440 Am J Exp Clin Res, Vol. 9, No. 1, 2022 http://www.ajecr.org American Journal of Experimental and Clinical Research Am J Exp Clin Res 2022;9(1):440-446 Review Article Migraine headaches as a preliminary symptom for cognitive decline Ahad Hasan Syed Hasani*, Melika Faani Shahid Beheshti University of Medical Sciences, Student Research Committee, Iran Abstract. Migraine headaches are amongst the most prevalent neurological disorders. Dementia on the other hand, is classified as a neurodegenerative disease with symptoms of slow progressive memory loss and cognitive decline. Identifying the preliminary signs and symptoms of such neurological diseases are crucial in preventing the onset of such disease. In this review article, we analyzed several studies signifying and or contradicting the claim of migraine headaches as a preliminary symptom of dementia. This can ultimately aid in focusing specific treatments to reduce the risk of patients developing dementia. Databases including Google Scholar, PubMed, and NCBI were searched by using keywords including migraine, dementia, association, symptom, etc. This study analyzed articles that were sought through various databases. Several studies signified a positive correlation between the two diseases. Studies that contradicted this claim, were vastly outnumbered by studies that depicted the claim to be true. It was eminent that preventing and treating migraine headaches in patients with a high-risk profile of dementia should be considered and studied more extensively. Keywords: Migraine, dementia, cognitive decline, neurodegenerative disease, headache Introduction Headaches, affect 46% of the world population [1]. They are considered as the leading cause for outpatient and emergency department visits [2]. Migraine headaches are defined as headaches lasting four to 72 hours with symptoms including unilateral location; pulsating quality; moderate to severe intensity; intensified by physical activity; occurrences of nausea, vomiting, phonophobia, and or photophobia [3]. The epidemiological burden of this disease has been observed to have a greater portion allocated to women. In a study conducted by Rebeca et al. a significant 2-fold difference was present when comparing females and males that showed symptoms consistent with Migraine [4]. Migraine headaches were also observed to have a maximum 33% prevalence in Asian countries as compared to 9% in western pacific countries such as China [3]. The variable prevalence in certain areas can be denotive of the cultural and dietary attitudes effective in causing Migraine headaches. The third most prevalent disorder that was suggested by the Global Burden of Disease study conducted in 2010 was Migraine headaches. Currently, it is suggested that 35 million American are victims of the mental disorder and suffer from migraines in a variety of ways [2]. Migraine Headaches The pathophysiology of migraine headaches has advanced over the previous decades. Current studies now point out peripheral nerve compression and or traction as the etiology of the disease. These compressed nerves can be found throughout the head and even the neck region. Migraine, can be considered an inherited, episodic disorder that is assisted with sensitivity of the ear and light receptors. The common symptoms and complaints include a throbbing headache, nausea, and vomiting. Dizziness and light headedness can also be noted in patients as many complain having a feeling of being drunk or have stepped off a boat. The nervous pathways allocated to cerebral pain include the ophthalmic branch of the trigeminal nerve (CN V), a sensory nerve that receives input from the orbital region. The facial nerve also consists of sensory fibers that perceive pain from the maxillary area [5]. Dementia Dementia, a general term which incorporates several diseases that cause a loss of function or cellular death in the Central Nervous System (CNS).As studies suggest, the behavior, memory and even personality of the patient are susceptible to change. Finding the main etiology and or the reason for such neurodegeneration can aid in treating the patient in a proper and rapid manner, limiting the adverse effects it could have on the patient. The chances of reversing the neurodegeneration and trauma in dementia is minimal and can be allocated to 9-11% of cases [6]. There are several forms of dementia, most of which are based on their primary cause, which include Alzheimer’s disease, Vascular dementia, Frontotemporal dementia, dementia with Lewy bodies, and mixed dementia [7, 8]. All ___________________________________________________________ * Corresponding author: Dr. Ahad Hasan Syed Hasani (ahad.sbmu@gmail.com) http://www.ajecr.org/ 441 Am J Exp Clin Res, Vol. 9, No. 1, 2022 http://www.ajecr.org types of dementia ultimately lead to neurodegeneration and an inability to fully use one’s cognition. Memory loss, personality change and an inability to properly process environmental phenomena are severe symptoms of dementia which if not treated can possibly lead to a shorter life time [9-11]. The Association between migraine headaches and dementia has been focused on in many studies. However, a vague conclusion for migraine headaches as a preliminary symptom of dementia still exists as many factors must be taken into consideration [12]. In this study, we review the existing literature for commonalities and relations between both mental discrepancies. Materials and Methods Search strategy included identifying Mesh terms and Keywords (i.e., Migraine, Dementia, Association, Symptom, etc.) and conducting an advanced search in databases such as Google Scholar, PubMed, and NCBI. Results were screened based on criteria and were selected for data extraction. Results and Discussion Migraine is considered to be a recurrent primary headache disease [93]. Several studies have demonstrated that migraine prevalence can range from 6 % to 13%. This headache disorder affects nearly 18% of the women population as well as 6% of the male population [41]. Furthermore, it has a pulsating attribute and usually lasts from a couple hours to 3 days [94]. Migraine can cause vomiting, nausea, sensitivity to smell and light as well as aura [95, 96]. Also, physical activity has been observed to worsen the situated pain [97]. This as a result, leads to limitations in a vast variety of activities, ranging from everyday chores to profession related tasks. Moreover, approximately 12% of individuals suffer from migraine, including 6% of men as well as 18% of women [98]. In other words, it is the third most common and prevalent global disease [108]. Nevertheless, both environmental and genetic factors trigger migraine [99]. It can be induced by hormonal changes in the body, for instance, girls tend to have more migraines after puberty as significant hormonal changes are eminent [107]. It is estimated that migraine is seen more in women as compared to men [100, 101]. Nonetheless, medications such as beta blockers, topiramate and sodium valproate are efficient in decreasing the pain [102]. The tension type headache (TTH) is considered the most prevalent kind of primary headache which comes along with mental tension and pain in the cerebral area. Also, this type of headache is not correlated to physical activity as it does not change when heart rate, blood pressure and or endocrine stimulation occurs [13]. This is true whilst the intensity of migraine is more severe than TTH [14]. On the other side recent evidence demonstrate an association between headache and dementia, while most studies are circulated around migraine [15-22]. Dementia is considered to be one of the most prevalent types of neurodegenerative diseases that has a huge effect on the quality of life [23]. Its symptoms are variable and include slow memory impairment, headache, and change in personality etc. [24]. Nearly 24.3 million people have been diagnosed with dementia globally, this number is expected to jump to 81.1 million people by the year 2040 [25]. There are several kinds of dementia that have been identified. Amongst them, non-vascular dementia (such as Alzheimer's disease (AD) is known to be the most common type, which makes up 80–90% of present cases [26, 27]. The risk of dementia increases with age, a variety of comorbidities, including hypertension, diabetes, dyslipidemia, heart failure (HF), ischemic heart disease (IHD), chronic obstructive pulmonary disease (COPD), head injury, depression, Parkinson’s disease and stroke [28- 32]. The association between somatic symptoms, like headaches, and clinical symptoms, is assumed to be more than a simplistic coincidence [33]. Several cohort studies have previously suggested a connection between migraine and dementia [34, 35]. Nonetheless, the results of other studies on migraine and cognitive disorders were controversial and mixed, with some of them failing to find any direct association. In most countries, Alzheimer is assumed to be the most common cause of dementia in senior citizens [36]. Women tend to contract Alzheimer’s disease approximately two times as much as men do. Which is induced by the fact that women tend to have much more life expectancy than men [37]. Numerous analyses imply that incidence rates are higher in older patients. Neuroprotective precautions along with estrogen effect on b-amyloid formation and basal forebrain cholinergic neurons appear relevant to the treatment as well as Alzheimer’s disease prevention. There is insignificant clinical support concerning whether estrogen has a part in treating Alzheimer or not, such as a year-long research conducted over 120 hysterectomized ladies in United States, where the interventions were unopposed conjugated equine estrogen [38] and or a 7-month research of 117 females in France, where the intervention applied was transdermal estradiol along with, oral micronized progesterone [39]. Primary results of WHIMS published in 2003 signified dementia as primary cause [40]. Nevertheless, migraines increase the risk of brain lesions statistically [42]. More recent research has associated brain lesions to incidence of cognitive decline and dementia. As a result, migraines might signify a positive correlation and a progressive brain disease [43]. Several studies have also contradicted such, and have shown no significant link between migraine and dementia [44, 45, 46]. This is, while others, proved cognitive function to decline amongst individuals with migraine [47, 48, 49]. A study from a valid national database showed that migraines end up in a higher risk of developing dementia in future by adjusting for hypertension, diabetes, depression and head injury, CAD, all of which, are able to boost the risk of dementia in patients suffering from migraine [50]. In Asia, migraine headaches are the most common kind of headache that is diagnosed in walk in clinics [51]. The prevalence of migraine headache is 6.5% in men and 18.2 % in women in the USA, as well as 7.5% and 16.8 %, respectively in Europe [52, 53]. People with migraine exhibit a high risk of vascular diseases due to the fact that migraine headaches, in nature, are a neurovascular dysregulation disorder [54, 55]. Nevertheless, http://www.ajecr.org/ 442 Am J Exp Clin Res, Vol. 9, No. 1, 2022 http://www.ajecr.org a theory about migraine mechanism demonstrates that the abnormality in electrophysiological activities of the cortex is of great importance in migraineurs [56, 57]. Epilepsy is another disease associated with the brain function, which is more severe than migraine, with a 0.5-1% prevalence rate globally [58, 59]. Seemingly, epilepsy and migraine have been assumed to be comorbid diseases for decades [60, 61]. It is estimated that 46 million individuals have dementia worldwide [62]. As the population ages, incidence rates of dementia may continue to rise [63]. However, there is no effective treatment for this condition. Investigations have shown that migraine affected approximately 1.04 billion people worldwide [64]. The overlap of biological mechanisms between dementia and migraine, including brain microstructural changes, neuro-inflammation, and subcortical white matter disorders [65-68]. This shows that migraine might elaborate the risk of dementia. On the other hand, recent studies that claim a link between dementia and migraine demonstrated inconsistent connections [69, 70]. Although many researches have suggested a possible association between dementia and migraine, there are concerns that these links be due to unmeasured, confounding or diagnostic bias. Although, the MGRS was significantly related to migraine (p < 0.0001), there was not any association between migraine and dementia [71]. Nevertheless, many studies found variable results such as Chabriat et al. [72] in a case study, where 8 cases of Dementia were collected as case reports and were analyzed to signify various symptoms. All of 8 patients were related as primary, secondary, or tertiary family. Each patient had separate diagnosis at various times and were cared for separately. Case reports from all 8 patients were summarized and compared in terms of symptoms such as headaches, fever, neurological disorders and etc. This study specifically focused on the outcome of common symptom findings amongst many patients. The Migraine headache was observed in 6 of 8 cases, which was included using IHS classification criteria for the disease. The patients were remarkable for the great frequency of throbbing headaches. In all but one patient focal neurological symptoms were present preceding headaches, gradually developing over a course of 5 to 15 minutes. 7 of 8 patients were found to have nausea and vomiting alongside their headaches. Thus, such symptoms were seen in almost all of 8 patients with diagnosis of dementia. Migraine headaches were noted as a cause for many of their symptoms including nausea, vomiting as well as neurological defects [72]. Finsterer [73], in a review article sought to observe cognitive decline alongside mitochondrial disorders. Respiratory chain disorder (RCD) was the prominent subject of discussion and was analyzed in different aspects. Various symptoms including Dementia, ataxia, migraine headaches and etc. were observed in most cases. RCD was prominent alongside other diseases such as Leigh syndrome, KS syndrome, and MELAS. As discussed in the review article, RCD diagnosis was based off symptoms such as cognitive impairment, neurological impairments, as well as dementia. A major tip off symptom for RCD diagnosis was considered to be migraine headaches with improper and short stature. A vague but present bond was noted between dementia and migraine headaches [73]. The most common cause for dementia is Alzheimer’s disease [74]. Thus, the comorbidity profile in dementia with Lewy bodies (DLB) compared to Alzheimer’s disease was studied by Fereshtehnejad et al. in a detailed format [17]. Information and data were sourced from the Swedish dementia registry as well as the National Patient Registry. This linkage study over saw 634 patient profiles with DLB and 9161 patient profiles diagnosed with AD between the years 2007-2021. Migraine diagnosis as a symptom was defined according to ICD version 10 codes. Taking into factor the timing of events, migraine and depression were more commonly significant preliminary to the diagnosis of DLB. Migraine headaches were seen more prominently in the DLB group as compared to the AD group. However, a minimal amount of 6 patients of the 634 were seen to have such headaches. Alongside migraine headaches, depression, stroke, and cerebrovascular infarctions were noted simultaneously. Consecutively, post diagnosis onset of migraine headaches was noted in none of the 634 patients. The correlation between migraine and dementia was observed in the DBL group. However, the strength of correlation can be debated as only 1 in 100 patients were considered to have migraine headaches before dementia onset [75]. Similarly, Lee et al. conducted a case-control study on 11,438 dementia patients. Diagnostic criteria were based off International Classification of Disease-10 (ICD- 10F00). Patients aged 60> were considered for the study due to ethical research purposes. The results signified that the average duration from significance of migraine until dementia diagnosis was 58.6 months compared to 60.8 months in the control group. Respectively, the rate of occurrence for migraine diagnosis preliminary to dementia was higher in the cases (7.7%) as compared to the control (6.3%) group. Like other studies conducted, it was also seen that dementia diagnosis was greater in women than in men. It was observed that the risk of dementia was higher in patients that were diagnosed with migraine headaches after matching for age, sex, income, region of residence and past medical history. Women above the age of 70 showed the greatest association between migraine and dementia. It was concluded that dementia rates could possibly be decreased by controlling migraine headaches before onset of dementia symptoms [76]. In a meta-analysis between 1966 and 2004, migraine headaches were proven to be a risk factor for ischemic stroke [77]. White matter hyperintensities were seen to be more prevalent in patients diagnosed with migraine headaches as compared to the general population [78-81]. Various studies showed migraine to have a negative effect on cognitive skills including attention, verbal ability, memory and psychomotor ability [81-87]. On the other hand, certain studies proved no correlation between migraine and cognitive decline and thus contradicting the argument [81, 87-92, 103]. Another population-based study that was noted by Koen was significant of no difference in cognitive tests on 536 migraineurs [81, 103]. As seen in most studies, dementia and migraine can be allocated to CADASIL as an intermediating factor. The http://www.ajecr.org/ 443 Am J Exp Clin Res, Vol. 9, No. 1, 2022 http://www.ajecr.org thickening of arteries can cause migraines, leukoencephalopathy, small deep and subcortical infarcts and ultimately lead to dementia [104, 105]. Recurrent migraines can be seen in mitochondrial myopathies, encephalopathy, lactic acidosis and stroke like episodes. Mitochondrial disorders such as Leber’s hereditary optic neuropathy, myoclonic epilepsy are also significant for migraine headaches [105, 106]. Research by Le Pira et al. [105] signified that migraineurs had a decrease in short- and long-term memory recall. The migraine groups self-reported problems with concentration, comprehension, and communication shortly after an onset of their migraine headaches. Signifying mild symptoms of dementia [105]. In a population-based study using data from the Nord- Trondelag Health Surveys conducted between the years 1995-1997 (HUNT2) and 2006-2008 (HUNT3) the relation between migraine and dementia was analyzed by Røttereng et al. In the study conducted years ago, Questionnaires consisting of more than 200 health-related items were presented to citizens of Nord-Trondelag County in Norway. Using the dementia registry, 1332 dementia patients were distinguished and identified. Diagnostic criteria for dementia were the same as national and international standards. After adjusting for age, gender, education, smoking, hospital anxiety and depression scale (HADS) and severe comorbid conditions, headaches were more persistent and more likely to be reported in HUNT2 from those who later on were associated with the Dementia Registry. This signified a direct and positive correlation between dementia and preceding headaches. It was also discussed that it was less likely for someone to report headaches that later were confirmed non-demented. In their other studies including 378 cases of dementia, patients with headaches proved to have higher risks for dementia onset [107, 108]. Multiple silent or sub-clinical lacunar strokes are amongst the findings in patients diagnosed with dementia. A hypothesis presented by Arnold Eggers, signified that a similar presence of silent cryptogenic strokes were seen in migraine patients. Thus, pointing out another relationship between the 2 diseases [109]. In a similar review article, the relationship between dementia and migraine was sought. The researchers deduced that migraines with or without aura can ultimately lead to cognitive decline. It was noted that the frequency of migraine headaches is also a contributing factor to onset of dementia. In some studies patients that signified migraine headaches had a higher chance of Alzheimer’s disease and dementia. However confounding factors including non-migraine headaches such as cluster and TTH headaches were seen to be similarly causal in the dementia patients [110-112]. Conflict of Interest The authors declare no conflicts of interest. References 1. Stovner L, et al. The global burden of headache: a documentation of headache prevalence and disability worldwide. Cephalalgia 27:193-210, 2007. 2. Olla, D., et al., Migraine Treatment. Clinics in Plastic Surgery 47:295-303, 2020. 3. Ha, H. and A. Gonzalez, Migraine Headache Prophylaxis. Am Fam Physician 99:17-24, 2019. 4. Burch, R.C., D.C. Buse, and R.B. Lipton, Migraine: Epidemiology, Burden, and Comorbidity. Neurol Clin 37:631-649, 2012. 5. Goadsby, P.J., Pathophysiology of migraine. Annals of Indian Academy of Neurology 15(Suppl 1):S15-S22, 2012. 6. Rone-Adams, S., et al. Understanding dementia: Etiology, communication, and exercise intervention 35:88- 98, 2013. 7. Anstey, K.J., et al. Estimates of probable dementia prevalence from population-based surveys compared with dementia prevalence estimates based on meta-analyses. BMC Neurol 10:62, 2010. 8. Barry, P.P. and M.A. Moskowitz, The diagnosis of reversible dementia in the elderly. A critical review. Arch Intern Med 148:1914-1918, 1988. 9. Joling, K.J., et al. Time from diagnosis to institutionalization and death in people with dementia. Alzheimers Dement 16:662-671, 2020. 10. Ikeda Y, Han G, Maruta M, Hotta M, Ueno E, Tabira T. Association between daily activities and behavioral and psychological symptoms of dementia in community- dwelling older adults with memory complaints by their families. Int J Environ Res Public Health 17:6831, 2020. 11. Cipriani, G., et al., Personality and dementia. J Nerv Ment Dis 203:210-214, 2015. 12. Kostev, K., J. Bohlken, and L. Jacob, Association Between Migraine Headaches and Dementia in More than 7,400 Patients Followed in General Practices in the United Kingdom. J Alzheimers Dis 71:353-360, 2019. 13. Jensen R. Diagnosis, epidemiology, and impact of tension-type headache. Curr Pain Headache Rep 7:455-459, 2003. 14.Crystal SC, Robbins MS. Epidemiology of tension- type headache. Curr Pain Headache Rep 14:449-454, 2010. 15. Stræte Røttereng AK, Bosnes O, Stordal E, Zwart JA, Linde M, Stovner LJ, et al. Headache as a predictor for dementia: The HUNT Study. J Headache Pain 16:89, 2015. 16. Baars MA, van Boxtel MP, Jolles J. Migraine does not affect cognitive decline: results from the Maastricht aging study. Headache 50:176-184, 2010. 17. Fereshtehnejad SM, Damangir S, Cermakova P, Aarsland D, Eriksdotter M, Religa D. Comorbidity profilein dementia with Lewy bodies versus Alzheimer’s disease: a linkage study between the SwedishDementia Registry and the Swedish National Patient Registry. Alzheimers Res Ther 6:65, 2014. 18. Gaist D, Pedersen L, Madsen C, Tsiropoulos I, Bak S, Sindrup S, et al. Long-term effects of migraine on cognitive function: a population-based study of Danish twins. Neurology 64:600-607, 2005. 19. Kalaydjian A, Zandi PP, Swartz KL, Eaton WW, Lyketsos C. How migraines impact cognitive function: findings from the Baltimore ECA. Neurology 68:1417-1424, 2007. 20. Rist PM, Dufouil C, Glymour MM, Tzourio C, Kurth T. Migraine and cognitive decline in the population based http://www.ajecr.org/ 444 Am J Exp Clin Res, Vol. 9, No. 1, 2022 http://www.ajecr.org EVA study. Cephalalgia 31:1291-1300, 2011. 21. Rist PM, Kang JH, Buring JE, Glymour MM, Grodstein F, Kurth T. Migraine and cognitive decline among women: prospective cohort study. BMJ 345:e5027- e5027, 2012. 22. Rist PM, Kurth T. Migraine and cognitive decline: A topical review. Headache 53:589-598, 2013. 23. Caselli RJ. Current issues in the diagnosis and management of dementia. Semin Neurol 23:231-240, 2003. 24. Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, et al. Global prevalence of dementia: a Delphi consensus study. Lancet 366:2112-2117, 2005. 25. Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, et al. Global prevalence of dementia: 26. Morris JC. Dementia update 2003. Alzheimer Dis Assoc Disord 17:245-258, 2003. 27. Alzheimer’s Association. Alzheimer’s disease facts and figures. Alzheimer’s Dement 9:110-133, 2013. 28. Qiu C, Xu W, Fratiglioni L. Vascular and psychosocial factors in Alzheimer’s disease: Epidemiological evidence toward intervention. J Alzheimer’s Dis 20:689-697, 2010. 29. Sahathevan R, Brodtmann A, Donnan GA. Dementia, stroke, and vascular risk factors; a review. Int JStroke 7:61- 73, 2012. 30. Schram MT, Euser SM, de Craen AJ, Witteman JC, Frölich M, Hofman A, et al. Systemic markers ofinflammation and cognitive decline in old age. J Am Geriatr Soc 55:708-716, 2007. 31. Poblador-Plou B, Calderón-Larrañaga A, Marta- Moreno J, Hancco-Saavedra J, Sicras-Mainar A, Soljak M, et al. Comorbidity of dementia: a cross-sectional study of primary care older patients. BMC Psychiatry 14:84, 2014. 32. Köhler S, Buntinx F, Palmer K, van den Akker M. Depression, vascular factors, and risk of dementia in primary care: a retrospective cohort study. J Am Geriatr Soc 63:692–698, 2015. 33. Ringman JM, Romano JD, Medina LD, Rodriguez- Agudelo Y, Schaffer B, Varpetian A, et al. Increased prevalence of significant recurrent headache in preclinical familial Alzheimer’s disease mutation carriers. Dement Geriatr Cogn Disord 25:380-384, 2008. 34. Chuang CS, Lin CL, Lin MC, Sung FC, Kao CH. Migraine and risk of dementia: A nationwide retrospective cohort study. Neuroepidemiology 41:139-145, 2013. 35. Hagen K, Stordal E, Linde M, Steiner TJ, Zwart JA, Stovner LJ. Headache as a risk factor for dementia: A prospective population-based study. Cephalalgia 34:327- 335, 2013. 36. Launer LJ, Andersen K, Dewey ME, et al. Rates and risk factors for dementia and Alzheimer’s disease: results from EURODEM pooled analyses. Neurology 52:7884, 1999. 37. Barford, A., Dorling, D., Smith, G. D., & Shaw, M. (2006). Life expectancy: women now on top everywhere. BMJ 332:808, 2006. 38. Mulnard RA, Cotman CW, Kawas C, et al. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. JAMA 283:1007-1015, 2000. 39. Rigaud AS, Andre G, Vellas B, Touchon J,Pere JJ, Loria-Kanza Y. Traitement estroprogestatifen association a` la rivastigmine chez des femmes me´nopause´es atteintes de la maladie d’Alzheimer. Presse Med 32:1649-1654, 2003. 40. Shumaker SA, Legault C, Kuller L, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women’s Health Initiative Memory Study. JAMA 291:2947-2958, 2004. 41. Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M: Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache 41:646-657, 2001. 42. Kruit MC, van Buchem MA, Hofman PA,Bakkers JT, Terwindt GM, Ferrari MD, Launer LJ: Migraine as a risk factor for subclinical brain lesions. JAMA 291: 427-434, 2004. 43. Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MM: Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med 348:1215- 1222, 2003. 44. Pearson AJ, Chronicle EP, Maylor EA, Bruce LA. Cognitive function is not impaired in people with a long history of migraine: a blinded study. Cephalalgia 26: 74-80, 2006. 45. Gaist D, Pedersen L, Madsen C, Tsiropoulos I, Bak S, Sindrup S, McGue M, Rasmussen BK, Christensen K: Long-term effects of migraine on cognitive function: a population-based study of Danish twins. Neurology 64:600- 607, 2005. 46. Jelicic M, van Boxtel MP, Houx PJ, Jolles J: Does migraine headache affect cognitive function in the elderly? Report from the Maastricht Aging Study (MAAS). Headache 40:715-719, 2000. 47. Calandre EP, Bembibre J, Arnedo ML, Becerra D: Cognitive disturbances and regional cerebral blood flow abnormalities in migraine patients: their relationship with the clinical manifestations of the illness. Cephalalgia 22:291-302, 2002. 48. Mulder EJ, Linssen WH, Passchier J, Orlebeke JF, de Geus EJ: Interictal and postictal cognitive changes in migraine. Cephalalgia 19:557-565, 1999. 49. Le Pira F, Zappalà G, Giuffrida S, Lo Bartolo ML, Reggio E, Morana R, Lanaia F: Memory disturbances in migraine with and without aura: a strategy problem? Cephalalgia 20:475-478, 2000. 50. Chuang CS, Lin CL, Lin MC, Sung FC, Kao CH. Migraine and risk of dementia: a nationwide retrospective cohort study. Neuroepidemiology 41:139-145, 2013. 51. Wang SJ, Chung CS, Chankrachang S, Ravishankar K, Merican JS, Salazar G, et al. Migraine disability awareness campaign in Asia: migraine assessment for prophylaxis. Headache 48:1356-1365, 2008. 52. Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M. Prevalence and burden of migraine in the United States: data from the American migraine study II. Headache 41:646-657, 2001. 53. Stovner LJ, Zwart JA, Hagen K, Terwindt GM, Pascual J. Epidemiology of headache in Europe. Eur J Neurol 13:333-345, 2006. http://www.ajecr.org/ 445 Am J Exp Clin Res, Vol. 9, No. 1, 2022 http://www.ajecr.org 54. Scher AI, Terwindt GM, Picavet HSJ, Verschuren WMM, Ferrari MD, Launer LJ. Cardiovascular risk factors and mi- graine. The GEM population-based study. Neuro- logy 64:614–620, 2005. 55. Rodriguez-Sainz A, Pinedo-Brochado A, Sa ́ nchez- Menoyo JL, Ruiz-Ojeda J, Escalza Cortina I, Garcia- Monco JC. Migraine, stroke and epilepsy: underlying and interrelated causes, diagnosis and treatment. Curr Treat Options Cardiovasc Med 15:322-334, 2013. 56. Leniger T, Diener HC, Hufnagel A. Altered cerebral excitabil- ity and spreading depression. Causes for the comorbidity of epilepsy and migraine? Der Nervenarzt 74:869-874, 2003. 57. Rogawski MA. Common pathophysiologic mecha- nisms in migraine and epilepsy. Arch Neurol 65:709-714, 2008. 58. Hauser WA, Annegers JF, Kurland LT. Prevalence of epilepsy in Rochester, Minnesota: 1940-1980. Epilepsia 32:429-445, 1991. 59. Benbadis SR, Allen Hauser W. An estimate of the prevalence of psychogenic non-epileptic seizures. Seizure 9:280-281, 2000. 60. Ottman R, Lipton RB. Comorbidity of migraine and epilepsy. Neurology 44:2105-2110, 1994. 61. Bigal ME, Lipton RB, Cohen J, Silberstein SD. Epilepsy and migraine. Epilepsy Behav 4:S13-24, 2003. 62. Elahi FM, Miller BL. A clinicopathological approach to the diagnosis of dementia. Nat Rev Neurol 13:457-476, 2017. 63. Prince M, Ali GC, Guerchet M, Prina AM, Albanese E, Wu YT. Recent global trends in the prevalence and incidence of dementia,and survival with dementia. Alzheimer's Res Therapy 8:23, 2016. 64. Collaborators GBDH. Global, regional, and national burden of migraine and tension-type headache, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 17:954-976, 2018. 65. Kruit MC, van Buchem MA, Launer LJ, Terwindt GM, Ferrari MD. Migraine is associated with an increased risk of deep white matter lesions, subclinical posterior circulation infarcts and brain iron accumulation: The population-based MRI CAMERA study. Cephalalgia 30:129-136, 2010. 66. Kurth T, Mohamed S, Maillard P, et al. Headache, migraine, and structural brain lesions and function: population based Epidemiology of Vascular Ageing-MRI study. BMJ 342:c7357, 2011. 67. Waller R, Narramore R, Simpson JE, et al. Heterogeneity of cellular inflammatory responses in ageing white matter and relationship to Alzheimer's and small vessel disease pathologies. Brain Pathol 31(3):e12928, 2021. 68. Edvinsson L, Haanes KA, Warfvinge K. Does inflammation have a role in migraine? Nat Rev Neurol 15:483-490, 2019. 69. Lee SY, Lim JS, Oh DJ, Kong IG, Choi HG. Increased risk of neurodegenerative dementia in women with migraines: a nested case-control study using a national sample cohort. Medicine 98:e14467, 2019. 70. Martins IP, Maruta C, Alves PN, et al. Cognitive aging in migraine sufferers is associated with more subjective complaints but similar age-related decline: a 5- year longitudinal study. J Headache Pain 21:31, 2020. 71. Ackley SF, Rist PM, Brenowitz WD, Graff RE, Glymour MM. The association between migraine genetic risk and dementia: A Mendelian randomization study. Alzheimer’s Dement 16:e045405, 2020. 72. Chabriat, H., et al., Autosomal dominant migraine with MRI white‐matter abnormalities mapping to the CADASIL locus. 45:1086-1091, 1995. 73. Finsterer, J. Cognitive decline as a manifestation of mitochondrial disorders (mitochondrial dementia). J Neurol Sci 272:20-33, 2008. 74. https://www.mayoclinic.org/diseases-conditions/ alzheimers-disease/symptoms-causes/syc-20350447 [accessed Nov 19, 2022]. 75. Fereshtehnejad SM, et al. Comorbidity profile in dementia with Lewy bodies versus Alzheimer’s disease: a linkage study between the Swedish Dementia Registry and the Swedish National Patient Registry. Alzheimer's Research & Therapy 6:65, 2014. 76. Lee, S-Y et al. Increased risk of neurodegenerative dementia in women with migraines: A nested case-control study using a national sample cohort. Medicine 98:e14467, 2019. 77. Etminan, M., et al., Risk of ischaemic stroke in people with migraine: systematic review and meta-analysis of observational studies 330:63, 2005. 78. De Benedittis, G., et al., Magnetic resonance imaging in migraine and tension‐type headache 35:264-268, 1995. 79. Rocca MA, Colombo B, Pratesi A, Comi G, Filippi M. A magnetization transfer imaging study of the brain in patients with migraine. Neurology 54:507-509, 2000. 80. Fazekas, F., et al., The prevalence of cerebral damage varies with migraine type: a MRI study. 32:287-291, 1992. 81. Paemeleire, K., Brain lesions and cerebral functional impairment in migraine patients. J Neurolog Sci 283:134- 136, 2009. Paemeleire K. Brain lesions and cerebral functional impairment in migraine patients. J Neurol Sci. 283:134-136, 2009. 82. Le Pira, F., et al., Memory disturbances in migraine with and without aura: a strategy problem? 20:475-478, 2000. 83. Riva, D., et al., Cognitive and behavioural effects of migraine in childhood and adolescence. 26: 596-603, 2006. 84. Calandre, E., et al., Cognitive disturbances and regional cerebral blood flow abnormalities in migraine patients: their relationship with the clinical manifestations of the illness 22:291-302, 2002. 85. Mulder, E., et al., Interictal and postictal cognitive changes in migraine. 19:557-565, 1999. 86. Hooker WD, Raskin NH. Neuropsychologic alterations in classic and common migraine. Arch Neurol. 43:709-712, 1986. 87. Le Pira F, Lanaia F, Zappalà G, Morana R, Panetta MR, Reggio E, Reggio A. Relationship between clinical variables and cognitive performances in migraineurs with and without aura. Funct Neurol 19:101-105, 2004. 88. Palmer JE, Chronicle EP. Cognitive processing in http://www.ajecr.org/ 446 Am J Exp Clin Res, Vol. 9, No. 1, 2022 http://www.ajecr.org migraine: a failure to find facilitation in patients with aura. Cephalalgia 18:125-132, 1998. 89. Bell, B.D., et al., Neuropsychological functioning in migraine headache, nonheadache chronic pain, and mild traumatic brain injury patients. 14:389-399, 1999. 90. Jelicic M, van Boxtel MP, Houx PJ, Jolles J. Does migraine headache affect cognitive function in the elderly? Report from the Maastricht Aging Study (MAAS). Headache 40:715-719, 2000. 91. Leijdekkers ML, Passchier J, Goudswaard P, Menges LJ, Orlebeke JF. Migraine patients cognitively impaired? Headache 30:352-358, 1990. 92. Pearson AJ, Chronicle EP, Maylor EA, Bruce LA. Cognitive function is not impaired in people with a long history of migraine: a blinded study. Cephalalgia 26:74-80, 2006. 93.https://www.who.int/en/news-room/fact sheets/detail /headache-disorders [accessed Nov 19, 2022]. 94. https://www.who.int/mediacentre/factsheets/fs277/ en/ [accessed Nov 19, 2022]. 95. Simon RP, Aminoff MJ, Greenberg DA. Clinical neurology (7 ed.). New York, N.Y: Lange Medical Books/McGraw-Hill. pp. 85-88, 2009. 96. Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 24 Suppl 1:9-160, 2004. 97. Headache Classification Subcommittee of the International Headache Society. "The International Classi- fication of Headache Disorders: 2nd ed. Cephalalgia 24: (Suppl 1): 9-160, 2004. 98. Lipton RB, Bigal ME, Diamond M, et al. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology 68(5):343-349, 2007. 99. Piane M, Lulli P, Farinelli I, Simeoni S, De Filippis S, Patacchioli FR, Martelletti P. "Genetics of migraine and pharmacogenomics: some considerations". J Headache Pain 8:334-339, 2007. 100. Lay CL, Broner SW. “Migraine in women”. Neurologic Clinics 27:503-511, 2009. 101. Stovner LJ, Zwart JA, Hagen K, Terwindt GM, Pascual J. "Epidemiology of headache in Europe". Eur J Neurol 13:333-345, 2006. 102. Ashina M. "Migraine". The New England J Med 383: 1866-1876, 2020. 103. Sinforiani E, Farina S, Mancuso A, Manzoni GC, Bono G, Mazzucchi A. Analysis of higher nervous functions in migraine and cluster headache. Funct Neurol 2:69-77, 1987. 103. Gaist D, Pedersen L, Madsen C, Tsiropoulos I, Bak S, Sindrup S, McGue M, Rasmussen BK, Christensen K. Long-term effects of migraine on cognitive function: a population-based study of Danish twins. Neurology 64:600- 607, 2005. 104. Joutel A, Corpechot C, Ducros A, et al. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 383(6602):707-710, 1996. 105. Sas K, Párdutz A, Toldi J, Vécsei L. Dementia, stroke and migraine- some common pathological mechanisms. J Neurol Sci 299:55-65, 2010. 106. Haan J, Terwindt GM, Ferrari MD. Genetics of migraine. Neurol Clin 15:43-60, 1997. 107. Lay CL, Broner SW. "Migraine in women".Neuro- logic Clinics 27:503-511, 2009. 108. Gobel H. "1. Migraine". ICHD-3 The International Classification of Headache Disorders 3rd edition. Retrieved 22 October 2020. http://www.ajecr.org/ https://doi.org/10.1111%2Fj.1468-1331.2006.01184.x