Hypertensive smoking women have higher risk of fatal brain bleeding

Subarachnoid haemorrhage (SAH) is one of the most devastating cerebrovascular catastrophes causing death in 40 to 50% of the cases. The most common cause of SAH is a rupture of an intracranial aneurysm. If the aneurysm is found, it can be treated before the possible rupture. However, some intracranial aneurysms will never rupture – the problem is that the doctors don’t know which aneurysms will and which will not. So, they don’t know which patients should be treated and who can safely be left untreated.

A long-term, population-based Finnish study on SAH, which is based on the FINRISK health examination surveys, and published in PLOS ONE on 9th September, shows that the risk of SAH depends strongly on the combination of certain risk factors. The SAH incidence was shown to vary from 8 up to 171 per 100 000 person-years, depending on whether people had multiple risk factors for SAH – such as smoking, hypertension and female sex – or not.

Such an extreme risk factor -dependent variation in the incidence of any cardiovascular disease is exceptional, and may have significant clinical implications, says one of the main authors, Associate Professor Miikka Korja from the Helsinki University Central Hospital and Australian School of Advanced Medicine.

This picture shows a middle cerebral artery bifurcation aneurysm.

If smoking women with high systolic blood pressure values have 20 times higher rate of these brain bleeds than never-smoking men with low blood pressure values, it may very well be that these women diagnosed with unruptured intracranial aneurysms should be treated. On the other hand, never-smoking men with low blood pressure values and intracranial aneurysms may not need to be treated at all.

In this largest SAH risk factor study ever, the study group also identified three new risk factors for SAH: previous myocardial infarction, history of stroke in mother, and elevated cholesterol levels in men. The results revise the understanding of the epidemiology of SAH and indicate that the risk factors for SAH appear to be similar to those for other cardiovascular diseases.

We have previously shown that lifestyle risk factors affect significantly the life expectancy of SAH survivors, and now we have shown that the same risk factors also affect dramatically the risk of SAH itself. Thus, it appears quite clear that especially smoking cessation and hypertension treatment are important in preventing SAH and increasing life expectancy after SAH, clarifies one of the study group members, Academy Professor Jaakko Kaprio, from the University of Helsinki and National Institute for Health and Welfare, referring to their previous publication on cause-specific mortality on SAH survivors (Korja et al., Neurology, 2013).

The study group members have previously published also the largest twin study to date, confirming that heritability for SAH is very low (Korja et al., Stroke, 2010), and the first study on the incidence of SAH in type 1 diabetes, showing that the rate of non-aneurysmal SAHs in type 1 diabetes is unusually high (Korja et al., Diabetes Care, 2013).

Many of the previous studies on the epidemiology of SAH have relied on retrospective and single-center databases, which are unfortunately not very reliable data sources. Due to the unique health care system and common academic interest among doctors in Nordic countries, it has been possible to conduct high-quality and unbiased studies on SAH. We hope that our studies truly help doctors and patients, and are not only of interest in coffee tables on university campuses, says neurosurgeon Korja, and rushes to continue his working day in the operation room in Macquarie University Hospital, Sydney, which is one of his current appointments.

Notes about this neurology and epidemiology research

Contact: Dr. Miikka Korja – University of Helsinki
Source: University of Helsinki press release
Image Source: The middle cerebral artery bifurcation aneurysm image is credited to Miikka Korja and is adapted from the University of Helsinki press release.
Original Research: Full open access research for “Risk Factors and Their Combined Effects on the Incidence Rate of Subarachnoid Hemorrhage – A Population-Based Cohort Study” by Miikka Korja, Karri Silventoinen, Tiina Laatikainen, Pekka Jousilahti, Veikko Salomaa, Juha Hernesniemi and Jaakko Kaprio in PLOS ONE. Published online September 9 2013 doi:10.1371/journal.pone.0073760
Abstract for “Subarachnoid Hemorrhage in Type 1 Diabetes: A prospective cohort study of 4,083 patients with diabetes” by Miikka Korja, Lena M. Thorn, Stefanie Hägg, Jukka Putaala, Ron Liebkind, Valma Harjutsalo, Carol M. Forsblom, Daniel Gordin, Turgut Tatlisumak, Per-Henrik Groop, and the FinnDiane Study Group in Diabetes Care. Published online July 22 2013 doi:10.2337/dc13-0260
Abstract for “Genetic Epidemiology of Spontaneous Subarachnoid Hemorrhage: Nordic Twin Study” by Miikka Korja, Karri Silventoinen, Peter McCarron, Slobodan Zdravkovic, Axel Skytthe, Arto Haapanen, Ulf de Faire, Nancy L. Pedersen, Kaare Christensen, Markku Koskenvuo, Jaakko Kaprio, and the GenomEUtwin Project in Stroke. Published online September 16 2013 doi:10.1161/STROKEAHA.110.586420

Brain Bleeding Risk for Men With Alzheimer’s Gene

Even though women for ApoE4 are at a higher risk for Alzheimer’s, men who have the gene and disease suffer more tiny hemorrhages in their brains.

A common genetic variation, ApoE4, linked to Alzheimer’s disease greatly raises the likelihood of tiny brain bleeds in some men, scientists have found.

Such hemorrhages in brain tissue – microbleeds – leave small points of damage throughout the brain and contribute to memory loss.

The study led by USC Davis School of Gerontology scientists reveals that the gene variant, ApoE4, has different effects on men and women diagnosed with mild cognitive impairment or Alzheimer’s disease.

The research further underscores the significance of ApoE4 (apolipoprotein E 4) in Alzheimer’s, and it builds upon prior studies that indicate the disease has sex-based differences that may affect treatment approaches.

“It’s important to study sex-based differences in Alzheimer’s because women live longer than men, and, as this study shows, the disease can affect them differently,” said corresponding author Caleb Finch, University Professor in the USC Davis School of Gerontology and Dornsife College of Letters, Arts, and Sciences.

Image of a Intracerebral and Intraventricular haemorrhage.

The finding is especially striking since prior research indicated that Alzheimer’s disease was more troublesome for women. Women with ApoE4 are almost twice more likely than men to be diagnosed with the disease. Also, women suffer worse memory loss than men for a given load of plaques and tangles of proteins – the classic Alzheimer’s disease markers.

USC studies have found ApoE4 can be an aggravating factor even for non-Alzheimer’s patients; ApoE4 is well known for worsening the effects of traumatic brain injury.

The latest study, which involved research on mice and on humans, also provides new evidence that Alzheimer’s disease is unique to humans.

“Most diseases can be studied in lab animals without introducing human genes,” Finch said. “That is not the case for Alzheimer’s.”

Even mice and apes that have some factors associated with the disease do not suffer the same cognitive impairments and neuron losses that Alzheimer’s patients do, the scientists noted. The likely difference that spares animals from this brain-wasting disease is that animals do not have multiple genetic variants of ApoE – lipid-carrying proteins produced by the liver and by the brain.

Humans have three variants, including ApoE4, the most common Alzheimer’s risk gene, while chimpanzees, their closest relative, have only one type of ApoE. The ApoE proteins transport cholesterol and other fats through the bloodstream.

Clinical scientists on Finch’s team examined brain scans of 658 subjects, aged 48 to 91 years old, in the United States and Canada, who are part of the Alzheimer’s Disease Neuroimaging Initiative. Of those subjects, 402 had mild cognitive impairment, 90 had early-stage Alzheimer’s disease, and 166 were cognitively normal.

The ongoing study in the Karolinska Institute Dementia Study in Sweden also analyzed the scans of 448 other subjects, aged 36 to 88 years old. Of those, 152 had mild cognitive impairment, 152 had Alzheimer’s, and 144 were cognitively normal.

The researchers found that ApoE4-carrying men with mild cognitive impairment or Alzheimer’s disease suffered twice as many microbleeds in their brains as women with similar diagnoses.

Microbleeds differ from stroke in size and impact, Finch said. Stroke is a macro event that usually occurs on one side of the brain and its effect is usually immediate. Microbleeds occur anywhere in the brain over time, with cumulative effect.

Finch said researchers must now see if they can reduce the microbleeds using sex steroids. They may consider other changes in treatment, too.

“We may need different therapeutic strategies for ApoE4-carrying men who are Alzheimer’s patients than for women,” he said.


Other authors were: USC Davis scientists Mafalda Cacciottolo, Amy Christensen, Alexandra Moser, Jiahui Liu, Christian Pike, and Todd Morgan; Egor Dolzhenko of the Department of Molecular and Computational Biology at USC Dornsife; Patrick Sullivan of Duke University’s Department of Medicine; Andreas Charidimou of Harvard Medical School and Massachusetts General Hospital Stroke Research Center; Lars-Olaf Wahlund, Maria Kristofferson Wiberg and Sara Shams at the Karolinska institute; and Gloria Chia-Yi Chiang at Weill Cornell Medical College.

Funding: The study was funded by NIH/National Institute on Aging, Northern California Institute for Research and Education, Alzheimer’s Disease Neuroimging Initiative.

Source: Emily Gersema – USC
Image Credit: The image is in the public domain
Original Research: Abstract for “The APOE4 allele shows opposite sex bias in microbleeds and Alzheimer’s Disease of humans and mice ” by Mafalda Cacciottolo, Amy Christensen, Alexandra Moser, Jiahui Liu, Christian J. Pike, Patrick M. Sullivan, Todd E. Morgan, Egor Dolzhenko, Andreas Charidimou, Lars-Olaf Wahlund, Maria Kristofferson Wiberg, Sara Shams, Gloria Chia-Yi Chiang, and Caleb E. Finch in Neurobiology of Aging. Published online October 19 2015 doi:10.1016/j.neurobiolaging.2015.10.010


The APOE4 allele shows opposite sex bias in microbleeds and Alzheimer’s Disease of humans and mice

The APOE4 allele confers greater risk of Alzheimer’s Disease (AD) for women than men, in conjunction with greater clinical deficits per unit of AD neuropathology (plaques, tangles). Cerebral microbleeds, which contribute to cognitive dysfunctions during AD, also show APOE4 excess, but sex-APOE allele interactions are not described. We report that elderly men diagnosed for mild cognitive impairment (MCI) and AD showed a higher risk of cerebral cortex microbleeds with APOE4 allele dose effect in two clinical cohorts (ADNI and KIDS). Sex-APOE interactions were further analyzed in EFAD mice carrying human APOE alleles and familial AD genes. At 7 months, E4FAD mice had cerebral cortex microbleeds with female excess, in contrast to humans. Cerebral amyloid angiopathy (CAA), plaques, and soluble Aβ also showed female excess. Both the cerebral microbleeds and CAA increased in proportion to individual Aβ load. In humans, the opposite sex bias of APOE4 allele for microbleeds vs the plaques and tangles is the first example of organ-specific, sex-linked APOE allele effects, and further shows AD as a uniquely human condition.

“The APOE4 allele shows opposite sex bias in microbleeds and Alzheimer’s Disease of humans and mice ” by Mafalda Cacciottolo, Amy Christensen, Alexandra Moser, Jiahui Liu, Christian J. Pike, Patrick M. Sullivan, Todd E. Morgan, Egor Dolzhenko, Andreas Charidimou, Lars-Olaf Wahlund, Maria Kristofferson Wiberg, Sara Shams, Gloria Chia-Yi Chiang, and Caleb E. Finch in Neurobiology of Aging. Published online October 19 2015 doi:10.1016/j.neurobiolaging.2015.10.010