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Abstract Background: Elevated total homocysteine (tHcy) levels are associated with an increased risk of cerebrovascular disease. It is uncertain whether tHcy is also an independent risk factor for cognitive impairment. Methods: We examined 95 stroke subjects 3 months after their strokes, and 55 healthy comparison subjects, with a detailed neuropsychological assessment, and MRI brain scans in a proportion (n = 97). Baseline measurements of tHcy, serum folate and B 12 , creatinine and plasma fibrinogen levels were obtained. Results: tHcy levels were higher in the stroke subjects by a mean 34%. These levels were significantly correlated with the first factor of a principal component analysis of the neuropsychological data, after controlling for age, folate, B 12 and creatinine levels. The correlation of Hcy levels was particularly significant with frontal-executive functioning and attention. tHcy levels were significantly correlated with number of infarcts and total stroke volume in the stroke group, but not with T 2 -weighted deep white matter hyperintensity scores, after correction for age. In the control group, tHcy levels were significantly correlated with ventricle-tobrain ratios as measures of brain atrophy. Conclusion: This study provides evidence that high tHcy levels are associated with cognitive impairment, in particular that of frontal-executive function. The major component of this association is accounted for by small and large strokes, but non-vascular neurotoxic effects of tHcy also appear to play a role. tHcy must receive greater attention as a risk factor for cognitive impairment. Copyright © 2003 S. Karger AG, Basel Homocysteine (Hcy) is a sulfur-containing amino acid formed during the metabolism of the essential amino acid methionine. Elevated plasma homocysteine levels were first linked with vascular disease by McCully A high level of Hcy is both proatherogenic and prothrombotic If Hcy promotes cognitive impairment and is a risk factor for AD, it has important epidemiological implications. In this study, we examined plasma Hcy levels in a stroke sample to determine if there was an association between Hcy levels and cognition, and if this could be accounted for by infarct size or small vessel disease as detected by MRI. Methods Sample Subjects (n = 95) were consecutive patients admitted to two large teaching hospitals affiliated with the University of New South Wales who had recently suffered an ischemic stroke as diagnosed by two neurologists, and who met the diagnostic criteria for cerebral infarction Assessment Stroke subjects had a baseline assessment within 1 week of admission which included a detailed medical history and examination, history of risk factors for cerebrovascular disease and dementia, a functional assessment and the Mini-Mental State Examination Homocysteine Measurement Fasting blood was collected and centrifuged within 6 h, and the plasma stored at -20°C for later analysis. Total Hcy was measured using a fluorescence-based immunochemical technique with demonstrated high repeatability Neuropsychological Assessment Premorbid ability was estimated on the basis of performance on the National Adult Reading Test MRI Brain Scans MRI was performed on a proportion of subjects (n = 55 stroke; n = 42 controls) using a 1.5-T Signa GE magnet and the following protocol: a scout mid-sagittal cut (2D, TR 300 ms, TE 14 ms; 5 mm thick, number of excitations 1.5); 1.5-mm-thick T 1 -weighted contiguous coronal sections through whole brain using a FSPGR sequence and 3D acquisition (TR 14.3 ms, TE 5.4 ms); 4-mm-thick T 2 -weighted FLAIR coronal slices through whole brain (TR 8900, TE 145, TI 2200, FOV 25, 256 ! 192). Fifty-three subjects did not receive MRI scans because of claustrophobia or unwillingness to undergo the test. Analysis of Data Neuropsychological Tests. Raw scores were converted to agescaled scores using published norms [24-26, 28, 36, 38-41]. Composite z-scores were obtained for each domain. The raw scores from individual tests were also used in the exploratory analyses. MRI Scans. These were rated by a trained rater with good interrater (Î scores from 0.7 to 0.9 on various measures) and intra-rater (Î 0.8 to 0.9) reliability determined on five scans each. All ratings were carried out on a computer console using ANALYZE (Mayo Foundation) software. Brain infarctions were identified on T 1 -Homocysteine and Cognitive Impairment Dement Geriatr Cogn Disord 2003;15:155-162 15

Safety and efficacy of fluoxetine on functional outcome after acute stroke (AFFINITY): a randomised, double-blind, placebo-controlled trial

Background Trials of fluoxetine for recovery after stroke report conflicting results. The Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) trial aimed to show if daily oral fluoxetine for 6 months after stroke improves functional outcome in an ethnically diverse population. Methods AFFINITY was a randomised, parallel-group, double-blind, placebo-controlled trial done in 43 hospital stroke units in Australia (n=29), New Zealand (four), and Vietnam (ten). Eligible patients were adults (aged ≥18 years) with a clinical diagnosis of acute stroke in the previous 2–15 days, brain imaging consistent with ischaemic or haemorrhagic stroke, and a persisting neurological deficit that produced a modified Rankin Scale (mRS) score of 1 or more. Patients were randomly assigned 1:1 via a web-based system using a minimisation algorithm to once daily, oral fluoxetine 20 mg capsules or matching placebo for 6 months. Patients, carers, investigators, and outcome assessors were masked to the treatment allocation. The primary outcome was functional status, measured by the mRS, at 6 months. The primary analysis was an ordinal logistic regression of the mRS at 6 months, adjusted for minimisation variables. Primary and safety analyses were done according to the patient's treatment allocation. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611000774921. Findings Between Jan 11, 2013, and June 30, 2019, 1280 patients were recruited in Australia (n=532), New Zealand (n=42), and Vietnam (n=706), of whom 642 were randomly assigned to fluoxetine and 638 were randomly assigned to placebo. Mean duration of trial treatment was 167 days (SD 48·1). At 6 months, mRS data were available in 624 (97%) patients in the fluoxetine group and 632 (99%) in the placebo group. The distribution of mRS categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio 0·94, 95% CI 0·76–1·15; p=0·53). Compared with patients in the placebo group, patients in the fluoxetine group had more falls (20 [3%] vs seven [1%]; p=0·018), bone fractures (19 [3%] vs six [1%]; p=0·014), and epileptic seizures (ten [2%] vs two [<1%]; p=0·038) at 6 months. Interpretation Oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and epileptic seizures. These results do not support the use of fluoxetine to improve functional outcome after stroke

Does somatostatin have a role to play in migraine headache?

Migraine is a condition without apparent pathology. Its cardinal symptom is the prolonged excruciating headache. Theories about this pain have posited pathologies which run the gamut from neural to vascular to neurovascular, but no observations have detected a plausible pathology. We believe that no pathology can be found for migraine headache because none exists. Migraine is not driven by pathology – it is driven by neural events produced by triggers – or simply by neural noise- noise that has crossed a critical threshold. If these ideas are true, how does the pain arise? We hypothesise that migraine headache is a consequence of withdrawal of descending pain control, produced by “noise” in the cerebral cortex. Nevertheless, there has to be a neural circuit to transform cortical noise to withdrawal of pain control. In our hypothesis, this neural circuit extends from the cortex, synapses in two brainstem nuclei (the periaqueductal gray matter and the raphe magnus nucleus) and ultimately reaches the first synapse of the trigeminal sensory system. The second stage of this circuit uses serotonin (5HT) as a neurotransmitter, but the neuronal projection from the cortex to the brainstem seems to involve relatively uncommon neurotransmitters. We believe that one of these is somatostatin (SST). Temporal changes in levels of circulating SST mirror the temporal changes in the incidence of migraine, particularly in women. The SST2 receptor agonist octreotide has been used with some success in migraine and cluster headache. A cortical to PAG/NRM neural projection certainly exists and we briefly review the anatomical and neurophysiological evidence for it and provide preliminary evidence that SST may the critical neurotransmitter in this pathway. We therefore suggest that the withdrawal of descending tone in SST-containing neurons, might create a false pain signal and hence the headache of migraine

Pituitary adenylate cyclase activating polypeptide and migraine

Pituitary adenylate cyclase activating peptide (PACAP) is found in human trigeminocervical complex and can trigger migraine. PACAP levels were measured using a sensitive radioimmunoassay. Stimulation of the superior sagittal sinus (SSS) in cat elevated PACAP levels in cranial blood. Patients with moderate or severe migraine headache had elevated PACAP in the external jugular vein during headache (n = 15), that was reduced 1 h after treatment with sumatriptan 6 mg (n = 11), and further reduced interictally (n = 9). The data suggest PACAP, or its receptors, are a promising target for migraine therapeutics

Pituitary adenylate cyclase activating polypeptide and migraine.

Pituitary adenylate cyclase activating peptide (PACAP) is found in human trigeminocervical complex and can trigger migraine. PACAP levels were measured using a sensitive radioimmunoassay. Stimulation of the superior sagittal sinus (SSS) in cat elevated PACAP levels in cranial blood. Patients with moderate or severe migraine headache had elevated PACAP in the external jugular vein during headache (n = 15), that was reduced 1 h after treatment with sumatriptan 6 mg (n = 11), and further reduced interictally (n = 9). The data suggest PACAP, or its receptors, are a promising target for migraine therapeutics

Wernicke's encephalopathy in a non-alcoholic patient with a normal blood thiamine level

A 64-year-old woman who had never consumed alcohol presented to hospital with a several-day history of vomiting and severe diarrhoea, secondary to Clostridium difficile colitis. She had suffered a similar episode 3 months earlier. Her symptoms settled after 7 days’ treatment with vancomycin and metronidazole, but her admission was complicated by nosocomial pneumonia and her oral intake was poor. Fifteen days into her stay, she became drowsy and less communicative and developed generalised weakness. Clinical examination revealed signs of encephalopathy. She had slowed mentation, paucity of facial expression and slow limb movements. She could follow one-stage commands but only slowly and with significant prompting. Her eye movements were normal. She had mild generalised weakness in all four limbs, but her deep tendon reflexes were intact and plantar responses were downgoing. Ataxia could not be assessed reliably due to impaired consciousness. Electroencephalography showed generalised slowing without focal features. Magnetic resonance imaging (MRI) of the patient’s brain revealed symmetrical changes of high signal in the periaqueductal grey matter, superior colliculi and medial thalami, most evident on the fluid-attenuated inversion recovery (FLAIR) sequences (Box 1, A–C). These symmetrical periventricular changes were consistent with typical findings recently described for Wernicke’s encephalopathy. Given the clinical history of dietary deprivation and colitis, together with the typical radiological changes, a diagnosis of Wernicke’s encephalopathy was strongly suspected. Hence, intravenous thiamine 500 mg three times a day was administered, after which the patient made a dramatic clinical and radiological recovery (Box 1, D–F) over a period of about 7 days. Despite this, her pretreatment (Day 15) blood thiamine pyrophosphate level, measured using high-performance liquid chromatography, was eventually reported as being normal (136 nmol/L [reference range, 67–200 nmol/L]). However, given her clinical history, the changes noted on MRI and the dramatic improvement in her condition with thiamine, the diagnosis of Wernicke’s encephalopathy remained the most likely explanation.2 page(s

Stimulation of the middle meningeal artery leads to Fos expression in the trigeminocervical nucleus: a comparative study of monkey and cat

The pain of a migraine attack is often described as unilateral, with a throbbing or pulsating quality. The middle meningeal artery (MMA) is the largest artery supplying the dura mater, is paired, and pain-producing in humans. This artery, or its branches, and other large intracranial extracerebral vessels have been implicated in the pathophysiology of migraine by theories suggesting neurogenic inflammation or cranial vasodilatation, or both, as explanations for the pain of migraine. Having previously studied in detail the distribution of the second order neurons that are involved in the transmission of nociceptive signals from intracranial venous sinuses, we sought to compare the distribution of second order neurons from a pain-producing intracranial artery in both monkey and cat. By electrically stimulating the middle meningeal artery in these species and using immunohistochemical detection of the proto-oncogene Fos as a marker of neuronal activation, we have mapped the sites of the central trigeminal neurons which may be involved in transmission of nociception from intracranial extracerebral arteries. Ten cats and 3 monkeys were anaesthetised with α-chloralose and the middle meningeal artery was isolated following a temporal craniotomy. The animals were maintained under stable anaesthesia for 24 h to allow Fos expression due to the initial surgery to dissipate. Following the rest period, the vessel was carefully lifted onto hook electrodes, and then left alone in control animals (cat n = 3), or stimulated (cat n = 6, monkey n = 3). Stimulation of the left middle meningeal artery evoked Fos expression in the trigeminocervical nucleus, consisting of the dorsal horn of the caudal medulla and upper 2 divisions of the cervical spinal cord, on both the ipsilateral and contralateral sides. Cats had larger amounts of Fos expressed on the ipsilateral than on the contralateral side. Fos expression in the caudal nucleus tractus solitarius and its caudal extension in lamina X of the spinal cord was seen bilaterally in response to middle meningeal artery stimulation. This study demonstrates a comparable anatomical distribution of Fos activation between cat and monkey and, when compared with previous studies, between this arterial structure and the superior sagittal sinus. These data add to the overall picture of the trigeminovascular innervation of the intracranial pain-producing vessels showing marked anatomical overlap which is consistent with the often poorly localised pain of migraine

A potential role for two brainstem nuclei in craniovascular nociception and the triggering of migraine headache

Aim: To use an animal model of migraine to test whether migraine headache might arise from a brainstem-trigeminal nucleus pathway. Methods: We measured evoked and spontaneous activity of second-order trigeminovascular neurons in rats to test whether the activity of these neurons increased following the induction of cortical spreading depression or the imposition of light flash – two potential migraine triggers, or headache provokers. We then tested whether drugs that could activate, or inactivate, neurons of the nucleus raphe magnus or the periaqueductal gray matter, would affect any such increases selectively for the dura mater. Results: Injection of sodium glutamate (a neuronal excitant) into these two nuclei selectively inhibited the responses of trigeminovascular second-order neurons to dura mater, but not to facial skin, stimulation. Injection of lignocaine (a local anaesthetic) into these nuclei selectively potentiated the responses of these neurons to dura, but not to facial skin, stimulation. Furthermore, injections into either nucleus of glutamate inhibited the increase in the ongoing discharge rate of these neurons produced by cortical spreading depression and light flash. Conclusions: These results provide indirect evidence that trigeminovascular nociception may be tightly controlled by these two nuclei, whereas cutaneous trigeminal sensation may be less so. These nuclei may be relays of one possible brainstem-trigeminal pathway that could mediate migraine headache. Modification of neuronal activity in these two nuclei produced by migraine (headache) triggers may lie behind the pain of a migraine attack, at least in some cases