Topiramate dose effects on cognition: a randomized double-blind study.

BACKGROUND: Topiramate (TPM), a broad-spectrum antiepileptic drug, has been associated with neuropsychological impairment in patients with epilepsy and in healthy volunteers. OBJECTIVE: To establish whether TPM-induced neuropsychological impairment emerges in a dose-dependent fashion and whether early cognitive response (6-week) predicts later performance (24-week). METHODS: Computerized neuropsychological assessment was performed on 188 cognitively normal adults who completed a double-blind, placebo-controlled, parallel-group, 24-week, dose-ranging study which was designed primarily to assess TPM effects on weight. Target doses were 64, 96, 192, or 384 mg per day. The Computerized Neuropsychological Test Battery was administered at baseline and 6, 12, and 24 weeks. Individual cognitive change was established using reliable change index (RCI) analysis. RESULTS: Neuropsychological effects emerged in a dose-dependent fashion in group analyses (p < 0.0001). RCI analyses showed a dose-related effect that emerged only at the higher dosing, with 12% (64 mg), 8% (96 mg), 15% (192 mg), and 35% (384 mg) of subjects demonstrating neuropsychological decline relative to 5% declining in the placebo group. Neuropsychological change assessed at 6 weeks significantly predicted individual RCI outcome at 24 weeks. CONCLUSIONS: Neuropsychological impairment associated with TPM emerges in a dose-dependent fashion. Subjects more likely to demonstrate cognitive impairment after 24 weeks of treatment can be identified early on during treatment (i.e., within 6 weeks). RCI analysis provides a valuable approach to quantify individual neuropsychological risk.

Abnormal emotional word ratings in Parkinson's disease.

Blunted facial expressions and diminished expressions of emotional prosody associated with Parkinson's disease (PD) could be attributed to motor rigidity/akinesia. Although impaired recognition of emotional faces and prosody in PD suggests emotional dysfunction is not entirely motor-efferent, comprehension might depend upon imitation with motor feedback. Thus, to learn if patients with PD have an emotional conceptual defect, we examined their ratings for the emotional connotations of words on a 1-9 scale for valence and arousal. When compared to control participants the valence (positive-negative) and arousal (excited-calm) ratings of the PD patients were blunted, but their ratings of the control expense words (expensive-cheap) were not. These blunted emotion ratings suggest that patients with PD have a degradation of their emotional conceptual-semantic system.

Voltage-dependent calcium channels are involved in neurogenic dural vasodilatation via a presynaptic transmitter release mechanism.

Amissense mutation of the CACNA1A gene that encodes the alpha1A subunit of the voltage-dependent P/Q-type calcium channel has been discovered in patients suffering from familial hemiplegic migraine. This suggested that calcium channelopathies may be involved in migraine more broadly, and established the importance of genetic mechanisms in migraine. Channelopathies share many clinical characteristics with migraine, and thus exploring calcium channel functions in the trigeminovascular system may give insights into migraine pathophysiology. It is also known that drugs blocking the P/Q- and N-type calcium channels have been successful in other animal models of trigeminovascular activation and head pain. In the present study, we used intravital microscopy to examine the effects of specific calcium channel blockers on neurogenic dural vasodilatation and calcitonin gene-related peptide (CGRP)-induced dilation. The L-type voltage-dependent calcium channel blocker calciseptine significantly attenuated (20 microg kg(-1), n=7) the dilation brought about by electrical stimulation, but did not effect CGRP-induced dural dilation. The P/Q-type voltage-dependent calcium channel blocker omega-agatoxin-IVA (20 microg kg-1, n=7) significantly attenuated the dilation brought about by electrical stimulation, but did not effect CGRP-induced dural dilation. The N-type voltage-dependent calcium channel blocker omega-conotoxin-GVIA (20 microg kg(-1), n=8 and 40 microg kg(-1), n=7) significantly attenuated the dilation brought about by electrical stimulation, but did not effect CGRP-induced dural dilation. It is thought that the P/Q-, N- and L-type calcium channels all exist presynaptically on trigeminovascular neurons, and blockade of these channels prevents CGRP release, and, therefore, dural blood vessel dilation. These data suggest that the P/Q-, N- and L-type calcium channels may be involved in trigeminovascular nociception.

Nitric oxide synthase inhibitors can antagonize neurogenic and calcitonin gene-related peptide induced dilation of dural meningeal vessels.

1. The detailed pathophysiology of migraine is beginning to be understood and is likely to involve activation of trigeminovascular afferents. 2. Clinically effective anti-migraine compounds are believed to have actions that include peripheral inhibition of calcitonin gene-related peptide (CGRP) release from trigeminal neurones, or preventing dural vessel dilation, or both. CGRP antagonists can block both neurogenic and CGRP-induced dural vessel dilation. 3. Nitric oxide (NO) can induce headache in migraine patients and often triggers a delayed migraine. The initial headache is thought to be caused via a direct action of the NO-cGMP pathway that causes vasodilation by vascular smooth muscle relaxation, while the delayed headache is likely to be a result of triggering trigeminovascular activation. Nitric oxide synthase (NOS) inhibitors are effective in the treatment of acute migraine. 4. The present studies used intravital microscopy to examine the effects of specific NOS inhibitors on neurogenic dural vasodilation (NDV) and CGRP-induced dilation. 5. The non-specific and neuronal NOS (nNOS) inhibitors were able to partially inhibit NDV, while the non-specific and endothelial NOS (eNOS) inhibitors were able to partially inhibit the CGRP induced dilation. 6. There was no effect of the inducible NOS (iNOS) inhibitor. 7. The data suggest that the delayed headache response triggered by NO donors in humans may be due, in part, to increased nNOS activity in the trigeminal system that causes CGRP release and dural vessel dilation. 8. Further, eNOS activity in the endothelium causes NO production and smooth muscle relaxation by direct activation of the NO-cGMP pathway, and may be involved in the initial headache response.

The anti-migraine 5-HT(1B/1D) agonist rizatriptan inhibits neurogenic dural vasodilation in anaesthetized guinea-pigs.

These studies investigated the pharmacology of neurogenic dural vasodilation in anaesthetized guinea-pigs. Following introduction of a closed cranial window the meningeal (dural) blood vessels were visualized using intravital microscopy and the diameter constantly measured using a video dimension analyser. Dural blood vessels were constricted with endothelin-1 (3 microg kg(-1), i.v.) prior to dilation of the dural blood vessels with calcitonin gene-related peptide (CGRP; 1 microg kg(-1), i.v.) or local electrical stimulation (up to 300 microA) of the dura mater. In guinea-pigs pre-treated with the CGRP receptor antagonist CGRP((8-37)) (0.3 mg kg(-1), i.v.) the dilator response to electrical stimulation was inhibited by 85% indicating an important role of CGRP in neurogenic dural vasodilation in this species. Neurogenic dural vasodilation was also blocked by the 5-HT(1B/1D) agonist rizatriptan (100 microg kg(-1)) with estimated plasma levels commensurate with concentrations required for anti-migraine efficacy in patients. Rizatriptan did not reverse the dural dilation evoked by CGRP indicating an action on presynaptic receptors located on trigeminal sensory fibres innervating dural blood vessels. In addition, neurogenic dural vasodilation was also blocked by the selective 5-HT(1D) agonist PNU-142633 (100 microg kg(-1)) but not by the 5-HT(1F) agonist LY334370 (3 mg kg(-1)) suggesting that rizatriptan blocks neurogenic vasodilation via an action on 5-HT(1D) receptors located on perivascular trigeminal nerves to inhibit CGRP release. This mechanism may underlie one of the anti-migraine actions of the triptan class exemplified by rizatriptan and suggests that the guinea-pig is an appropriate species in which to investigate the pharmacology of neurogenic dural vasodilation.

The effect of adrenergic compounds on neurogenic dural vasodilatation.

The pharmacology of neurogenic trigeminovascular vasodilator responses in the dura mater is of interest for understanding the pathophysiology of migraine and to develop new therapies for this disabling common condition. Aminergic mechanisms have been implicated in migraine through direct study of amines in patients, and by inference from the pharmacology of many effective anti-migraine compounds, particularly preventative agents. This study used intravital microscopy to assess the role of aminergic transmission in neurogenic dural vasodilatation (NDV) by measuring directly the diameter of dural arteries in sodium pentobarbitone anaesthetised rats. Electrical stimulation of a closed cranial window produces, by local depolarisation of nerves, dural vessel dilation that is monitored continuously on-line using video-microscopy and a video dimension analyser. This dural vasodilatation was not affected by pre-treatment with an alpha1-adrenoceptor agonist (phenylephrine, 1 and 5 microg/kg), or antagonist (corynanthine, 1 and 2 mg/kg), nor by an alpha2-adrenoceptor agonist (UK14,304, 5 microg/kg) or antagonist (yohimbine, 1 and 3 mg/kg). Similarly, we saw no effect of beta-adrenoceptor blockade (propranolol, 1 and 3 mg/kg). The lack of an inhibitory effect of UK14,304 the model of neurogenic dural vasodilation contrasts with its effect in neurogenic dural plasma protein extravasation model. The lack of inhibition of beta-adrenoceptor antagonists in the neurogenic vasodilatation model contrasts with their usefulness as migraine prophylactics, and suggests that their mechanism of action in migraine is unlikely to be through sensory trigeminal fibre terminals at the neurovascular junction. Moreover, the data indicate that the adrenergic system does not play a significant role in neurogenic dural vasodilation.

Role of opioid receptors in neurogenic dural vasodilation and sensitization of trigeminal neurones in anaesthetized rats.

Migraine headache is thought to be caused by a distension of meningeal blood vessels, the activation of trigeminal sensory neurones and the the development of a central sensitization within the trigeminal nucleus caudalis (TNC). It has been proposed that clinically effective 5-HT(1B/1D) agonists act peripherally to inhibit the release of calcitonin gene-related peptide (CGRP) and neurogenic dural vasodilation, and to attenuate nociceptive neurotransmission within the TNC. Since opioids are also effective anti-migraine agents the present studies investigated the role of opioids within the trigemino-vascular system in anaesthetised rats. Electrical stimulation of the dura mater evoked neurogenic dural vasodilation which was significantly inhibited by morphine (1 mg kg(-1)) the selective mu-opioid agonist DAGO (10 microg kg(-1)) and the mixed agonist/antagonist butorphanol (1 mg kg(-1)) but not by the kappa- and delta-opioid agonists (+/-) U50488H (100 microg kg(-1)) and DPDPE (1 mg kg(-1)). Morphine had no effect on CGRP-evoked dural vasodilation. In electrophysiological studies morphine (1 - 10 mg kg(-1)) significantly attenuated brainstem neuronal activity in response to electrical stimulation of the dura by 65% at 10 mg kg(-1). Morphine (3 mg kg(-1)) also inhibited the TNC neuronal sensitization following CGRP-evoked dilation. The present studies have demonstrated that opioids block the nociceptive neurotransmission within the trigeminal nucleus caudalis and in addition inhibit neurogenic dural vasodilation via an action on mu-opioid receptors located on trigeminal sensory fibres innervating dural blood vessels. These peripheral and central actions are similar to those of the 'triptan' 5-HT(1B/1D) agonists and could account for the anti-migraine actions of opioids.

Neurogenic inflammation in the context of migraine.

Despite considerable research into the pathogenesis of idiopathic headaches, such as migraine, the pathophysiological mechanisms underlying them remain poorly understood. Although it is well established that the trigeminal nerve becomes activated during migraine, the consequences of this activation remain controversial. One theory, based on preclinical observations, is that activation of trigeminal sensory fibers leads to a painful neurogenic inflammation within the meningeal (dural) vasculature mediated by neuropeptide release from trigeminal sensory fibres and characterized by plasma protein extravasation, vasodilation, and mast cell degranulation. Effective antimigraine agents such as ergots, triptans, opioids, and valproate inhibit preclinical neurogenic dural extravasation, suggesting that this activity may be a predictor of potential clinical efficacy of novel agents. However, several clinical trials with other agents that inhibit this process preclinically have failed to show efficacy in the acute treatment of migraine in man. Alternatively, it has been proposed that painful neurogenic vasodilation of meningeal blood vessels could be a key component of the inflammatory process during migraine headache. This view is supported by the observation that jugular plasma levels of the potent vasodilator, calcitonin gene-related peptide (CGRP) are elevated during the headache and normalized by successful sumatriptan treatment. Preclinically, activation of trigeminal sensory fibers evokes a CGRP-mediated neurogenic dural vasodilation, which is blocked by dihydroergotamine, triptans, and opioids but unaffected by NK1 receptor antagonists that failed in clinical trials. These observations suggest that CGRP release with associated neurogenic dural vasodilation may be important in the generation of migraine pain, a theory that would ultimately be tested by the clinical testing of a CGRP receptor antagonist.

Effects of bromocriptine in a patient with crossed nonfluent aphasia: a case report.

OBJECTIVE: Because studies have shown some positive effects of the dopaminergic agent bromocriptine for improving verbal production in patients with nonfluent aphasia, we examined its effect in a patient with an atypical form of crossed nonfluent aphasia from a right hemisphere lesion. DESIGN: Open-label single-subject experimental ABAB withdrawal design. PATIENT: A right-handed man who, after a right frontal stroke, developed nonfluent aphasia, emotional aprosodia, and limb apraxia. INTERVENTION: Escalating doses up to 20mg of bromocriptine in 2 separate phases. MAIN OUTCOME MEASURES: We measured verbal fluency (words/min in discourse, Thurstone letter fluency), expression of emotional prosody, and gesture production. RESULTS: The patient showed substantial improvement in both verbal fluency measures and no significant improvement in gesture or emotional prosody. Verbal fluency improvements continued in withdrawal phases. CONCLUSIONS: Our results are less likely caused by practice or spontaneous recovery because we observed little improvement in emotional prosody and gesture tasks. Verbal fluency improvements during treatment and withdrawal phases suggest that the effects of bromocriptine may be long-lasting in its influence on the neural networks subserving verbal initiation.

Hemodynamic effects of Bosentan, an endothelin receptor antagonist, in patients with pulmonary hypertension.

BACKGROUND: Few treatments are available for isolated pulmonary hypertension (PHT), which has a high morbidity and mortality. This trial was designed to assess the hemodynamic effects of bosentan, an endothelin receptor antagonist, in patients with PHT, in which local overproduction of endothelin-1 (ET-1) is thought to play a pathogenic role. METHODS AND RESULTS: An open-label, dose-ranging study was performed in 7 female patients with primary PHT (n=5) or isolated PHT associated with limited scleroderma (n=2). Infusions of 50, 150, and 300 mg were administered at 2-hour intervals, and the hemodynamic responses were measured. Bosentan caused a dose-dependent fall in total pulmonary resistance (-20.0+/-11.0%, P=0.01) and mean pulmonary artery pressure (-10.6+/-11.0%, P>0.05). However, there was also a fall in the systemic vascular resistance (-26.2+/-12.8%, P<0.005) and mean arterial pressure (-19.8+/-14.4%, P<0.001). There was a slight increase in cardiac index (15+/-12%, P>0.05) and a dose-dependent rise in ET-1 but no significant change in other hemodynamic variables, gas exchange, or other vasoactive mediators. CONCLUSIONS: Intravenous bosentan is a potent but nonselective pulmonary vasodilator at the doses tested, even in patients resistant to inhaled nitric oxide. Transient increases in plasma ET-1 were observed, consistent with a blockade of endothelial ET(B) receptors. Systemic hypotension and other significant events during the study indicate that its intravenous use in patients with severe PHT may be limited. Implications for future trial design and studies of chronic oral treatment are discussed.

hnRNP C is required for postimplantation mouse development but Is dispensable for cell viability.

The hnRNP C1 and C2 proteins are among the most abundant proteins in the nucleus, and as ubiquitous components of RNP complexes, they have been implicated in many aspects of mRNA biogenesis. In this report, we have characterized a null mutation induced in embryonic stem cells by insertion of the U3His gene trap retrovirus into the first intron of the hnRNP C1/C2 gene. cDNAs encoding murine hnRNP C1 and C2 were characterized, and the predicted protein sequences were found to be highly conserved among vertebrates. A human consensus sequence, generated from over 400 expressed sequence tags, suggests two revisions to the previously published human sequence. In addition, alternatively spliced transcripts, expressed only by the murine gene, encode four novel proteins: variants of C1 and C2 with either seven additional amino acids or one fewer amino acid in a region between the oligomerization and C-terminal acidic domains. The disrupted gene was transmitted into the germ line and is tightly linked to a recessive, embryonic lethal phenotype. Homozygous mutant embryos fail to develop beyond the egg cylinder stage and are resorbed by 10.5 days of gestation, a phenotype consistent with a fundamental role in cellular metabolism. However, hnRNP C1 and C2 are not required for cell viability. Embryonic stem cell lines established from homozygous mutant blastocysts did not express detectable levels of either protein yet were able to grow and differentiate in vitro, albeit more slowly than wild-type cells. These results indicate that the C1 and C2 hnRNPs are not required for any essential step in mRNA biogenesis; however, the proteins may influence the rate and/or fidelity of one or more steps.

Conceptual apraxia in probable Alzheimer's disease as demonstrated by the Florida Action Recall Test.

Patients with probable Alzheimer's disease (AD) often have difficulties associated with semantic knowledge. Therefore, conceptual apraxia, a defect of action semantics and mechanical knowledge, may be an early sign of this disease. The Florida Action Recall Test (FLART), developed to assess conceptual apraxia, consists of 45 line drawings of objects or scenes. The subject must imagine the proper tool to apply to each pictured object or scene and then pantomime its use. Twelve participants with Alzheimer's disease (NINCDS-ADRDA criteria) and 21 age- and education-matched controls were tested. Nine Alzheimer's disease participants scored below a 2-standard-deviation cutoff on conceptual accuracy, and the three who scored above the cutoff were beyond a 2-standard-deviation cutoff on completion time. The FLART appears to be a sensitive measure of conceptual apraxia in the early stages of Alzheimer's disease.

The novel NK1 receptor antagonist MK-0869 (L-754,030) and its water soluble phosphoryl prodrug, L-758,298, inhibit acute and delayed cisplatin-induced emesis in ferrets.

The anti-emetic profile of the novel brain penetrant tachykinin NK1 receptor antagonist MK-0869 (L-754,030) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluor o)phenyl-4-(3-oxo-1,2,4-triazol-5-yl)methylmorpholine and its water soluble prodrug, L-758,298, has been examined against emesis induced by cisplatin in ferrets. In a 4 h observation period, MK-0869 and L-758,298 (3 mg/kg i.v. or p.o.) inhibited the emetic response to cisplatin (10 mg/kg i.v.). The anti-emetic protection afforded by MK-0869 (0.1 mg/kg i.v.) was enhanced by combined treatment with either dexamethasone (20 mg/kg i.v.) or the 5-HT3 receptor antagonist ondansetron (0.1 mg/kg i.v.). In a model of acute and delayed emesis, ferrets were dosed with cisplatin (5 mg/kg i.p.) and the retching and vomiting response recorded for 72 h. Pretreatment with MK-0869 (4-16 mg/kg p.o.) dose-dependently inhibited the emetic response to cisplatin. Once daily treatment with MK-0869 (2 and 4 mg/kg p.o.) completely prevented retching and vomiting in all ferrets tested. Further when daily dosing began at 24 h after cisplatin injection, when the acute phase of emesis had already become established, MK-0869 (4 mg/kg p.o. at 24 and 48 h after cisplatin) prevented retching and vomiting in three out of four ferrets. These data show that MK-0869 and its prodrug, L-758,298, have good activity against cisplatin-induced emesis in ferrets and provided a basis for the clinical testing of these agents for the treatment of emesis associated with cancer chemotherapy.

Emotional and physiological responses to false feedback.

The relationship between autonomic-visceral arousal and emotional experience is unclear. The attribution or cognitive-arousal theory of emotional experience posits that emotional experience is dependent on both visceral-autonomic nervous system feedback and the cognitive interpretation of the stimulus that induced this visceral activation. The finding that false cardiac feedback can alter emotional experience suggests that it may be the conscious perception that one is aroused, together with the cognitive interpretation of the stimulus that are important in developing emotional experience. Because the right hemisphere appears to play a special role in modulating arousal and interpreting emotional stimuli, it is possible that right hemisphere damage may interfere with developing the computations needed for emotional experience. To test this hypothesis we exposed men, both neurologically intact and those with right and left hemisphere lesions, to emotionally provocative pictures that were paired with false cardiac feedback, and examined the effects of this false feedback on their ratings of attractiveness of these pictures and their cardiac reactivity to this information. Subjects with left hemisphere damage, but not right hemisphere damage, showed significant changes in their emotional rating whereas control subjects showed marginal reactivity in their emotional ratings. Subjects with left hemisphere damage also showed significant changes in their cardiac reactivity. This finding is consistent with prior reports that indicate, when compared to right hemisphere damaged patients and normal controls, patients with left hemisphere lesions have an increased visceral-autonomic response to stimuli. These findings further provide support for the postulate that it is the cognitive interpretation of perceived physiological arousal together with the cognitive interpretation of the stimulus that is important in the development of emotional judgment and experience. These results do not support the approach-left hemisphere/avoidance-right hemisphere dichotomy, but instead suggest that left hemisphere damage increases reactivity to false feedback, and that the intact right hemisphere function integrates the cognitive interpretation of the emotional information and perceived arousal that lead to that emotional judgment. That these subjects showed no consistent relationship between their measures of cardiac reactivity and their ratings of attractiveness detracts from the James-Lange and attribution theories. These subjects also showed no consistent relationship between their knowledge of affective physiological reactivity and their ratings of attractiveness, or between their knowledge of physiological reactivity and actual measures of cardiac reactivity, suggesting that other neuropsychological factors are involved in making an emotional judgment.

Cognitive impairment in elderly who are not yet demented.

Patients with neuropathological changes of Alzheimer disease may not be demented during initial evaluation of memory disturbance. Understanding current issues regarding the patient with incipient degenerative dementia should help identify those at greatest risk for progression and may help delay onset of symptoms.

Apraxia and motor-skill acquisition in Alzheimer's disease are dissociable.

Many patients with Alzheimer's disease (AD) are apraxic and the apraxia has been posited to be related to a loss of movement representations. Whereas patients with Alzheimer's disease have been reported to demonstrate normal motor learning on a rotor pursuit skill acquisition task, it is unknown whether AD subjects who are apraxic demonstrate normal skill-learning. We tested subjects with probable AD and normal controls on a rotor pursuit task. We also tested the AD subjects for ideomotor apraxia. Subjects with AD who were apraxic had normal motor learning. In addition, praxis score did not correlate with performance on the skill-acquisition task. The results suggest that ideomotor praxis and motor learning are at least partly dissociable.

Crossed apraxia: implications for handedness.

Liepmann posited that right hand preference relates to left hemisphere dominance for learned skilled movements. Limb apraxia, impairment of skilled movement, typically occurs in individuals with left hemisphere (LH) lesions. The occurrence of apraxia in right-handed individuals following right-hemisphere lesions appears to refute Liepmann's hypothesis. We studied the apraxia of a right-handed man, RF, following a right frontal lesion to determine whether his apraxia paralleled the apraxia seen following LH lesions. Results of behavioral testing indicated that, like individuals with apraxia following left frontal lesions, RF was better at gesture recognition than gesture production which was significantly impaired across tasks. Kinematic motion analyses of movement linearity, planarity, and the coupling of temporospatial aspects of movements substantiated the parallel impairments in RF and patients with LH apraxia. The impairment seen in our patient with crossed apraxia provides evidence for the fractionation of systems underlying hand preference and skilled movement.

Articulatory processes and phonologic dyslexia.

BACKGROUND/OBJECTIVE: Grapheme-to-phoneme conversion (GPC) allows the pronunciation of nonword letter strings and of real words with which the literate reader has no previous experience. Although cross-modal association between visual (orthographic) and auditory (phonemic-input) representations may contribute to GPC, many cases of deep or phonologic alexia result from injury to anterior perisylvian regions. Thus, GPC may rely upon associations between orthographic and articulatory (phonemic-output) representations. METHOD/RESULTS/CONCLUSION: Detailed analysis of a patient with phonologic alexia suggests that defective knowledge of the position and motion of the articulatory apparatus might contribute to impaired transcoding from letters to sounds.