P53 aggregation, interactions with tau, and impaired DNA damage response in Alzheimer's disease.

The transcription factor, p53, is critical for many important cellular functions involved in genome integrity, including cell cycle control, DNA damage response, and apoptosis. Disruption of p53 results in a wide range of disorders including cancer, metabolic diseases, and neurodegenerative diseases. Alzheimer's disease (AD) is a neurodegenerative disorder characterized by protein aggregates that contribute to disease pathology. Although p53 is known to aggregate, its propensity to aggregate in AD has never been assessed. Moreover, AD neuropathology includes lethal cell cycle re-entry, excessive DNA damage, and abnormal cell death which are all controlled by p53. Here, we show p53 forms oligomers and fibrils in human AD brain, but not control brain. p53 oligomers can also be detected in htau and P301L mouse models. Additionally, we demonstrate that p53 interacts with tau, specifically tau oligomers, in AD brain and can be recapitulated by in vitro exogenous tau oligomer treatment in C57BL/6 primary neurons. p53 oligomers also colocalize, potentially seeding, endogenous p53 in primary neurons. Lastly, we demonstrate that in the presence of DNA damage, phosphorylated p53 is mislocalized outside the nucleus and p53-mediated DNA damage responders are significantly decreased in AD brain. Control brain shows a healthy DNA damage response, indicating a loss of nuclear p53 function in AD may be due to p53 aggregation and/or interactions with tau oligomers. Given the critical role of p53 in cellular physiology, the disruption of this crucial transcription factor may set an irreversible course towards neurodegeneration in AD and potentially other tauopathies, warranting further investigation.

Tau oligomers mediate α-synuclein toxicity and can be targeted by immunotherapy.

BACKGROUND: We have evaluated the efficacy of targeting the toxic, oligomeric form of tau protein by passive immunotherapy in a mouse model of synucleinopathy. Parkinson's disease and Lewy body dementia are two of the most common neurodegenerative disorders and are primarily characterized by the accumulation of α-synuclein in Lewy bodies. However, evidence shows that smaller, oligomeric aggregates are likely the most toxic form of the protein. Moreover, a large body of research suggests that α-synuclein interacts with tau in disease and may act in a synergistic mechanism, implicating tau oligomers as a potential therapeutic target. METHODS: We treated seven-month-old mice overexpressing mutated α-synuclein (A53T mice) with tau oligomer-specific monoclonal antibody (TOMA) and a control antibody and assessed both behavioral and pathological phenotypes. RESULTS: We found that A53T mice treated with TOMA were protected from cognitive and motor deficits two weeks after a single injection. Levels of toxic tau oligomers were specifically decreased in the brains of TOMA-treated mice. Tau oligomer depletion also protected against dopamine and synaptic protein loss. CONCLUSION: These results indicate that targeting tau oligomers is beneficial for a mouse model of synucleinopathy and may be a viable therapeutic strategy for treating diseases in which tau and α-synuclein have a synergistic toxicity.

Tau oligomers in cerebrospinal fluid in Alzheimer's disease.

OBJECTIVE: With an increasing incidence of Alzheimer's disease (AD) and neurodegenerative tauopathies, there is an urgent need to develop reliable biomarkers for the diagnosis and monitoring of the disease, such as the recently discovered toxic tau oligomers. Here, we aimed to demonstrate the presence of tau oligomers in the cerebrospinal fluid (CSF) of patients with cognitive deficits, and to determine whether tau oligomers could serve as a potential biomarker for AD. METHODS: A multicentric collaborative study involving a double-blinded analysis with a total of 98 subjects with moderate to severe AD (N = 41), mild AD (N = 31), and nondemented control subjects (N = 26), and two pilot studies of 33 total patients with AD (N = 19) and control (N = 14) subjects were performed. We carried out biochemical assays to measure oligomeric tau from CSF of these patients with various degrees of cognitive impairment as well as cognitively normal controls. RESULTS: Using a highly reproducible indirect ELISA method, we found elevated levels of tau oligomers in AD patients compared to age-matched controls. Western blot analysis confirmed the presence of oligomeric forms of tau in CSF. In addition, the ratio of oligomeric to total tau increased in the order: moderate to severe AD, mild AD, and controls. CONCLUSION: These assays are suitable for the analysis of human CSF samples. These results here suggest that CSF tau oligomer measurements could be optimized and added to the panel of CSF biomarkers for the accurate and early detection of AD.

Managing migraine by patient profile: role of frovatriptan.

For the last quarter of a century, triptans have been available for acute treatment of migraine but with little guidance on which of the different triptan products to use for which patient or which attack of migraine. In this article, we propose a structured approach to analysis of individual migraine attacks and patient characteristics as a means of defining and optimizing acute intervention. Assessment of patient and attack profiles includes the "5-Ps": pattern, phenotype, patient, pharmacology, and precipitants. Attending to these five components of information can assist in developing an individualized behavioral, pharmacological, and nonpharmacological comprehensive treatment plan for most migraine patients. This clinical approach is then focused on frovatriptan because of its unique molecular signature and potential novel clinical applications. Frovatriptan like all triptans is indicated for acute treatment of migraine but its role has been explored in management of several unique migraine phenotypes. Frovatriptan has the longest half-life of any triptan and consequently is often promoted for acute treatment of migraine of longer duration. It has also been studied as a short-term preventive treatment in women with menstrual-related migraine. Given that 60% of female migraineurs suffer from menstrual-related migraine, this population is the obvious group for continued study. Small studies have also explored frovatriptan's use in treating migraine predicted by premonitory symptoms as a preventive for the headache phase of migraine. By identifying patient and attack profiles, clinicians may effectively determine the viability of frovatriptan as an effective pharmacological intervention for migraine.

Acupuncture in the treatment of headache: a traditional explanation of an ancient art.

BACKGROUND: Over the past 4000 years, acupuncture has survived the test of time. Recent scientific studies posit acupuncture is an effective intervention for back and joint pain and headache, including migraine. METHODS: The process of acupuncture is explained, including the role of Qi, the integration of Yang and Yin, the 5 elements, the 8 trigrams, and the metaphors that help the acupuncturist understand the patient, interpret symptoms, and determine acupuncture points in the meridians used to prevent or treat disease. A case study is presented from 3 perspectives: allopathic, traditional acupuncture, and Western acupuncture. RESULTS: Selected acupuncture studies in headache are reviewed. The safety of acupuncture is discussed as well as the challenges in conducting clinical studies of acupuncture.

Evaluation of sumatriptan-naproxen in the treatment of acute migraine: a placebo-controlled, double-blind, cross-over study assessing cognitive function.

OBJECTIVE: To assess the cognitive effects of acute migraine and the subsequent impact of acute treatment in a controlled setting. BACKGROUND: Cognitive dysfunction may be an associated symptom in patients with migraine with or without aura. The loss of cognitive efficiency in migraine may be disabling and is often under recognized. METHODS: Thirty migraine patients were prospectively studied for cognitive function before and then at the beginning of a migraine using a computerized cognitive battery (Mental Efficacy Workload Test). Each patient then was treated for 2 headaches in a cross-over manner with sumatriptan-naproxen (Treximet®) or placebo in a double-blind, placebo-controlled fashion with cognitive testing repeated at 1 and 2 hours post-dose. RESULTS: Twenty-five of the 30 screened migraine subjects completed study-specific procedures and were included in the data analyses. There were no significant side effects from Treximet or placebo and no serious adverse events. At the onset of headache, there was a statistically significant decline in overall cognitive efficiency compared with the baseline cognitive testing (migraine-free) for all subjects (P = .001 paired samples t-test). For subjects taking Treximet compared with taking placebo, there was a statistically significant return to cognitive efficiency by measures of immediate and sustained attention, visual-spatial awareness, mental flexibility, and reaction time between 1 hour and 2 hours (P = .05). There was no statistical significance between patients taking Treximet or placebo in measures of complex reasoning or fine motor coordination. Subanalysis showed a correlation between headache severity and Performance Index in the Treximet group but not in the placebo group (∼Fig. ). CONCLUSIONS: There is a significant decline in global cognitive efficiency at the onset of an attack of migraine. The use of Treximet allows a significantly faster recovery time in some measures of cognitive efficiency compared with placebo. Decline of cognitive efficiency may be independent of headache severity.

The bowel and migraine: update on celiac disease and irritable bowel syndrome.

This article explores possible relationships between migraine, irritable bowel syndrome (IBS), celiac disease (CD), and gluten sensitivity. These seemingly distinct medical entities curiously share many common epidemiological, psychosocial, and pathophysiological similarities. Considerable evidence is emerging to support a concept that experiencing significant threatening adverse events creates a state of hypervigilance in the nervous system, which associates with exaggerated response to future threats and episodic attacks of migraine and IBS. While this sensitizing response is generally considered to reside in the central nervous system, it may be possible that the initiation resides in the enteric nervous system as well. What appears to link migraine, IBS, and CD is a disease model of a genetically sensitive nervous system transformed into one that is hypervigilant, and that over time can often develop disabling and pervasive disease.

Two center, randomized pilot study of migraine prophylaxis comparing paradigms using pre-emptive frovatriptan or daily topiramate: research and clinical implications.

OBJECTIVE: To compare the efficacy and clinical benefit of 2 paradigms of migraine prevention using pre-emptive frovatriptan and daily topiramate. The study compares the paradigms of pre-emptive use of frovatriptan, a drug approved for acute migraine, and the daily use of topiramate, a Federal Drug Administration-approved and -accepted standard for migraine prophylaxis. BACKGROUND: Traditionally, preventive treatment of migraine required daily medication. However, recent studies suggest that pre-emptive prophylaxis may be beneficial to those migraineurs who can predict an attack of migraine based on premonitory symptoms and treat during that phase. METHODS: A total of 76 adult subjects with a diagnosis of migraine were screened for the study. During a 1-month baseline period, subjects demonstrated through a daily diary that they predicted at least 50% of migraine attacks during the premonitory phase and treated with their usual medication. Of these, 55 were randomized to either Group A (daily topiramate) or Group B (frovatriptan during premonitory symptoms); 44 completed the study. The treatment period lasted 2 months. The subjects answered the Migraine-Specific Quality of Life Questionnaire at randomization, and at Weeks 4 and 8. The revised Patient Perception of Migraine Questionnaire was answered 24 hours after taking frovatriptan (Group A, for break-through headaches; Group B, treatment during premonitory symptoms). RESULTS: The number of migraine attacks and headache days per month decreased significantly from baseline for both Groups A and B. Subjects in Group A had considerably more adverse events leading to study withdrawal than in Group B (18% vs 4%). Though this study was not powered to directly compare the efficacy of the 2 drugs, topiramate showed superiority over frovatriptan at Month 2 in reduction of headache days, which was a secondary end point in the study (P = .036). CONCLUSIONS: This pilot study demonstrated that statistical benefit for reduction of headache days over baseline for both pre-emptive frovatriptan and daily topiramate. Subjects utilizing pre-emptive frovatriptan experienced fewer adverse events leading to study withdrawal. Subjects utilizing daily topiramate had fewer headache days at Month 2.

Multi-center comparison of response to a single tablet of sumatriptan 85 mg and naproxen 500 mg vs usual therapy treating multiple migraine attacks as measured by the completeness of response survey.

OBJECTIVE: To investigate a broad definition of migraine resolution that extends beyond specific migraine-associated diagnostic symptoms as measured by the Completeness of Response Survey. METHODS: Conducted at 8 sites, 135 subjects treated migraines with SumaRT/Nap over 2 months. To measure subjects' experiences with SumaRT/Nap compared to their usual migraine medication, the Headache Impact Test, Revised Patient Perception of Migraine Questionnaire, and Completeness of Response Survey were administered at baseline and at 2 months. RESULTS: The effects of the study medicine compared to the subjects' usual migraine medicine reached statistical significance in decreasing headache severity, lessening of associated symptoms, and attaining complete relief with a single dose (60.04% of attacks resolved at 2 hours post-treatment). CONCLUSION: Compared to a subject's usual treatment, SumaRT/Nap used early and consistently for treatment of acute migraine offers important clinical improvements, including lessening of associated symptoms beyond International Headache Society criteria. CLINICAL TRIAL REGISTRATION NUMBER: NCT00893737.

A multi-center double-blind pilot comparison of onabotulinumtoxinA and topiramate for the prophylactic treatment of chronic migraine.

OBJECTIVE: This multi-center pilot study compared the efficacy of onabotulinumtoxinA with topiramate (a Food and Drug Administration approved and widely accepted treatment for prevention of migraine) in individuals with chronic migraine (CM). METHODS: A total of 59 subjects with CM were randomly assigned to one of 2 groups: Group 1 (n = 30) received topiramate plus placebo injections, Group 2 (n = 29) received onabotulinumtoxinA injections plus placebo tablets. Subjects maintained daily headache diaries over a 4-week baseline period and a 12-week active study period. The primary endpoint was the Physician Global Assessment, which measured the treatment responder rate and indicated improvement in both groups over 12 weeks. Secondary endpoints, measured at weeks 4 and 12, included headache days per month, migraine days, headache-free days, days on acute medication, severity of headache episodes, Migraine Impact & Disability Assessment, Headache Impact Test, effectiveness of and satisfaction with current treatment on the amount of medication needed, and the frequency and severity of migraine symptoms. At 12 weeks subjects were re-evaluated and tapered off oral study medications over a 2-week time period. Subjects not reporting a >50% reduction of headache frequency at 12 weeks were invited to participate in a 12-week open label extension study with onabotulinumtoxinA. Of these, 20 subjects, 9 from the Topiramate Group and 11 from the OnabotulinumtoxinA Group, volunteered for this extension from weeks 14 to 26. RESULTS: This study demonstrated positive benefit for both onabotulinumtoxinA and topiramate in subjects with CM. Overall, the results were statistically significant within groups but not between groups. By week 26, subjects had a reduction of headache days per month compared with baseline. This was a significant within-group finding. CONCLUSION: OnabotulinumtoxinA and topiramate demonstrated similar efficacy for subjects with CM as determined by Global Physician Assessment and supported by multiple secondary endpoint measures.

Psychological factors in childhood headaches.

Recurrent headaches in children are most often migraines and are based in a genetic predisposition with a low headache threshold. As with any pain experience, there is a large emotional component associated with an attack of migraines that grows in amplitude as the headaches become more frequent and resistant to medicine, sleep, or other agents that used to work. Childhood headaches are especially complicated for 3 reasons: (1) the parents' fear (communicated to the child that serious medical pathology underlies the head pain), (2) the lack of evidence-based pharmacologic treatment, and (3) the belief that these headaches are largely psychological. This article addresses the mystery surrounding childhood headaches by delving into the influence of school, friends, and family; the impact of divorce; the coping skills required for a child to manage a migrainous nervous system; the potential secondary gain from headaches; psychiatric comorbidities and how to treat them; and the role of psychological intervention.

Nurse-based education: an office-based comparative model for education of migraine patients.

BACKGROUND: A person with migraine needs to be prepared to make therapeutic decisions on her own. For this reason, patients often need education to understand the nuisances of managing theirmigraines. In this study an educationalCD-ROM/DVD that described the pathophysiology was utilized by nurses in an office-based primary care setting for patient education. Outcomes from this encounter were measured. OBJECTIVES: (1) Identify educational information that assisted migraine patients feel empowered to more effectively manage migraine; (2) encourage patients to intervene during the mild headache phase of the migraine; (3) measure education related changes in patient satisfaction and confidence regarding management of migraine; (4) measure changes in nurse satisfaction and confidence in educating migraine patients; (5) compare the effectiveness of 3 methods of delivery of nurse-based migraine education. METHODS: One hundred and eighty migraineurs at 21 primary care practices were divided into 4 groups: group A watched the CD-ROM/DVD in the office with a nurse available to answer questions; group B was given the CD-ROM/DVD by a nurse knowledgeable of the content; group C received the educational CD-ROM/DVD from a nurse without comment; group D received no educational material. The 10 nurses in groups A and B participated in a 45-minute teleconference that reviewed the information on the CD-ROM/DVD. Patients and nurses answered a pre- and post-study migraine questionnaire. Patients filled in a treatment diary online within 24 hours of treating a migraine. Nurses completed a satisfaction questionnaire. RESULTS: Of the 17 educational points tested on the pre-test, 75% of patients and nurses already knew about 1/3 of the information. There was significant improvement noted for both patients and nurses on the post-test in groups A, B, and C but not in group D. The percentage of correct responses by patients and nurses was directly and statistically significantly correlated with the involvement of the nurse in the educational effort. As a result of the education, patients felt more confident in their ability to manage and treat migraine. Likewise, nurses gained increased confidence in teaching patients about migraine. Patients did not intervene with acute therapy during the mild headache phase. Overall, 94% of the nurses were very satisfied or satisfied with the format and information provided. CONCLUSIONS: All but objective 2 were met for groups A, B, and C compared to control group D. Patients readily accepted nurse-directed education and assimilated information that increased their confidence to manage migraine. This emphasizes the importance of training nurses about materials used to educate patients.

Cosensitization of pain and psychiatric comorbidity in chronic daily headache.

Chronic migraine occurs in approximately 20% of migraineurs, typically developing over a period of many years. The pathophysiology of this transformation is unknown. However, experts have associated chronic headache with analgesic overuse, physical injury, and psychologic trauma. Research in post-traumatic stress disorder has found that hippocampal sensitivity to stress alters and often amplifies future pain behaviors. Although the most obvious difference between migraine and chronic migraine is the frequency of headaches, this article discusses chronic migraine as a more pervasive neurologic disease in which the patient's neurologic and psychologic function fails to return to a normal baseline. The sensory and affective components of pain are cosensitized, producing other neurologic and psychologic symptoms during and between episodes of headache. A staging paradigm is suggested that defines patients and assesses their overall neurologic function. The goal of this classification is to identify cosensitization early and pinpoint migraine patients who are at risk of developing chronic migraine.

Understanding the patient with migraine: the evolution from episodic headache to chronic neurologic disease. A proposed classification of patients with headache.

Traditionally, episodic primary headache disorders are characterized by a return of preheadache (normal) neurologic function between episodes of headache. In contrast, patients with chronic headache often do not return to normal neurologic function between headache attacks. This article proposes that the evolution from episodic migraine to chronic headache may parallel the neurologic disruption observed during the progression of an acute migraine attack and that changes in baseline neurologic function between episodes of headache may be a more sensitive indicator of headache transformation than headache frequency alone. Early recognition of nonheadache changes in nervous system function may offer a more sensitive and specific approach to migraine prevention.

Primary headaches: a convergence hypothesis.

After reviewing the historic differentiation between migraine and tension-type headache, the authors note that the similarities between these two types of primary headaches outweigh the differences, and so hypothesize that these headaches share a common pathophysiology. The convergence hypothesis for primary headaches links the clinical features of an evolving headache to current pathophysiological models. The authors suggest that successive symptoms experienced clinically reflect an escalating pathophysiological process, beginning with the premonitory period and progressing into tension-type headache and, if uninterrupted, finally into migraine. The clinical manifestations of other headache types, such as so-called sinus headache or temporomandibular headache, may also be explained by this model. A convergence hypothesis for primary headaches has important implications for earlier recognition, diagnosis, and treatment.