Cristiano Batista, PhD – Brain Blogger Health and Science Blog Covering Brain Topics Wed, 30 May 2018 15:00:03 +0000 en-US hourly 1 Familial Hemiplegic Migraine – Within and Beyond Genes Mon, 10 Jun 2013 11:00:02 +0000 Migraine is a common, disabling, and highly prevalent disorder of neurovascular origin, leading to a diminished quality of life in both those affected and their relatives. It’s not an uncommon disorder either, affecting between 12% and 15% in most populations. But what do we understand of migraine’s genetic and non-genetic causes?

Migraine attacks are characterized by a throbbing, often unilateral, headache, accompanied by symptoms such as nausea, vomiting, and sensitivity to light and sound. In about one third of patients, the headache is preceded by an aura phase, consisting of visual and sometimes sensory symptoms, known as migraine with aura (MA) rather than migraine without aura (MO). Migraine is also defined by the recurrence of attacks. As things stand, it is largely unknown why migraine patients suffer so many attacks.

Migraine episodes seem to be triggered by specific events, when a certain internal threshold is reached which the nervous system cannot cope with. Internal and environmental factors such as hormonal, emotional, nutritional, physiological or weather changes may act as triggers, leading to the activation of several pathophysiological mechanisms. However, pathophysiology of migraine is still being widely discussed since it is still not well understood.

Migraine clusters in families and it is well established that it has a strong genetic component. But unraveling the genetic determinants for the common forms of migraine has been challenging, because of its high prevalence and complexity, and because both genetic and environmental factors are involved.

However, genetic studies of familial hemiplegic migraine (FHM), a monogenic subtype of MA have identified three genes of importance. All of these genes code for ion transporters: one is a calcium channel subunit gene (CACNA1A), one is a sodium potassium pump subunit gene (ATP1A2), and one is a sodium channel subunit gene (SCN1A).

FHM is a rare form of migraine with aura characterized by reversible motor weakness (hemiparesis). With the exception of motor weakness, FHM episodes are similar to MA. Typically, at least three or four aura symptoms occur during an FHM attack (frequently in the temporal order: visual, sensory, motor, aphasic). To be considered as familial, at least one first or second degree-relative must have also hemiplegic migraine.

The familial clustering of migraine is largely assessed by calculation of relative risk (RR), although twin studies have also been reported. Methodological differences have provided variations in familial aggregation results, evaluated by calculation of RR, ranging from 1.5 to 11.8.

RR estimations suggest that familial factors — environmental and/or genetic — account for less than half of all cases, and that RR is higher in families of affected relatives. A pivotal study showed that there is an increased disease risk for relatives, with first-degree relatives of those with MO having 1.9 times the risk of MO and 1.4 times the risk of MA; while first-degree relatives of those with MA have nearly 4 times the risk of MA but no increased risk of MO. Earlier onset and greater severity of migraine are associated with higher familial aggregation.

Another intriguing question that has been addressed is how characteristics such gender can influence RR estimation. In addition, higher risks have also been shown among siblings from three-generation families with MA, when compared to families with fewer generations. One study presented young age, female gender, no education, familial history and high workload as factors of increased risk for migraine. Therefore, despite its name, familial hemiplegic migraine is likely to be influenced by different genetic and non-genetic factors.


Hansen JM, Hauge AW, Ashina M, & Olesen J (2011). Trigger factors for familial hemiplegic migraine. Cephalalgia : an international journal of headache, 31 (12), 1274-81 PMID: 21784774

Montagna P (2008). The primary headaches: genetics, epigenetics and a behavioural genetic model. The journal of headache and pain, 9 (2), 57-69 PMID: 18345478

Pelzer N, Stam AH, Haan J, Ferrari MD, & Terwindt GM (2013). Familial and sporadic hemiplegic migraine: diagnosis and treatment. Current treatment options in neurology, 15 (1), 13-27 PMID: 23203776

Pietrobon D (2007). Familial hemiplegic migraine. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 4 (2), 274-84 PMID: 17395138

Stovner LJ, Zwart JA, Hagen K, Terwindt GM, & Pascual J (2006). Epidemiology of headache in Europe. European journal of neurology : the official journal of the European Federation of Neurological Societies, 13 (4), 333-45 PMID: 16643310

Image via Evgeny Atamanenko / Shutterstock.

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Exercise for Depression – A Gold Standard Therapy Wed, 08 May 2013 11:00:18 +0000 Depression has become a common medical issue worldwide. Conventional treatments, generally, have not been effective in preventing recurrence of this condition. SSRIs can take months to provide a beneficial effect. Adverse side effects of antidepressant medications are a further concern, based on individual physical and mental health status. Additionally, in order to achieve remission, the most depressed patients require two or more different treatments.

A number of studies have shown exercise to be beneficial in the treatment of depression or depressive symptoms. Further, exercise has remarkable positive, and few negative effects on other disorders. From a physical standpoint, exercise engagement may improve hippocampal volume, pre-frontal cortex blood flow, and increase brain mediators such as brain-derived neurotrophic factor (which may be a key marker of depression).

With several other diseases, there is a concern regarding the effectiveness of different types of exercises: resistance or aerobic. However, in the context of treating depression and its symptoms, research shows that little difference exists between them, making  the prescription far easier to physicians and the engagement almost limitless to patients.

Moreover, major depression is now well recognized as a risk factor for some of the most serious chronic diseases such as cardiovascular disease and diabetes, and similar in potency with traditional risk factors. Therefore, exercise prescription as a medical treatment would result not only in the improvement of depression, but also in preventing the occurrence of other diseases.

Vitally, data from several studies have shown exercise to be just as effective as medication in the treatment of depressive disorders. Furthermore, engaging in regular physical activity can reduce medication dependence. Even more importantly, other studies have demonstrated that exercise is more effective than medication in preventing relapse of the disease. It is also well established that additional benefits of exercise to individuals suffering from depression include reduced moodiness, better attitude, improved outlook, increased self-confidence, and enhanced mental well-being.

While the benefits of exercise as a depression treatment are undeniable, it may also have some barriers, for example intimidation, cost, or physical limitation. Therefore it is necessary to develop strategies for successful compliance by the patient, setting reasonable goals and preparing them for setbacks or obstacles.

Whether exercise is used as a first-line treatment or as a supplement to medication or psychotherapy, patients have virtually nothing to lose and much to gain from adopting an exercise approach in dealing with the symptoms of depression. Therefore, beyond the documented and aforementioned benefits of exercise on overall health, it is also time to more avidly begin considering exercise as a therapeutic strategy for patients suffering from depression.


Berlin AA, Kop WJ, & Deuster PA (2006). Depressive mood symptoms and fatigue after exercise withdrawal: the potential role of decreased fitness. Psychosomatic medicine, 68 (2), 224-30 PMID: 16554387

Blumenthal JA, Sherwood A, Babyak MA, Watkins LL, Smith PJ, Hoffman BM, O’Hayer CV, Mabe S, Johnson J, Doraiswamy PM, Jiang W, Schocken DD, & Hinderliter AL (2012). Exercise and pharmacological treatment of depressive symptoms in patients with coronary heart disease: results from the UPBEAT (Understanding the Prognostic Benefits of Exercise and Antidepressant Therapy) study. Journal of the American College of Cardiology, 60 (12), 1053-63 PMID: 22858387

Booth FW, & Laye MJ (2010). The future: genes, physical activity and health. Acta physiologica (Oxford, England), 199 (4), 549-56 PMID: 20345416

Pilu A, Sorba M, Hardoy MC, Floris AL, Mannu F, Seruis ML, Velluti C, Carpiniello B, Salvi M, & Carta MG (2007). Efficacy of physical activity in the adjunctive treatment of major depressive disorders: preliminary results. Clinical practice and epidemiology in mental health : CP & EMH, 3 PMID: 17620123

Rozanski, A. (2012). Exercise as Medical Treatment for Depression Journal of the American College of Cardiology, 60 (12), 1064-1066 DOI: 10.1016/j.jacc.2012.05.015

Rozanski A, Blumenthal JA, Davidson KW, Saab PG, & Kubzansky L (2005). The epidemiology, pathophysiology, and management of psychosocial risk factors in cardiac practice: the emerging field of behavioral cardiology. Journal of the American College of Cardiology, 45 (5), 637-51 PMID: 15734605

Image via Dmitry Berkut / Shutterstock.

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On the Path to Preventing Alzheimer’s Disease Sat, 23 Mar 2013 11:00:35 +0000 Nearly 30 million people worldwide are affected by the Alzheimer’s disease (AD) and the most recent estimates indicate that this number will quadruple within the next 40 years. The concern increases as AD is the leading cause of dementia, and, so far, there is no effective treatment to slow the progression or delay the onset of this malady.

It is known that AD is a disease of protein aggregation mainly involving accumulation of beta-amyloid (Abeta) in the brain, a peptide of 36-43 amino acids, mostly in the form of tau fibrils and amyloid plaques.

Currently, 10 genes have been identified as influencers of the AD’s risk. The autosomal dominant mutations in the precursor protein (APP) and presenilin (PSEN) genes encoding amyloid precursor protein and the presenilin proteins are accepted as the causes of the hereditary forms of AD.

Most of these mutations increase total Abeta or Abeta42 production, leading to an increased amyloid plaque formation — a pathological hallmark of AD. Thus, Abeta lowering has become a vital therapeutic goal, with various paths within antibodies against Abeta (anti-Abeta) being tested. Over the past few years, the research has been mostly developed after the detection of disease, pursuing a means of lowering the production of the Abeta by inhibiting the enzymes responsible for the generation of this peptide, preventing the formation of Abeta aggregates, and increasing the rate of Abeta clearance from the brain. Presently, several different anti-Abeta therapies are in clinical trials worldwide. Although some modest reductions in plaque burden have been achieved, no obvious clinical benefit or arrest in the progression of cognitive decline was further confirmed.

Given this lack of success, the Alzheimer’s research community has moved toward a consensus that diagnosing and treating the disease before overt symptoms may be more advantageous to slow the disease’s pathogenic process. Among this novel approach, has been particularly suggested that pre-symptomatic individuals with deterministic mutations in APP, PSEN1, or PSEN2 could undergo treatment with an anti-Abeta agent before the expected age of onset of frank symptoms. Individuals with brain amyloid deposits (detected by positron emission tomography) exceeding normal thresholds, as well as low cerebrospinal fluid Abeta 42 levels, may respond to an anti-Abeta treatment.

The Dominantly Inherited Alzheimer Network (DIAN) investigators showed that the changes in cerebrospinal fluid levels of Abeta42 that accompany Abeta deposition are possible to be detected nearly 25 years before the symptom’s onset. This suggests that, in persons with mutations for dominantly inherited AD, the primary prevention with anti-Abeta agents might need to begin, at least, 25 years before the earliest signs.

Following this lead, a prevention trial with an anti-Abeta in around 300 presymptomatic individuals with presenilin mutations has been approved to be carried out by an academic consortium sponsored in part by the United States National Institutes of Health (NIH) and a biotechnology company. Still in the domain of the autosomal dominant AD, another secondary prevention trial has been proposed to the NIH by the Dominantly Inherited Alzheimer Network, the Alzheimer’s Association and some pharmaceutical companies.

Nevertheless, beyond these prevention trials in presymptomatic participants with rare, dominantly inherited AD, there is an intention to initiate similar studies in presymptomatic persons with common, late-onset (so-called sporadic) AD. Hereupon, another secondary prevention trial of an anti-Abeta in sporadic AD subjects (the A4 trial) will be carried out by a consortium led by the Alzheimer’s Disease Cooperative Study group funded by NIH. They recently announced the selection of Eli Lilly’s monoclonal antibody solanezumab as the first therapeutic drug to be evaluated.

Will this novel approach help overcoming this terrible disease? We shall see.


Bateman RJ, Aisen PS, De Strooper B, Fox NC, Lemere CA, Ringman JM, Salloway S, Sperling RA, Windisch M, & Xiong C (2011). Autosomal-dominant Alzheimer’s disease: a review and proposal for the prevention of Alzheimer’s disease. Alzheimer’s research & therapy, 3 (1) PMID: 21211070

Gandy S (2012). Lifelong management of amyloid-beta metabolism to prevent Alzheimer’s disease. The New England journal of medicine, 367 (9), 864-6 PMID: 22931321

Golde TE, Schneider LS, & Koo EH (2011). Anti-a? therapeutics in Alzheimer’s disease: the need for a paradigm shift. Neuron, 69 (2), 203-13 PMID: 21262461

Holtzman DM, Morris JC, & Goate AM (2011). Alzheimer’s disease: the challenge of the second century. Science translational medicine, 3 (77) PMID: 21471435

Holtzman DM, Goate A, Kelly J, & Sperling R (2011). Mapping the road forward in Alzheimer’s disease. Science translational medicine, 3 (114) PMID: 22190237

NIH Fogarty International Center. First-ever Alzheimer’s prevention trial to take place in Colombia. 2012.

Selkoe DJ (2012). Preventing Alzheimer’s disease. Science (New York, N.Y.), 337 (6101), 1488-92 PMID: 22997326

Image via Sebastian Kaulitzki / Shutterstock.

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