rats.

More than 200 proteins were misfolded in the cognitively impaired rats yet maintained their shapes in the cognitively healthy rats. The findings suggest that some of those proteins are contributing to cognitive decline, the researchers said.

Misfolded proteins are unable to carry out tasks necessary for a cell to function properly, so cells have a natural surveillance system that identifies and destroys these misbehaving proteins. Previously, researchers thought misfolded proteins — specifically A-beta and tau proteins — were only disruptive when they clumped into amyloids.

“We think there are a lot of proteins that can be misfolded, not form amyloids, and still be problematic,” Fried said. “And that suggests these misfolded proteins have ways of escaping this surveillance system in the cell.”

But exactly how those misfolded proteins slip past a cell’s security system remains a mystery.

Next, the team plans to look at misfolded proteins under high-resolution microscopes to get a more detailed picture of what their deformities look like at the molecular level.

“A lot of us have experienced a loved one or a relative who has become less capable of doing those everyday tasks that require cognitive abilities,” Fried said. “Understanding what’s physically going on in the brain could lead to better treatments and preventive measures.”

Four main themes were created; 1) Adapting to new circumstances influence reproductive intentions; (2) Reproductive decision-making – the women’s choice but partner’s support is important; (3) Conflicting information on contraceptives creates hesitancy; and (4) Trust and mistrust in antenatal and postpartum contraceptive services. Each theme includes four to five sub-themes, see Fig. 1. Below, the themes are described and illustrated with selected quotes. In brackets the number of the FGD, and the individual are presented as follows: (FGD1, P2). The participants will be referred to as women from here on.

Adapting to new circumstances influence reproductive intentions

This theme highlights how women’s changing life circumstances, following migration to Sweden, changed their reproductive intentions. Women were hesitant to having children in times of uncertainty and various aspects were considered in the reproductive decision-making.

Raising a child in Sweden, compared to country of birth, was expressed as a double burden, with added responsibilities for the woman besides childcare. Aspects of the integration process, like learning a new language, working, and studying were identified as putting pressure on the family and affecting the desired family size. Being more isolated in raising children in Sweden was also brought up as a challenge, referring to not having the extended family close by for support.

Yes, it is very true, especially as we are in a new country, we want to learn the language and expand our knowledge. In other words, I am a Syrian university graduate from the Faculty of Law, when I moved to Sweden, I had to start from zero, so I needed to improve myself because if I didn’t, I’d be mentally exhausted. So, all these factors influenced my decision to become pregnant. (FGD1, P1)

The main priority for the women was being able to provide secure conditions for the children they already had, including good housing and financial stability, as well as being able to devote sufficient time and emotional support to each child.

I came to Sweden a year and four months ago, and my house is small. I cannot have another child at the present time. I must work so that we can get a loan and buy a house. (FGD1, P3)

Many of the women described that the responsibility for childcare fell on them, impacting their life choices as well as their mental health. As a way of managing the increased stress from raising children in a new setting, birth spacing was described as essential for both the woman’s and the entire family’s wellbeing. On top of a stressful life situation, the women also highlighted the need to let the body rest between pregnancies and expressed a wish that midwives would invite to dialogues about the various benefits of birth spacing.

I think the midwifes can help, they can explain to women how the situation is with one child with two or three children./……/Meaning they should explain that the more children you have, the more it will drain your ability, and your interest in the rest of the children will decrease./………/I see that she needs to provide more information about having children and its impact, I mean. (FGD1, P1)

However, a few women also described that being alone in new context could be a reason for wanting a larger family, since children can provide a sense of belonging. The concept of planning your pregnancies was seen as fluctuating, e.g. deciding your family size ahead is not always feasible, since you do not know how your circumstances might change.

In conclusion, living in the new Swedish context made women think more about contraception. However, this was not only the women’s decision as presented in the next theme.

Reproductive decision-making – the women’s choice but partner’s support is important

Most women shared the view that contraceptive use is a joint matter concerning both the woman and her partner, and the number of children and contraception were regularly discussed with the partner. However, despite considering the partner to have a significant role in the reproductive decision-making, women also expressed that using contraceptives and or becoming pregnant should be the woman’s choice in the end. The women rationalized that the partner does not need to endure side effects, and that it is the woman that bears the consequences and risks with pregnancy and childbirth, thus it should be her final choice.

As for contraception, the first and last decision is for a woman, because she is the one who gets pregnant, gets tired and gives birth, and sometimes contraceptive methods are not suitable for her body, and the woman becomes like a field of experiment, unfortunately. (FGD4, P1)

Women in this study were in general positive to involving the partner in the contraceptive counselling. They stated that including the partner was important to increase men’s, according to the women, often limited knowledge on contraceptives, hormones, and reproductive health. Another important aspect of involving the partner was to expand his understanding of the woman’s life situation. The women expressed a great need for the partner to better recognize how pregnancies, childbirth, and contraceptives (e.g. hormones) affect the woman’s body and wellbeing. Inviting the partner to the contraceptive counselling and receiving information from the midwife was thought to enhance the partner’s support and help emphasize shared responsibility of contraceptive use.

I mean, I think, in order for him to have a background in contraceptives, so if we plan not to have children, it is good for him to hear from the midwife about contraceptives and their effect on my body. Planning for childbearing is not only the responsibility of the woman, but the responsibility of the man as well and the decision is shared between them, whether to become pregnant or stop childbearing. (FGD5, P3)

However, a few women preferred not to include the partner in the contraceptive counselling session, due to privacy reasons or that the partner could be embarrassed by the sensitive topic. Furthermore, religion can influence reproductive choices for some. A few women explained for example that Islam does not allow abortions but supports birth spacing.

It is not a mistake to have many children, but our Islamic religion also advised us to distance between pregnancies, as the woman should take a break between them, at least three years. (FGD3, P3)

In summary, men’s involvement in postpartum contraceptive counselling was seen by many as an opportunity for the couple to access information needed to support their reproductive choices. The importance of detailed information in the contraceptive counselling is further described in the next theme.

Conflicting information about contraceptives creates hesitancy

Conflicting information from friends, family, and healthcare providers in the woman’s home country, compared to information from midwives in Sweden was perceived as confusing and created a feeling of not knowing what information to trust. The contraceptive knowledge prior to moving to Sweden was to a large extent from family and friends, and pre-marital contraceptive counselling was described as uncommon.

A wish for more detailed information about various contraceptive methods during counselling was expressed, and the women explained that insufficient information could lead to misunderstandings and incorrect use of contraceptives. There was a request for more comprehensive information on side effects, health benefits, and risks. Women preferred to receive information from reliable sources, written information was highly appreciated and some women also found information from websites like the Swedish national health advice homepage helpful.

…regarding the use of the new type of contraceptive pill, the midwife gave me many papers that talk about this contraceptive in details. This is a very good thing, because this written information is from a reliable source, so I read it and I am confident, not like what I read from the internet, for example. (FGD5, P2)

However, some women believed that even detailed information was not enough; the woman need to try the contraceptive herself to see whether it fits the nature of her body. They acknowledged that different methods work well for some women but not for others, and described that it was often difficult to find a suitable contraceptive method. This trial-and-error process (trying many different contraceptive methods) could be frustrating according to the participating women.

… [I] also agree that according to the nature of the body, for example, the pills so far are very good for me, while neither the IUD (intrauterine device) nor the skin implant suited me. My body did not accept anything from outside, such as the IUD, so the pills suited me very well, and on the contrary, they did not cause me nervousness or weight gain. (FGD5, P4)

Fears about hormones were commonly described, and women expressed concerns about side effects such as cancer, amenorrhea, infertility, and anxiety. Hormone use was seen as scary and harmful for the body. Previous negative experiences of contraceptives often influenced the women’s contraceptive choices, as well as experiences and advice from friends and relatives.

Frankly, the pills have side effects, obesity, headaches, as well as the IUD, they say that it causes cancer, so I am very far from using any type of contraceptives. (FGD 2, P3)

The fear of infertility was particularly strong, and some women had been advised by both family and health care providers in their home country not to use any contraceptives before giving birth to their first child.

It can cause harm when used from the beginning of the marriage before pregnancy occurs, infertility may occur. From the experience of one of my friends in Jordan, she got married and wanted to use birth control pills, so she consulted, and they told her not to use them from the beginning, it would be better to have a child and then think about using it. (FGD2, P3)

Some women expressed that the midwife has an important role in dispelling myths about contraceptives and to reassure about contraceptives and health concerns. One woman said it would be useful with educational lectures and even suggested mandatory appointments after childbirth to give information about contraceptives. Others said that “It is necessary that the midwife perform her role at the fullest and give a lot of information to the women”. (FGD4, P1).

Frankly, sometimes these questions that we also ask ourselves, the fact that contraceptives sometimes cause infertility? Does it really cause cancer, as many people are talking about? I really feel that this information is incomplete, and the midwife needs to explain more about it (FGD5, P1)

A lack of trust in the effectiveness of contraceptives was also discussed. Some women had either experienced themselves, or heard from others, that contraceptives sometimes fail, resulting in unplanned pregnancies. This was described for both modern contraceptives and natural methods. Thus, both fears for side effects and rumours were barriers for contraceptive use. However, some side effects were perceived as acceptable if the contraceptive method was efficient to prevent pregnancies. The women also discussed that they were left with no other choice than to accept side effects, despite experiencing a negative impact on their body or mental health.

Frankly, from my experience, it [contraception] is absolutely not good and harmful. I tried contraceptives and suffered greatly./……./I was always in appointments and hospitals, and you know here in Sweden everything is slow. From my point of view contraceptives are bad, but I have to use it as well, as all women have to use it to avoid pregnancy. (FGD5, P4).

Natural contraceptive methods were the first choice for many women, especially for women with previous negative experiences of hormonal contraceptive methods. Several women were satisfied with the use of natural methods and stated that the method had worked well for them for years. Despite being a common choice, information on natural methods was absent from the contraceptive counselling and was specifically asked for to be included.

Educate us on the natural method of contraception and the method of counting, we know it and we can read about it from the internet, but she [the midwife] can give us more reliable information for sure. (FGD4, P2)

Despite wanting to use contraceptives, fear of hormones was common, and women asked for more comprehensive information on side effects and natural methods. Another aspect discussed was the importance of establishing trust – both in the relationship with the midwife and at an organisational level– and this will be presented next.

Trust and mistrust in antenatal and postpartum contraceptive services

While many women reported trustworthy contraceptive counselling by their midwives, there were also some experiences of mistrust in the antenatal and postpartum period. Trust included an empathetic counselling experience. Mistrust involved limited support in handling concerns about side effects of contraceptives, limited decision support, too little focus on the woman’s health postpartum and a feeling of breached privacy.

To receive contraceptive counselling antenatally was met with mixed feelings. Many were positive since it allowed some time for the woman to think about it, to prepare and plan. It was also seen as a useful tool for supporting birth spacing. Others thought antenatal counselling was overwhelming and one woman described it as; “I honestly feel that the issue is a bit difficult during pregnancy, I think of childbirth and its troubles.” (FGD4, P1).

Some women felt that midwives had preconceived ideas about their needs as immigrant women, especially in the sensitive time of postpartum, when the women had other priorities and expectations. Women felt that other things were more important, for example advice on breastfeeding. Another example was midwives asking questions about their relationship and domestic abuse rather than focusing on the woman’s physical health after giving birth. Some women saw personal questions about the (male) partner as interfering with their private life, affecting their trust in the midwife, which in turn could hinder the dialogue in general.

Frankly, I do not like questions of the investigative type. I mean, for example, is your husband violent with you? Is there something going on with you that you would not like to talk about in front of your husband? These questions are very annoying and unacceptable to me. (FGD4, P3)

On the other hand, some women stated the opposite, saying that it was the midwife’s obligation to ask about these matters and appreciated that it was brought to attention. Many women also described experiences of the midwife being understanding and mindful of cultural differences.

Honestly from my experience, I feel that she is very understanding and understands that I am a Muslim woman, and I have my own customs and traditions. For example, when she asks me, do you drink alcohol, she tells me that I know that you are Muslim and you wear the hijab, but I just have to ask, I mean, I feel that the midwives are very understanding and educated in this regard. (FGD5, P4)

Emotional support from the midwife was mentioned as important in the antenatal and postpartum period, both in general but also in relation to contraceptives. Some women expressed that their mental health was very important to them, and that concerns about contraceptive’s effect on mental health should be embraced in the contraceptive counselling.

Ok, it is not wrong to ask about my psychological condition, for example, and whether I am nervous by nature or not, because for example, it is possible for contraceptive pills to increase nervousness and the situation to get worse. (FGD5, P1)

The women agreed that the midwife does not interfere in the decision regarding type of contraceptive method, explaining that the midwife would provide information about each type of contraceptive, but would not advise the woman to select a specific type. Experience of patient-driven decision-making could sometimes create a feeling of being lonely when choosing a contraceptive method. One woman described that she received information about all available options and their effect, but that the midwife did not “offer any other help”, it was up to the woman to decide “according to the nature of her body” (FGD2, P1).

I think that the midwife does not interfere in these matters at all. For example, I asked her (what do you think about the skin implant? And what is your advice?), she explained to me how it works, and she said that she had nothing to do with my decision, and she could not advise me on a specific thing. She was so impartial, it means she has nothing to do with the matter. (FGD1, P1).

Women that had received advice on certain methods from the midwife perceived it as helpful, explaining that the midwife’s opinion was important in making their choice, without experiencing feelings of being pressured: “Just advice, I mean she doesn’t force you”. (FGD3, P1)

Some other examples of mistrust in contraceptive counselling were also discussed among the women. A difficulty to book a health care appointment in Sweden and long waiting times were considered barriers to contraceptive access and use. This created a hesitancy of using contraceptives, since the women were not confident that they would receive timely help in case of side effects. Many also expressed concerns about the lack of routine check-ups of intra uterine devices (IUDs) to confirm correct position, making them hesitant to insert an IUD in the first place.

I am not talking about pregnancy, but sometimes I feel that I have pain from the IUD, and I want to meet her (the midwife), I call but I do not get an appointment until after a long time. (FGD3, P2)