Alzheimer’s Disease, Music Therapy and Sex Hormones: An Unexpected Solution

Alzheimer’s disease (AD) is all around us, with over 5 million individuals diagnosed across the United States. Interestingly, of these 5 million Americans, over 3.5 million of them are women, suggesting women are significantly more likely to suffer from AD than men.^1,2 While AD is best known for its impairment of memory, both short-term and long-term depending on the extent of the illness, a variety of other symptoms may accompany memory loss such as disorientation, confusion about time and place, changes in mood and behavior, and difficulties with speech, eating, and walking. These symptoms, collectively, lead to a significant loss in communication and personal identity.

Low levels of sex hormones plays a significant role in the onset of AD, and have led many scientists and doctors to propose Hormone Replacement Therapy (HRT) as a potential treatment for this disease.^4,5 While levels of sex hormones decrease with age, Alzheimer’s patients routinely possess especially low levels of both testosterone and estrogen. Women see an especially rapid, significant drop in sex hormone levels with menopause, which subsequently leads to their significantly increased risk for developing AD. Both estrogen and testosterone have been linked to cell proliferation and nerve protection, and estrogen has been shown to increase cholinergic activity.^4,5 Additionally, these hormones have been shown to suppress the effects of beta-amyloid, a series of peptides which are involved in plaque formation and the development of AD. Specifically, estrogen and testosterone prevent beta-amyloid accumulation by increasing the activity of beta-amyloid-degrading enzymes, and also protect against its neurotoxicity. Collectively, testosterone and estrogen improve cognitive function and delay the progression and effects of AD.⁴ Despite the clear importance of these two hormones, HRT has not been accepted as a treatment of AD due to inconsistent results and a series of serious side-effects, such as heart-attack, stroke, and an increased risk for breast cancer and prostatic cancer.⁴

Recently, an article was published in the International Journal of Alzheimer's Disease which links sex hormones with music therapy, and thus proposes music therapy as an alternative to hormone replacement therapy.⁴ Stimulatory therapies, such as music therapy, have been extremely useful in the management of AD for many individuals. I have personally witnessed the benefits music can have on the mood and cognition of someone diagnosed with AD, and it is widely accepted as an effective treatment both in neuroscientific blogs (BrainBlogger), and the AD support community (Alz.org Blog). While music therapy can have a wide variety of effects, scientific studies have shown that music therapy moderates problematic behavior, improves social involvement, promotes better cognition and awareness, increases brain plasticity, and reduces levels of stress, anxiety and depression.⁶

Figures taken from Fukui et al. 2012 (see reference 4).

Although the behavioral effects of music therapy are well-supported, our understanding of why and how this treatment works biologically has been extremely limited. Fukui et al. have investigated these biological causes by measuring levels of testosterone and estradiol in 6 female AD patients in a nursing home, before and after three different therapy conditions: therapist only, music only, and music + therapist. Note that estradiol is one of three hormones which are collectively known as estrogens. Music therapy proved to be the only treatment which resulted in a significant increase in both estrogen and testosterone, while music alone solely increased estrogen levels (Figures 1 & 2). ⁴ Additionally, caregivers noted that problematic behavior decreased for 24 hours after music therapy, supporting previous behavioral observations associated with AD and music therapy. These results suggest that music therapy could be used as a natural alternative to hormone replacement therapy, increasing hormone levels by engaging in an activity, as opposed to direct injection.

Of course, it should be noted that this study’s methodology is far from full-proof. With only six participants it can hardly be considered an all-inclusive study, and Fukui et al. make no mention of how much music therapy is needed before results are seen. Perhaps most importantly, the authors fail to include how severe each patient’s AD was, leading to questions about how effective this treatment will be at various stages of the disease. However, despite these experimental flaws, I hope that this study encourages other researchers to investigate music therapy as a natural alternative to hormone replacement therapy for Alzheimer’s disease. While these studies are difficult, research on larger populations with AD of varying severity as well as differences in exposure to music therapy are necessary for the implementation of this treatment on a larger scale. Music therapy would be a fantastic treatment in that it is low-cost, non-invasive, and perhaps even enjoyable for these patients who so badly deserve relief from their symptoms.

References:

1. Alzheimer's Association. (2014). 2014 Alzheimer's Disease Facts and Figures. Retrieved from: http://www.alz.org/downloads/facts_figures_2014.pdf
2. Bao A., Swaab D.F. (2011). Sexual differentiation of the human brain: relation to gender identity, sexual orientation and neuropsychiatric disorders. Front Neuroendocrinol, 32, 214-226.
3. Alzheimer's Association. (2014). What is Alzheimer’s? Retrieved from: http://www.alz.org/alzheimers_disease_what_is_alzheimers.asp
4. Fukui H., Arai, A., Toyoshima, K. (2012). Efficacy of Music Therapy in Treatment for the Patients with Alzheimer’s Disease. Int J Alzheimers Dis, vol 2012.
5. Barron A.M., Pike, C.J. (2013) Sex hormones, aging, and Alzheimer’s disease. Front Biosci (Elite Ed), 4, 976-997.
6. Wollen, K. A. (2010). Alzheimer’s disease: the pros and cons of pharmaceutical, nutritional, botanical, and stimulatory therapies, with a discussion of treatment strategies from the perspective of patients and practitioners. Altern Med Rev, 15(3), 223-44; Sakamoto, M., Ando, H., & Tsutou, A. (2013). Comparing the effects of different individualized music interventions for elderly individuals with severe dementia. International Psychogeriatrics, 25(5), 775-784; Koger, S. M., Chapin, K., & Brotons, M. (1999). Is music therapy an effective intervention for dementia? A meta-analytic review of literature. Journal of Music Therapy, 36, 2-15.

Folk Psychology, Gender, and Autism

Our species’ survival and reproduction has long depended on our ability to understand and predict the behaviors of the elements of our environment, and the world we live in seems to contain two fundamentally different kinds of entities: On one side there are the ordinary objects that behave according to causal physical laws, like falling boulders or flowing bodies of water. On the other hand there are humans and animals which seem to get up and move by their own volition and act in accord with underlying intentions, beliefs, and desires. In order to negotiate this duality in our environment, it makes sense that we might have evolved two corresponding representational subsystems. Neurophilosphers refer to our intuitive, separate cognizing of things and people as "folk physics" and "folk psychology". Examining this distinction may shed light on observed gender differences in sociality, as well as the sexed nature of neurodevelopmental disorders like autism.

Neurological evidence has been found to support the theoretical distinction made between folk psychology and folk physics. There are a set of brain regions referred to as “the social brain” that have been found to increase in activity when we represent the appearances, actions, and thoughts of living things. These include the tempoparietal junction, thought to represent actions perceived to be goal directed, the amygdala, implicated in responding to emotionally charged stimuli, and the medial prefrontal cortex, which has a role in representing others’ mental states (Farah & Heberlein, 2006). Collectively, the structures of the social brain constitute our folk psychological sense: they enable us to recognize when we are dealing with other minds as distinct from mere objects, to understand their actions as motivated by intentions, emotions, and beliefs, and subsequently to act more rationally ourselves. When these structures are not as active we instead rely on folk physics—apprehending the objects of our perception more purely in terms of their bare sensory features, like Newtonian motion in space.

Current research suggests that women on average have more folk psychological aptitude than men, who excel in folk physics. That is, women develop a social theory of mind faster and to a higher proficiency than men, who instead show greater aptitudes in spatial and mechanical representation.  Specifically, studies have shown that men lag behind women in the acquisition of certain social skills and language abilities and perform worse on tests measuring “mindreading” abilities, or levels of empathetic cognition, but outperform women in tasks more oriented towards the physical, such as spatial reasoning, visuospatial acuity, and motor coordination (Baron-Cohen, 1999). A further study has also been able to explain differences in men and women’s career preferences in terms of differential psychological orientation to things vs. people (Beltz, Swanson, & Berenbaum, 2011), with women tending to occupy more people-oriented careers. Many hypothesize such gender differences to be the result of masculinization of the brain in response to prenatal exposure to androgens like testosterone in (typically) the male embryo.

Potentially, Autism Spectrum Disorder (ASD) may be reconceived along the lines of the preceding discussion on gender, folk psychology, and folk physics. 75% of all individuals with ASD are male, and differences in brain anatomy and social development which parallel those observed between the sexes are even more apparent between autistic and "neurotypical" individuals (Baron-Cohen, 1999). For example, while men typically have larger brain sizes but smaller corpus callosa than women, people with ASD have the largest mean brain sizes and smallest corpus callosa of all. Autistic individuals also show the greatest delays in language acquisition, yet often possess exceptional spatial and mathematical reasoning abilities.  Furthermore, functional activation of the social brain in autistic individuals is diminished relative to their neurotypical counterparts (Farah & Heberlein, 2006). As a consequence of autistic individuals' resultant diminished capacity to represent beliefs and intentions, they often have difficulty understanding why people act as they do, and may fail to act according to social expectations by treating people more bluntly and like objects than others might. Together, these findings suggest that typical masculinization of the brain may predispose one to develop ASD, explaining the 3:1 :: male:female ratio of autistic individuals.

The following video from a 1944 study by Heider & Simmel illustrates how when things move like living creatures rather than dumb, physically determined matter, we automatically find ourselves attributing to them goals and psychological states: 

When prompted to describe the video, individuals with ASD are less likely to use as deeply intentional language as neurotypical individuals, revealing a less developed folk psychological sense. Thus, we might view autism as a hyper-masculinization of the brain and a strong orientation to things rather than people. In this way, relative ability in folk physics and folk psychology may be taken as measures on a continuum of masculinization of the brain, with ASD being a part of the extreme male end.

References:

Baron-Cohen, S. (1999). The extreme male-brain theory of autism The MIT Press, Cambridge, MA. Retrieved from http://search.proquest.com/docview/619398505?accountid=7379

Beltz, A. M., Swanson, J. L., & Berenbaum, S. A. (2011). Gendered occupational interests: Prenatal androgen effects on psychological orientation to things versus people. Hormones and Behavior, 60(4), 313-317. doi:http://dx.doi.org/10.1016/j.yhbeh.2011.06.002

Farah, Martha J. & Heberlein, Andrea S. (2006). “Personhood” Farah 321-338.

What can Parkinson’s disease teach us about sex differences?

You probably have heard of Parkinson’s disease, a neurodegenerative disorder that affects motor ability, usually in older people. It is known for causing symptoms such as tremors, slowing of movement, and muscle stiffness. People with Parkinson’s can also have many other symptoms, such as  anxiety, trouble sleeping, dementia, trouble swallowing, constipation, and depression [1]. Parkinson’s is linked to losing neurons in the brain that produce dopamine, a neurotransmitter that your body uses to signal between neurons, especially in pathways that involve motivation and reward seeking. The area of the brain that loses dopamine during Parkinson's disease is called the substantia nigra, which, unsurprisingly, helps control movement.

As you can see in the graph below, Parkinson’s disease is much more common in men than in women. Interestingly, a study conducted by Haaxma et al. has found that there are also sex differences in symptom progression [2]. According to this study, women are more likely to develop a tremor as their initial symptom, while men are more likely to develop rigidity first. This is important because tremor dominant Parkinson's is usually characterized by a slower and milder progression of the disease. The study also found that on average, women are about two years older when they are diagnosed, and more dopamine was lost in women before symptoms developed. 

Figure 1: Age and gender of Parkinson’s diagnosis in the U.K. Fewer women are diagnosed with Parkinson's and they tend to be diagnosed at a later age (bathnes). 

The researchers explained that these differences could be caused by a neuroprotective effect of a female sex hormone, estrogen. This means that the presence of estrogen helps prevent, or at least delay, the development of Parkinson's disease. Supporting this, they found that among women with children, the more children they had, the older the average age of diagnosis. Estrogen levels are extremely high during pregnancy, so more children means more estrogen exposure during the women's life. Also, the age of diagnosis correlated with a longer fertile life span (amount of time between first period and menopause). A longer fertile life span indicates that the women were exposed to a higher level of estrogen for more years, because estrogen levels decrease during menopause. Both of these findings could mean that more estrogen means more protection against Parkinson’s disease.

The neuroprotection of estrogen against parkinson’s disease points to a possible link of estrogen and dopamine activity, possibly by estrogen preventing toxins from being transported to the dopamine nerve terminal [3]. In fact, dopamine levels have been shown to be higher in female than in male rats [4]. Because dopamine is involved in pathways of reward seeking, arousal, and attention, this trend has been used to explain many sex differences, such as the fact that males have higher rates of ADHD and alcohol dependence. It’s good to remember that anything to do with the brain is probably too complex to attribute just to one hormone or neurotransmitter. Sex differences in Parkinson’s disease are probably way more complicated than just an estrogen-dopamine connection. However, it is important to study potential causes, however partial, because these can be used as targets in developing treatments.

Fun fact: If you are male, and are feeling jealous of estrogen’s neuroprotective effects against Parkinson’s, try drinking coffee. Caffeine intake has shown to decrease the likelihood of developing Parkinson’s in men (but not in women).

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1. Gillies, G.E., Pienaar, I.S., Vohra, S., and Qamhawi, Z. 2014. Sex differences in parkinson's disease. Front Neuroendocrinol 35: 370-384.

2. Haaxma, C.A., Bloem, B.R., Borm, G.F., Oyen, W.J., Leenders, K.L., Eshuis, S., Booij, J., Dluzen, D.E., and Horstink, M.W. 2007. Gender differences in parkinson's disease. J Neurol Neurosurg Psychiatry 78: 819-824

3. Dluzen, D.E. 2000. Neuroprotective effects of estrogen upon the nigrostriatal dopaminergic system. J Neurocytol 29: 387-399

4. Walker, Q.D., Rooney, M.B., Wightman, R.M., and Kuhn, C.M. 2000. Dopamine release and uptake are greater in female than male rat striatum as measured by fast cyclic voltammetry. Neuroscience 95: 1061-1070