Biological sex matters, also for our social brain
By M. Florencia Iulita and Ignacio Illán Gala
While it is increasingly clear that sex differences in brain structure and function may be subtle in a healthy person, the key question is: do men and women experience disease differently? Mounting new data in the field of brain and mental health indicates that the answer is indeed yes. Thus, although our brain’s ‘building blocks’ may be similar between sexes, it is now known that men and women experience different risk factors, response to pathology, symptom manifestation and response to treatment. At the Women’s Brain Project, we have been spearheading a global discussion using Alzheimer’s disease as an example, on how the study of brain disease through a sex and gender angle can help gain new insights to more effectively diagnose and treat brain diseases.
While interest in Alzheimer’s disease spread quickly, other important neurodegenerative dementias have been less investigated, but this promises to change. Driving this effort is my colleague Ignacio Illán Gala, neurologist at the Sant Pau Memory Unit in Barcelona. We had the chance to collaborate on a most interesting study he recently completed, describing sex differences in brain structure in the behavioral variant of frontotemporal dementia (bvFTD), a neurodegenerative disease targeting our social brain. We sat down to discuss this work and its potential implications for future research.
MFI: Thank you Ignacio for sharing your story with us. There is a growing body of literature looking at sex differences in Alzheimer’s disease, yet less is known about frontotemporal dementia; could you tell us briefly about this disease and what was the purpose of your study?
IIG: Frontotemporal dementia encompasses a group of neurodegenerative syndromes characterized by prominent behavioral changes or language symptoms. This large multicenter study was the first to specifically investigate sex-related differences in bvFTD, the most common presentation of frontotemporal dementia. The bvFTD syndrome is characterized by prominent behavioral changes with relative sparing of cognition and independence in activities of daily living. Patients with bvFTD can present with a wide range of abnormal behaviors and may abandon hobbies, approach strangers with unwanted questions, make inappropriate comments on others’ physical appearance, show emotional detachment to loved ones, display ritualistic behaviors or present changes in eating habits. The bvFTD syndrome is one of the most common causes of early-onset dementia, together with Alzheimer´s disease. However, in contrast with Alzheimer´s disease, the bvFTD is more commonly diagnosed in men than in women. Indeed, men usually represent 60% to 80% of participants diagnosed with bvFTD in the largest pathology-proven cohorts. The reasons for this male predominance in the bvFTD syndrome are unknown and previous studies suggested that women with bvFTD could be more frequently misdiagnosed with psychiatric disorders than men. As a clinician I have always found these observations intriguing. Indeed, the bvFTD is a fascinating clinical syndrome that is characterized by progressive personality change due to neurodegeneration of the brain’s frontal and temporal lobes. These cerebral structures shape our personality and ensure an adaptive social behavior and, under normal conditions, the cortical thickness in these brain regions is usually higher in women. Hence, I think the study of differences linked to sex is especially relevant to understand whether men are more vulnerable to suffering from this disease. Our study aimed to shed some light on how sex may impact neurodegenerative diseases targeting our social brain.
MFI: Very interesting, particularly the issue on potential misdiagnosis of bvFTD in women. What was done in this study exactly?
IIG: In this study we compared the clinical, prognostic, and brain atrophy characteristics between men and women diagnosed with bvFTD. I conceptualized this work during my time at the University of California San Francisco as an Atlantic Fellow for Equity in Brain Health (https://www.gbhi.org/). We measured cortical thickness with magnetic resonance imaging (MRI) and compared patients diagnosed with bvFTD and healthy controls of the same sex and similar age distribution. We included more than four hundred participants from the USA (University of California, San Francisco) and Catalonia (Hospital de Sant Pau and Hospital Clinic). Also, behavioral changes and cognitive performance at the time of diagnosis were quantified to compare men and women’s cognitive reserve. The concept of cognitive reserve refers to the ability to maintain brain function in the presence of neurodegenerative changes. This work’s main finding was that women presented more significant brain damage (studied by cortical thickness in brain MRI) than men, despite showing a similar cognitive and behavioral alteration. In addition, we obtained evidence of a greater behavioral reserve in women. That is, women required greater brain damage to present the same behavioral changes as men.
MFI: What does this study mean for future research? Will it have implications on your clinical practice as a neurologist?
IIG: In this study we report for the first-time critical sex-related differences in the behavioral variant of frontotemporal dementia and suggest that the female brain may be more resilient to this disease by unknown mechanisms. Our results add to previous evidence suggesting that women’s brains may be more resilient to conditions targeting the brain’s frontal structures. For example, autism spectrum disorder and attention deficit hyperactivity disorder are two diseases that affect men more frequently than women. Interestingly, executive dysfunction, and impaired social cognition are central clinical features of these heterogeneous diseases. These results also open the door to new studies aiming to improve the diagnosis of bvFTD. Future studies should examine the specific mechanisms underlying the observed differences and consider biological sex for the design of research studies and clinical trials in bvFTD and other neurodegenerative dementias. Our findings could also be relevant in clinical practice and suggest that objective cut-offs for the definition of significant frontotemporal brain atrophy should be adjusted by sex. Interestingly, previous studies found that a group of non-neurodegenerative bvFTD mimics, also known as “phenocopies,” are almost universally men. These previous observations support the view that men may be more vulnerable to display the clinical symptoms necessary for the diagnosis of bvFTD. In these cases, additional biomarkers are needed to differentiate neurodegenerative cases from cases with primary psychiatric disorders. However, many questions remain unanswered and more studies are needed to clarify the role of sex in the diagnosis of the bvFTD and other FTD syndromes.
MFI: Thank you Ignacio, we look forward to seeing future discoveries that your work will certainly inspire.
Image/Illustration by: Carles Esquembre – Comic Artist