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Life events that influence estrogen levels may be linked to woman’s dementia risk in later life

Life events that influence estrogen levels may be linked to woman's dementia risk in later life

Life events that influence levels of the female hormone estrogen may be linked to a woman’s risk of developing dementia in later life, according to new research.

The analysis found that some reproductive events – like an early or late start to menstruation, early menopause and hysterectomy – were linked to higher risk of dementia while ever having been pregnant or having had an abortion and later menopause were linked to lower risk.

But childbearing was not one of them, with a similar relationship observed between the number of children and dementia risk in men and women.

Lead author Jessica Gong from The George Institute for Global Health said that although it appeared reproductive events related to changes in hormone levels in women may be involved in dementia risk, the exact relationship was still unknown.

“While the risk of developing dementia increases with age, we don’t yet know whether the higher rates seen in women are simply because they live longer,” explained Ms Gong. “But it’s possible that female-specific reproductive factors may be able to explain some of the sex differences.”

Dementia is fast becoming a global epidemic, currently affecting an estimated 50 million people worldwide. This is projected to triple by 2050 – mainly driven by aging populations. Rates of dementia and associated deaths are both known to be higher in women than men.

Estradiol is the most predominant form of estrogen during reproductive life (from the start of menstruation to menopause) and estriol is the primary estrogen during pregnancy. Use of hormones that originate from outside the body, such as oral contraceptives during reproductive years, and hormone replacement therapy (HRT) in later life can also influence estrogen levels.

To examine these relationships in more detail, George Institute researchers analyzed data on a total of 273,240 women without dementia who were registered with the UK Biobank, a large-scale biomedical database. After adjusting for other factors that could have influenced the results, they found the following were associated with an increased risk of dementia:

  • Early and late first occurrence of menstruation, younger age at first birth, and hysterectomy – specifically hysterectomy without surgical removal of one or both ovaries, or if the hysterectomy took place after ovary removal.

Conversely, the factors associated with a decreased risk were ever having been pregnant, ever having had an abortion, longer reproductive lifespan and later menopause.

“With regard to external hormones, the use oral contraceptive pills was associated with a lower risk of dementia, but our study findings did not support an association between HRT and dementia risk,” Ms Gong said.

The authors proposed that risk variation in women may not be associated with childbearing because a similar pattern was observed between number of children fathered and dementia risk among a similar number men in the same study.

“We found that the higher dementia risk linked to early (natural and artificial) menopause was more pronounced in women of lower socioeconomic status,” she added.

“Social deprivation is likely to be an important determinant of dementia risk as well as other aspects of women’s health.”

With dementia on the rise and in the absence of significant treatment breakthroughs, the focus has been on reducing the risk of developing the disease.

“More research is needed to understand whether these differences are associated with life-long exposure to the body’s own estrogen, and whether external hormone use could influence the risk of developing dementia,” added Ms Gong.

“Our findings may be helpful for identifying high-risk women to participate in future clinical trials to assess potential preventive measures and treatments.”


Journal reference:

Gong, J., et al. (2022) Reproductive factors and the risk of incident dementia: A cohort study of UK Biobank participants. PLOS Medicine.

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People with elevated blood pressure upon standing more likely to have risk for cardiovascular events

People with elevated blood pressure upon standing more likely to have risk for cardiovascular events

Among young and middle-aged adults with high blood pressure, a substantial rise in blood pressure upon standing may identify those with a higher risk of serious cardiovascular events, such as heart attack and stroke, according to new research published today in the American Heart Association’s peer-reviewed journal Hypertension.

This finding may warrant starting blood-pressure-lowering treatment including medicines earlier in patients with exaggerated blood pressure response to standing.”

Paolo Palatini, M.D., lead author of the study and professor of internal medicine at the University of Padova in Padova, Italy

Nearly half of Americans and about 40% of people worldwide have high blood pressure, considered to be the world’s leading preventable cause of death. According to the American Heart Association’s 2022 heart disease statistics, people with hypertension in mid-life are five times more likely to have impaired cognitive function and twice as likely to experience reduced executive function, dementia and Alzheimer’s disease.

Typically, systolic (top number) blood pressure falls slightly upon standing up. In this study, researchers assessed whether the opposite response – a significant rise in systolic blood pressure upon standing – is a risk factor for heart attack and other serious cardiovascular events.

The investigators evaluated 1,207 people who were part of the HARVEST study, a prospective study that began in Italy in 1990 and included adults ages 18-45 years old with untreated stage 1 hypertension. Stage 1 hypertension was defined as systolic blood pressure of 140-159 mm Hg and/or diastolic BP 90-100 mm Hg. None had taken blood pressure-lowering medication prior to the study, and all were initially estimated at low risk for major cardiovascular events based on their lifestyle and medical history (no diabetes, renal impairment or other cardiovascular diseases). At enrollment, participants were an average age of 33 years, 72% were men, and all were white.

At enrollment, six blood pressure measurements for each participant were taken in various physical positions, including when lying down and after standing up. The 120 participants with the highest rise (top 10%) in blood pressure upon standing averaged an 11.4 mm Hg increase; all increases in this group were greater than 6.5 mm Hg. The remaining participants averaged a 3.8 mm Hg fall in systolic blood pressure upon standing.

The researchers compared heart disease risk factors, laboratory measures and the occurrence of major cardiovascular events (heart attack, heart-related chest pain, stroke, aneurysm of the aortic artery, clogged peripheral arteries) and chronic kidney disease among participants in the two groups. In some analyses, the development of atrial fibrillation, an arrhythmia that is a major risk factor for stroke, was also noted. Results were adjusted for age, gender, parental history of heart disease, and several lifestyle factors and measurements taken during study enrollment.

During an average 17-year follow-up 105 major cardiovascular events occurred. The most common were heart attack, heart-related chest pain and stroke.

People in the group with top 10% rise in blood pressure:

  • were almost twice as likely as other participants to experience a major cardiovascular event;
  • did not generally have a higher risk profile for cardiovascular events during their initial evaluation (outside of the exaggerated blood pressure response to standing);
  • were more likely to be smokers (32.1% vs. 19.9% in the non-rising group), yet physical activity levels were comparable, and they were not more likely to be overweight or obese, and no more likely to have a family history of cardiovascular events;
  • had more favorable cholesterol levels (lower total cholesterol and higher high-density-lipoprotein cholesterol);
  • had lower systolic blood pressure when lying down than the other group (140.5 mm Hg vs. 146.0 mm Hg, respectively), yet blood pressure measures were higher when taken over 24 hours.

After adjusting for average blood pressure taken over 24 hours, an exaggerated blood pressure response to standing remained an independent predictor of adverse heart events or stroke.

“The results of the study confirmed our initial hypothesis – a pronounced increase in blood pressure from lying to standing could be prognostically important in young people with high blood pressure. We were rather surprised that even a relatively small increase in standing blood pressure (6-7 mm Hg) was predictive of major cardiac events in the long run,” said Palatini.

In a subset of 630 participants who had stress hormones measured from 24-hour urine samples, the epinephrine/creatinine ratio was higher in the people with a rise in standing blood pressure compared to those whose standing blood pressure did not rise (118.4 nmol/mol vs. 77.0 nmol/mol, respectively).

“Epinephrine levels are an estimate of the global effect of stressful stimuli over the 24 hours. This suggests that those with the highest blood pressure when standing may have an increased sympathetic response [the fight-or-flight response] to stressors,” said Palatini. “Overall, this causes an increase in average blood pressure.”

“The findings suggest that blood pressure upon standing should be measured in order to tailor treatment for patients with high blood pressure, and potentially, a more aggressive approach to lifestyle changes and blood-pressure-lowering therapy may be considered for people with an elevated [hyperreactor] blood pressure response to standing,” he said.

Results from this study may not be generalizable to people from other ethnic or racial groups since all study participants reported white race/ethnicity. In addition, there were not enough women in the sample to analyze whether the association between rising standing blood pressure and adverse heart events was different among men and women. Because of the relatively small number of major adverse cardiac events in this sample of young people, the results need to be confirmed in larger studies.


Journal reference:

Palatini, P., et al. (2022) Blood Pressure Hyperreactivity to Standing: a Predictor of Adverse Outcome in Young Hypertensive Patients. Hypertension.

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Digital social events worked well for people living with dementia – Dr Gary Kerr

Digital social events worked well for people living with dementia - Dr Gary Kerr
Dr Gary Kerr, Associate Professor in Festival and Event Management at Edinburgh Napier University.

In Scotland, around two-thirds of those diagnosed with dementia are living at home, with the remainder in acute or residential care. A key challenge for all is the sense of isolation that can manifest early on after a diagnosis.

Pre-pandemic, social events were a key factor in boosting a sense of wellbeing for those affected, but lockdown brought with it particular challenges for this community.

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Our highly collaborative research project, Unlock & Revive, identified six active ingredients needed to deliver accessible online cultural and heritage events. The research was led by Edinburgh Napier, working with the University of Edinburgh, during a three-month period from April to June 2021 and involved seven Edinburgh-based cultural and heritage organisations running weekly online events that featured gardening, painting, art, cookery, history, literature and music amongst other topics.

We monitored the sessions in person, ran post-event focus groups with attendees, and carried out interviews with event organisers and found online events do boost attendees’ sense of wellbeing; build confidence; and establish a newfound appreciation for leisure activities and hobbies.

1 – Keep any event under sixty-minutes-long. A mid-morning start time is preferred.

2 – Include short interactive presentations, using simple language and supplemental visuals.

3 – Keep the number of attendees low and aim for engagement over education; and presenters should use multi-sensory triggers to create engaging narratives, allocating plenty of time for participant-led discussions.

4 – Ensure all event facilitators have up-to-date Dementia Training from a reputable institution.

5 – Organise regular socials and not one-off events. Using Zoom is the ideal platform: its ‘spotlight’ function is effective when combined with an administrator’s support to let people in, oversee the chatbox and monitor participants’ wellbeing.

6 – Lastly, Unlock & Revive emphasises that a grassroots approach is taken to advertise these events, as social media promotions are less effective in reaching this audience.

As restrictions begin to ease, online events should still be considered, with most of those participating keen to see some form of online delivery maintained.

The format for an in-person event does not easily transfer to a digital delivery model, and particular effort must be made to facilitate maximum engagement and participation from participants when delivering events online for those living with dementia. Although 100% of participants told us they prefer in-person Dementia Socials, we found clear evidence that digital events do provide opportunities for social connection, and stimulation for individuals unable to attend live events – whether that is due to mobility and/or transportation barriers.

Everyone involved in our research expressed their appreciation and enjoyment of online socials and now see them as a useful option for a hybrid event model in the future. Our research has identified the active ingredients needed to deliver accessible online cultural and heritage events, which can only bring positive benefits to people living with dementia, and their caregivers.

Our full report can be downloaded at here.

Dr Gary Kerr, Associate Professor in Festival and Event Management at Edinburgh Napier University.

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Cell stress-related biochemical events may be partly driving Parkinson’s disease

Cell stress-related biochemical events may be partly driving Parkinson's disease

Parkinson’s disease may be driven in part by cell stress-related biochemical events that disrupt a key cellular cleanup system, leading to the spread of harmful protein aggregates in the brain, according to a new study from scientists at Scripps Research.

The discovery, published in The Journal of Neuroscience in February 2022, offers a clear and testable hypothesis about the progression of Parkinson’s disease, and may lead to treatments capable of significantly slowing or even stopping it.

We think our findings about this apparent disease-driving process are important for developing compounds that can specifically inhibit the process of disease spread in the brain.”

Stuart Lipton, MD, PhD, study senior author, Step Family Endowed Chair, founding co-director of the Neurodegeneration New Medicines Center, and professor in the Department of Molecular Medicine at Scripps Research

Parkinson’s disease affects roughly one million people in the United States. Its precise trigger is unknown, but it entails the deaths of neurons in a characteristic sequence through key brain regions. The killing of one small set of dopamine-producing neurons in the midbrain leads to the classic Parkinsonian tremor and other movement impairments. Harm to other brain regions results in various other disease signs including dementia in late stages of Parkinson’s. A closely related syndrome in which dementia occurs early in the disease course is called Lewy Body Dementia (LBD), and affects about 1.4 million people in the U.S.

In both diseases, affected neurons contain abnormal protein aggregations, known as Lewy bodies, whose predominant ingredient is a protein called alpha-synuclein. Prior studies have shown that alpha-synuclein aggregates can spread from neuron to neuron in Parkinson’s and LBD, apparently transmitting the disease process through the brain. But precisely how alpha-synuclein aggregates build up and spread in this way has been unclear.

One clue, uncovered by Lipton’s lab and others in prior research, is that the Parkinson’s/LBD disease process generates highly reactive nitrogen-containing molecules including nitric oxide. In principle, these reactive nitrogen molecules could disrupt important cellular systems, including “housekeeping” systems that normally keep protein aggregates under control.

In the new study, the Scripps Research team demonstrated the validity of this idea by showing that a type of nitrogen-molecule reaction called S-nitrosylation can affect an important cellular protein called p62, triggering the buildup and spread of alpha-synuclein aggregates.

The p62 protein normally assists in autophagy, a waste-management system that helps cells get rid of potentially harmful protein aggregates. The researchers found evidence that in cell and animal models of Parkinson’s, p62 is S-nitrosylated at abnormally high levels in affected neurons. This alteration of p62 inhibits autophagy, causing a buildup of alpha-synuclein aggregates. The buildup of aggregates, in turn, leads to the secretion of the aggregates by affected neurons, and some of these aggregates are taken up by nearby neurons.

“The process we observed seems very similar to what is seen in Parkinson’s and LBD brains,” says study first author Chang-Ki Oh, PhD, a staff scientist in the Lipton laboratory.

The researchers also tested postmortem brains of LBD patients, and again found that levels of S-nitrosylated p62 were abnormally high in affected brain areas-;supporting the idea that this process occurs in humans.

Lipton and Oh say that S-nitrosylation of proteins becomes more likely in many situations of cellular stress, including the presence of protein aggregates. Thus, this chemical modification of p62 could be a key factor in a self-reinforcing process that not only stresses brain cells beyond their limits, but also spreads the source of stress to other brain cells.

The team is now working to develop drug-like compounds that specifically inhibit the S-nitrosylation of p62. Although it would take years to develop such compounds as potential commercial drugs, they could, in principle, slow the Parkinson’s/LBD disease process or prevent its further spread in the brain after it begins, Lipton says.


Journal reference:

Oh, C., et al. (2022) S-Nitrosylation of p62 Inhibits Autophagic Flux to Promote α-Synuclein Secretion and Spread in Parkinson’s Disease and Lewy Body Dementia. Journal of Neuroscience.