Sex differences in the blood-brain barrier: Implications for mental health, 2022, Dion-Albert et al

[SNT Gatchaman]

Sex differences in the blood-brain barrier: Implications for mental health
Dion-Albert L, Bandeira Binder L, Daigle B, Hong-Minh A, Lebel M, Menard C

Prevalence of mental disorders, including major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia (SZ) are increasing at alarming rates in our societies. Growing evidence points toward major sex differences in these conditions, and high rates of treatment resistance support the need to consider novel biological mechanisms outside of neuronal function to gain mechanistic insights that could lead to innovative therapies. Blood-brain barrier alterations have been reported in MDD, BD and SZ.

Here, we provide an overview of sex-specific immune, endocrine, vascular and transcriptional-mediated changes that could affect neurovascular integrity and possibly contribute to the pathogenesis of mental disorders. We also identify pitfalls in current literature and highlight promising vascular biomarkers. Better understanding of how these adaptations can contribute to mental health status is essential not only in the context of MDD, BD and SZ but also cardiovascular diseases and stroke which are associated with higher prevalence of these conditions.

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[SNT Gatchaman]

Review article.

Selected background quotes —

Growing evidence shows that mental disorders substantially increase the risk to develop cardiovascular (CVD) and metabolic diseases. Conversely, people suffering from heart diseases or stroke are more likely to experience mental disorders.

It is widely acknowledged that BBB disruption can precede or exacerbate the progression of neurodegenerative and neurological afflictions, such as Alzheimer’s disease, Parkinson’s disease or epilepsy. Increasing evidence also indicates that neurovascular function is altered in stress and mental disorders.

Interestingly, the inflammatory profile is not only distinct between mental disorders, but central and peripheral inflammation can impact BBB function via several pathways.

The role of neuroinflammation in depressive disorders has become a hot topic in the field of psychiatry with clinical studies indicating that high levels of inflammatory mediators, such as cytokines, can induce depressive behavior in humans.

The first evidence of BBB leakiness in human depression was observed in the 1960′ s by detection of brain-related proteins in the blood. Twenty-four years later, studies reported altered cerebrospinal fluid (CSF) to serum ratio of various peripheral markers in individuals with MDD, indirectly implicating compromised BBB integrity in this disorder.

On top of mounting evidence supporting an active role of inflammation and BBB permeability in MDD etiology, new data suggest that stress-induced neurovascular changes occur in a sex-dependent manner.

Paper then discusses BBB function and dysfunction, effects of gonadal hormones on neurovascular unit, concluding with —

In this review, we provide an overview of important mechanisms and sex differences underlying BBB changes observed in mental disorders. Despite growing numbers of studies including female subjects and considering sex as a biological variable in mental health research, more work is critically needed in both preclinical and clinical settings. First, we detailed some inflammation-related mechanisms which could promote loss of BBB integrity in mental disorders. Sex hormones modulate neurovascular integrity through regulation of neuroinflammation and by directly affecting astrocyte and endothelial cell functions. Sex- specific alterations in CBF and transcriptional pathways could hold the key to discovering novel biomarkers of mental disorders as well as promising adapted diagnostic tools.

 

[Hutan]

Mental disorders, including major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia (SZ), affect approximately 1 in 4 people across the world (WHO | Depression and Other Common Mental Disor- ders, 2017).

First sentence, and it's not starting well for me. Seriously? 1 in 4 people are affected by mental disorders? - and they make it sound as though that ratio is at this point in time, rather than 1 in 4 people will suffer from a mental disorder in their lifetime. That suggests to me that the diagnosis criteria for these various conditions is medicalising very common human conditions of grief, sadness and worry.

With "mental health" or more accurately, "mental illness" covering such a diverse range of mood disorders, behaviours, 'stress', and illnesses such as schizophrenia which must surely have a biological basis, and with so little known about what is causing each of the conditions, to me it doesn't make sense to try to propose some overarching biological mechanism.

 

[Hutan]

Learned helplessness (LH)

LH can be used as an acute or chronic paradigm to induce depressive-like behavior in rodents. In this paradigm, animals experience uncontrollable stressful events, such as foot or tail shocks. Helplessness can be assessed by evaluating performance in an active escape paradigm, where the animal is reintroduced into the same environment with the possibility to escape the stressful event. Most of the stressed animals will not attempt to escape, indicative of a depressive-like phenotype (Baker and Bielajew, 2007; Dalla et al., 2005; Maier and Seligman, 1976; Overmier and Seligman, 1967; Seligman and Beagley, 1975). LH can be reversed by acute (subchronic) antidepressant treatments (Takamori et al., 2001).

The validity of the LH paradigm has been questioned, as female rats to not express helplessness behavior to the same degrees as males, which is independent of sex hormones (Dalla et al., 2008).

Yeah, I just find a lot of this stuff (things to do with gender and mental illness and links with cardiovascular issues) a bit questionable - there's so much scope for prejudices to colour what is studied and the interpretation of any results. Take for example that section on learned helplessness. I don't think that mice study set-up really creates a 'depressive-like phenotype'. What the researchers have done is trained some mice to know that there is no escape from a specific stressful event (electric shocks) and so it needs to be endured as it will eventually stop. So, when those mice are put back in that same specific situation, they know that it is probably not worth running around, and they wait it out. It's quite a leap to extrapolate from that one specific situation to suggesting that the mice have a 'depressive-like phenotype'. What's the bet that those same mice, when exposed to a different challenge, would try to find a way to avoid it?

The authors cite one old study in rats as proving that short antidepressant treatment reverses this learned helplessness. I haven't bothered to look to see what anti-depressant was used, but to me it's extremely unlikely that the drug was 'curing depression caused by a series of electric shocks'.

And then there's that amazing last paragraph: the validity of the learned helpless paradigm has been questioned, not because it's been done in mice, nor because it's a very specific set-up that hardly equates to human life, or even because mice waiting out a series of electric shocks is really nothing like depression. No. The thing that makes the paradigm questionable is that female mice supposedly don't express this helpless 'depressive-like' behaviour as much as the male mice do. I presume the problem is that the female mice should be cowering like proper damsels in distress, while the male mice should be showing greater resilience and initiative in the face of a painful challenging situation?

Given what we know about how common problems with studies are, a lot of this stuff becomes very much like a house of cards. We've seen flimsy constructions built on unreliable research findings and prejudices before.


There may well be something true in this paper, but I'm pretty sure there are plenty of things that are not. I'd much rather see the authors study a single mental health condition and critically review the literature for it, rather than mashing all sorts of information together.

Male mice seem to display more sickness-behavior than females following LPS administration. Females, on the other hand, display higher serum corticosterone concentrations following LPS treat- ment (Girard-Joyal et al., 2015), constituting an interesting paradigm to explore sex-specific regulation of immune challenges that could underlie MDD.

I rather doubt the finding of sickness behaviour differences, but it might be worth having a look at that cited Girard-Joyal paper.

 

[Hutan]

I've read a bit more, and I have to note that this discussion about the natural experiments created by changes in female hormones over a woman's life is interesting:

3.3. Women’s mental health:Is women’s susceptibility to mental disorders variable throughout the reproductive lifespan?

3.3.1. From puberty to menopause: The impacts of hormones

Puberty is a critical transitional period when the body and the brain undergo a transformation towards adulthood. It is also a period of intense hormonal fluctuations that has often been associated with heightened prevalence and exacerbation of psychiatric illnesses (Soares et al., 2002; van der Leeuw et al., 2013, refer to Yazici et al., 2013 for review). Conversely, a recent clinical study involving 5000 individuals from 11 to 16-year-old showed that associations between puberty and the development of psychiatric diseases are weak and should not war- rant major concerns (Smith-Woolley et al., 2017). In rodents, however, female mice were found to be more susceptible to LPS-induced BBB disruption during puberty, in a sex- and brain region-dependent manner (Kolmogorova et al., 2021), suggesting that a vascular challenge during this critical period may affect behavioral responses in adulthood.

Pregnancy is another period of life characterized by hormonal fluc- tuations and for which, interestingly, BBB and vascular functions are altered. Indeed, pregnancy requires active vasculogenesis and angio- genesis, with increased levels of circulatory VEGF, a known promoter of vascular permeability (Segarra et al., 2021). Clinical studies highlighted an association between postpartum depression and increased plasma inflammatory markers, such as IL-1β, IL-6 and IL-16 soluble receptor antagonists during the perinatal period (Corwin et al., 2008; Maes et al., 2001). During pregnancy, the cerebrovascular system is subjected to hemodynamic fluctuations that can affect BBB permeability which could lead to the entry of inflammatory markers to the CNS (Cipolla, 2013). It is yet to be determined if this could be exacerbated under chronic stress conditions, as most studies focus on the offspring. Most women are diagnosed with BD and SZ between 18 and 30 years old and between 25 and 35 years old, respectively, which overlaps with childbearing years (Kessler et al., 2005). Pregnancy and, in particular, the postpartum period are characterized by elevated relapse in women diagnosed with BD and SZ (Edinoff et al., 2022; Jones et al., 2014; McNeil et al., 1984; Robinson, 2012; Rusner et al., 2016; Viguera et al., 2011). Unfortu- nately, it remains poorly understood.

Psychotic episodes in women with SZ are more frequent during pe- riods of estrogen withdrawal, for example during the menses phase of the menstrual cycle, postpartum period, or menopause (Markham, 2012). Menopause and ageing occur concomitantly in a women’s life- time and have impacts on BBB permeability and inflammation. Age-related alterations in cell components of the BBB, such as decreased endothelial mitochondrial number, larger pericyte mitochondria and increased tortuosity in tight junctions (Frías-Anaya et al., 2021), might contribute to the heightened prevalence of mental disorders. This is further supported by reports of increased serum levels of IL-2 and a positive correlation between IL-6 expression and age in postmenopausal women (Yasui et al., 2007). Inflammation is a key aspect of mental disorders, and we believe that possible changes to the BBB and CBF during puberty, pregnancy or menopause could affect vulnerability and relapse in MDD, BD, and SZ. However, there is a lack of studies evalu- ating the direct relationship between them. This could unravel impor- tant information regarding women’s mental health and possible therapies for different phases in the woman’s life cycle.

If female hormones affect BBB permeability and vascular function, and these are relevant to ME/CFS pathology, then we might expect to see some changes in symptoms aligned with the menstrual cycle, and/or some major changes during pregnancy and at menopause. I'm not sure that we do see these changes, but there hasn't been much investigation, as far as I know. There are studies there begging to be done that might produce clues.

 

[CRG]

First sentence, and it's not starting well for me. Seriously? 1 in 4 people are affected by mental disorders? - and they make it sound as though that ratio is at this point in time, rather than 1 in 4 people will suffer from a mental disorder in their lifetime. That suggests to me that the diagnosis criteria for these various conditions is medicalising very common human conditions of grief, sadness and worry.

That one in four figure is banded about a lot - there's 2016 NHS study that says 1 in 5 ! Adult Psychiatric Morbidity Survey: Survey of Mental Health and Wellbeing, England, 2014

"Highlights

39 per cent of adults aged 16-74 with conditions such as anxiety or depression, surveyed in England, were accessing mental health treatment, in 2014. This figure has increased from one in four (24 per cent) since the last survey was carried out in 2007.

Overall, around one in six adults (17 per cent) surveyed in England met the criteria for a common mental disorder (CMD) in 2014.

Women were more likely than men to have reported CMD symptoms. One in five women (19 per cent) had reported CMD symptoms, compared with one in eight men (12 per cent). Women were also more likely than men to report severe symptoms of CMD - 10 per cent of women surveyed reported severe symptoms compared to 6 per cent of men."