Diffusion tensor imaging (DTI) in the detection of white matter lesions in patients with mild cognitive impairment (MCI).

Mild cognitive impairment (MCI) is recognized as a precursor to dementia. The amnestic MCI progresses usually to Alzheimer disease. Amnestic MCI multiple domain (md-MCI) seems to progress more rapidly than amnestic MCI single domain (a-MCI). In an attempt to identify patients at risk, we examined white matter changes in MCI subtypes using diffusion tensor imaging (DTI). We also tried to correlate DTI findings to neuropsychological tests. Forty-four amnestic single domain (a-MCI) patients, 19 amnestic multi domain (md-MCI), and 25 cognitively normal (NC) controls were included in the present study. All participants were assessed clinically using a battery of cognitive tests. DTI was performed to measure fractional anisotropy (FA) and apparent diffusion coefficient (ADC). Areas studied were corpus callosum, posterior cingulum (PC), anterior cingulum (AC), and superior longitudinal fasciculus (SLF). ADC and FA of the above areas were related to the scores of certain neuropsychological tests that evaluate visual and verbal memory. No difference in DTI measurements was found between the two MCI subtypes. ADC in MCI cases was increased in comparison with NC in the genu, PC, right SLF, and left AC. FA was spared. Verbal memory was related to ADC of the genu, PC, right AC and right SLF, and to FA of the left SLF. Visual memory was related to ADC of the genu, PC, right AC, and SLF. The strongest correlation found was between the visual memory and the ADC of the right PC (Spearman ρ = 0.45, p < 0.001). DTI revealed that ADC was increased in certain brain areas in MCI patients. No difference in DTI measurements was found between the two MCI subtypes. DTI indices correlate with cognitive performance.

Intravenous valproate aborts glyceryl trinitrate-induced migraine attacks: a clinical and quantitative EEG study.

We evaluated EEG changes and pain relief in migraineurs with glyceryl trinitrate (GTN)-induced attacks treated with intravenous sodium valproate (iSVP). EEG frequency analysis was performed in 45 migraineurs without aura and in 19 controls at baseline, at the time of maximum GTN-induced headache, and 30 min after 300 mg iSVP. Nineteen migraineurs presented early specific headache (migraine identical to spontaneous attacks; MSp) and 26 presented early non-specific headache (MnSp). During attacks in MSp there was an increase of theta [16.6% (14.8-19.3) to 19.4% (17.4-22.1), P = 0.02] and delta activity [3.6% (3.1-4.4) to 5.4% (3.9-6.5), P = 0.009], whereas there was no decrease in alpha [41.4% (36.2-45.1) to 39.7% (34.7-44.8)] or beta activity [37.6% (34.7-40.3) to 35.1% (33.5-38.8)]. iSVP reduced migraine from severe/moderate to mild/no pain in 17 (90%) MSp patients, and was associated with reversion of the slow rhythmic activity to baseline levels [theta 16.9% (14.6-18.9); delta 3.2% (3-4.1)]. There was no change in EEG frequency activity after administration of GTN or iSVP in controls and in MnSp. iSVP is well tolerated and effective in treating GTN-induced migraine in migraineurs without aura, and appears to restore the disturbances of cortical electrogenesis associated with these attacks.

Are transient increases in blood pressure during the treadmill stress test associated with headache?

We aimed to investigate whether transient increases in blood pressure (BP) are associated with headache, by provoking hypertension in 50 non-hypertensive cephalalgia sufferers (Ce), 50 hypertensive cephalalgia sufferers (HyCe) and 50 healthy subjects (C) with a treadmill stress test. Occurrence of headache among groups did not differ (P = 0.81); however, women developed headache more frequently than men (P < 0.0001). The 35 individuals who developed headache during the test compared with those who did not (regardless of their original group) had higher absolute diastolic BP and higher absolute and relative diastolic BP increase during the test (P < 0.0001). HyCe patients that developed headache had higher diastolic BP than those that did not (P < 0.002). For each group, the absolute/relative mean increases of systolic/diastolic BP did not differ between patients that developed headache and those that did not excepting relative diastolic BP increase in Ce (28% vs. 15%, P = 0.006). The appearance of headache during dynamic exercise is not associated with a history of headache or hypertension. In non-hypertensive cephalalgia sufferers, relative diastolic BP increases of >27% are associated with headache attacks whereas in HyCe sufferers absolute diastolic BP values may be more important.

Gastric emptying after semi-solid food in multiple system atrophy and Parkinson disease.

BACKGROUND: Gastrointestinal symptoms such as nausea, abdominal pain, and bloating are frequent complaints in patients with Parkinson disease (PD) and in patients with multiple system atrophy (MSA), and may be associated with delayed gastric emptying (GE). Although several GE studies in patients with PD have been performed, scant data exist in patients with MSA. METHODS: We assessed GE half-times (T50) in 12 patients with MSA and compared them with those of 12 patients with PD and 12 age-matched healthy controls.GE was estimated scintigraphically using the left anterior oblique method after ingestion of a (99m)Tc colloid-labeled balanced semi-solid meal (yogurt). GE data were obtained every 15 minutes until there was complete emptying of the stomach. Blood pressure, heart rate, plasma glucose and glucosylated hemoglobin were regularly determined. RESULTS: Reproducibility of the GE technique was excellent (Bland-Altman analysis, limits of agreement: -2.3 to 2.8). T50 was longer in MSA (82+/-3.4 min) and in PD (90.6+/-3.9 min) patients compared with controls (46.2+/-0.7) (two-way ANOVA, p<0.0001). T50 did not differ between patients with MSA and those with PD. No correlation existed between T50 and age, duration of the disease, magnitude of postprandial hypotension, levels of plasma glucose and glucosylated hemoglobin (Kendall's tau, p>0.05). CONCLUSIONS: Our results suggest that patients with MSA have GE rates similar to those of patients with PD, but slower than healthy age matched individuals. It remains to be investigated whether gastrointestinal dysfunction in MSA is related to both brain and peripheral pathology, as is presumed for PD.

Expression of beta2 adrenoreceptors on peripheral blood mononuclear cells in patients with primary and secondary progressive multiple sclerosis: a longitudinal six month study.

BACKGROUND: Beta(2) adrenoreceptor expression on peripheral blood mononuclear cells is increased in progressive multiple sclerosis. This increase has been correlated with disease activity in relapsing-remitting multiple sclerosis. OBJECTIVE: To determine the beta(2) adrenoreceptor expression in primary and secondary progressive multiple sclerosis in relation to findings on magnetic resonance imaging (MRI) and clinical disease activity. METHODS: 10 patients with multiple sclerosis were studied (five with primary progressive and five with secondary progressive forms of the disease) over a period of six months. Monthly clinical and MRI assessments of the brain and spinal cord were carried out. Beta(2) adrenoreceptor expression was assessed monthly using a ligand binding assay with [(125)I]iodocyanopindolol. Expression of beta(2) adrenoceptors on peripheral blood mononuclear cells was also assessed in five normal controls over a similar period. RESULTS: The mean (SEM) value of beta(2) adrenoreceptor density for the five normal controls was 1346 (183) sites/cell, with affinity Kd of 120 (40) pM. MRI disease activity in primary progressive multiple sclerosis was reported on two occasions and on those occasions the expression of beta(2) adrenoreceptors was increased in excess of 1900 sites/cell; in the remaining 28 observations beta(2) adrenoreceptor expression was within the normal range (800 to 1900 sites/cell). In patients with secondary progressive disease, MRI disease activity was observed on 16 occasions. In these patients expression of beta(2) adrenoreceptors was increased in excess of 2000 sites/cell in all measurements except in one subject who did not show MRI activity throughout the six months period of study. The affinity of the receptors was within the normal range in all cases. CONCLUSIONS: Increased expression of beta(2) adrenoreceptors was correlated with MRI disease activity in two patients with primary progressive multiple sclerosis. In secondary progressive multiple sclerosis, increased expression of beta(2) adrenoreceptors tended not to correlate with MRI disease activity. This may reflect a persistent Th1 immune reaction in the secondary progressive form of the disease.

Changes of gastric emptying rate and gastrin levels are early indicators of autonomic neuropathy in type II diabetic patients.

The authors investigated the effect of a balanced meal on gastric emptying rate and gastrin plasma concentrations in patients with type II diabetes and autonomic neuropathy, in diabetic patients without autonomic neuropathy, and in healthy subjects (controls). Before food the gastrin plasma concentrations were higher in patients with diabetes with autonomic neuropathy. After food, gastric emptying rate was slower in patients with diabetes with autonomic neuropathy, whereas gastrin plasma concentrations increased in 30 minutes in all groups but to a greater extent in patients with diabetes with autonomic neuropathy. Sixty minutes after food, there was a significant decrease in gastrin plasma concentrations in patients with diabetes with autonomic neuropathy, compared with the other two groups. These data suggest that in patients with type II diabetes with autonomic neuropathy, food causes slower gastric emptying and different plasma gastrin level responses from those in patients with type II diabetes without autonomic neuropathy and controls. There are therefore differences in the responses to food ingestion between these groups because of vagal denervation induced by autonomic neuropathy. These tests should be reserved for patients with symptoms suggestive of disturbed gastric emptying, or for patients with autonomic neuropathy without symptoms of gastroparesis.

The use of clonidine in the management of autonomic overactivity in neuroleptic malignant syndrome.

The aim of this study was to identify the effectiveness of clonidine in the recovery of patients with neuroleptic malignant syndrome and autonomic dysfunction, including blood pressure lability. Nine patients with neuroleptic malignant syndrome and autonomic dysfunction were treated with clonidine in the intensive care unit, according to a protocol, and the results were compared with those of seven patients with the same syndrome who were not treated with clonidine. Clonidine was administered until blood pressure stability was fully restored, and thereafter the dose was gradually reduced. There was a significant reduction in the duration of ventilation and stay in the intensive care unit in the clonidine group. Three patients from the nonclonidine group died. The data suggest that in the clonidine group, patients with neuroleptic malignant syndrome and autonomic dysfunction appear to have better and faster recovery, especially in blood pressure control, after intravenous clonidine treatment.

Postprandial hypotension and parkinsonian state in Parkinson's disease.

Abnormal postprandial cardiovascular responses such as postprandial hypotension (PPH) occur in primary autonomic failure and contribute significantly to morbidity. The extent and frequency of PPH and its relationship to the parkinsonian state in idiopathic Parkinson's disease (IPD) is unknown. By studying 20 patients with IPD (without autonomic failure) and 16 age-matched controls after both groups ingested a standard isocaloric balanced liquid meal, we have shown that supine PPH complicates IPD and is related to marked worsening of the parkinsonian state as measured by a cumulative score of tremor, rigidity, bradykinesia, posture, and gait. Furthermore, significant postural hypotension is unmasked that results in postural intolerance due to presyncopal symptoms. Our study indicates that, in patients with IPD, ingestion of a meal may lead to abnormal postprandial cardiovascular responses and aggravation of the parkinsonian stage. The underlying mechanisms are unclear, although vasodilatory gut peptides released in response to food ingestion may be contributory.

Management of blood pressure instability in severe tetanus: the use of clonidine.

OBJECTIVE: To evaluate the effectiveness of clonidine in the management of unstable blood pressure in severe tetanus. DESIGN: Patients with severe tetanus and blood pressure instability were treated with clonidine and the results were compared with those of other patients with severe tetanus who were not treated with clonidine. SETTING: Intensive care unit of the Chest Hospital of Athens. PATIENTS: We studied 27 patients with severe tetanus and autonomic dysfunction. INTERVENTIONS: Patients were managed according to a protocol. MEASUREMENTS AND RESULTS: Clonidine was administered until blood pressure stability was the fully restored and the dose was then gradually reduced. Five patients from the nonclonidine group and 2 from the clonidine group died. CONCLUSIONS: These results suggest that clonidine is effective in the treatment of blood pressure instability in severe tetanus.

Auditory event related potentials in patients with epilepsy on sodium valproate monotherapy.

OBJECTIVES: The effects of antiepileptic drugs on event related potentials (ERPs) have been studied, but with contradictory results. In this study we examine the effect of sodium valproate (VPA) on ERPs in patients with epilepsy. MATERIALS AND METHODS: Auditory event related potentials were recorded in 40 patients with idiopathic generalized epilepsy, 20 on monotherapy with sodium valproate (VPA), 20 on monotherapy with carbamazepine and 20 age and sex matched controls. All subjects performed a simple auditory discrimination task in which a target tone was presented on 20% of the trials. RESULTS: Mean P3 latency of the VPA group was significantly prolonged but not in carbamazepine group and healthy controls. CONCLUSION: We conclude that VPA monotherapy has an effect on P300 latency in patients with epilepsy. This difference might be attributed to effects of treatment with VPA and may clarify in the future the mechanism of P300.

EEG and topographic frequency analysis in migraine attack before and after sumatriptan infusion.

Electroencephalographic changes occurring in patients with migraine have received much attention. Although in migraineurs a number of studies have been done after nitroglycerin-induced attacks, there is no reported EEG study before and after nitroglycerin-induced sumatriptan-treated attacks. We, therefore, studied the EEG topographic frequency analysis in 19 symptom-free, otherwise healthy, unmedicated patients with common migraine and in 19 age- and sex-matched controls before nitroglycerin, at the time of maximum pain, and 30 minutes after sumatriptan. During headache attacks, an increase of slow rhythmic activity of the theta and delta range and a decrease of activity in the alpha and beta range were observed. These abnormalities disappeared 30 minutes after a sumatriptan injection. This suggests that common migraine is associated with disturbances of cortical electrogenesis and may provide insight into the causes of migraine and aid in the development of effective therapies.

Octreotide reduces alcohol-induced hypotension and orthostatic symptoms in primary autonomic failure.

Symptomatic postural hypotension is a major problem in patients with primary idiopathic autonomic failure, and ingestion of small quantities of alcohol may worsen the degree of postural hypotension. The proposed mechanisms include mesenteric vasodilation and release of vasodilatory gut peptides. We measured systemic, mesenteric, other regional vascular and biochemical responses to alcohol ingestion before and after pre-treatment with the somatostatin analogue Octreotide (which inhibits the release of a wide range of gut peptides normally released in response to food ingestion) in six patients with primary autonomic failure. Octreotide effectively prevented alcohol-induced hypotension and vasodilatation of the mesenteric vascular bed, with improvement of signs and symptoms of hypotension post-alcohol. This suggests that the mechanism of alcohol-induced symptomatic hypotension in autonomic failure is at least partly mediated by release of vasodilatatory gut peptides with resultant mesenteric vasodilatation.

Central defects of autonomic function in secondary progressive multiple sclerosis: observations based on cardiovascular and growth hormone responses to clonidine.

The haemodynamic, autonomic and hormonal effects of the centrally acting sympatholytic drug clonidine have been studied in 10 patients with secondary progressive multiple sclerosis (MS) and 10 age- and sex-matched normal subjects (controls). Detailed physiological studies, previously described in these 10 MS patients, indicated that none had postural hypotension or an abnormal Valsalva manoeuvre; six, however, had impaired responses to a range of pressor tests, suggestive of a central autonomic abnormality. In the controls after clonidine, there was a fall in blood pressure and superior mesenteric artery vascular resistance. Finger temperature and growth hormone levels rose. In the MS patients after clonidine, the haemodynamic responses varied. In five out of ten MS patients, as in the controls, there was a fall in blood pressure and superior mesenteric vascular resistance, while finger temperature rose. There was no haemodynamic response to clonidine in the other five MS patients. In eight out of ten MS patients there was no rise in plasma growth hormone levels after clonidine. The abnormal haemodynamic responses to clonidine, taken in conjunction with the previous physiological studies, suggest involvement of central sympathetic interconnections in five of the MS patients, probably as part of the demyelinating process. The impaired growth hormone response to clonidine occurred in a greater number of patients and may indicate lesions in the hypothalamus. These observations in MS patients, without overt clinical evidence of autonomic failure, indicate that the haemodynamic and growth hormone responses to clonidine may be an early indicator of autonomic dysfunction involving central autonomic centres and pathways.

High beta-adrenoceptor density on peripheral blood mononuclear cells in progressive multiple sclerosis: a manifestation of autonomic dysfunction?

In multiple sclerosis (MS) up-regulation of beta-adrenoceptors on peripheral blood mononuclear cells (PBMCs) has been attributed to either autonomic dysfunction, inflammation or a combination of the two. We have compared secondary progressive MS patients with normal subjects (NS) and two models of autonomic dysfunction; pure autonomic failure (PAF) and multiple system atrophy (MSA, Shy-Drager syndrome). There was up-regulation of beta-adrenoceptors on PBMCs in MS and PAF patients but not in MSA patients. Only in PAF patients beta-adrenoceptor up-regulation was correlated with low plasma levels of noradrenaline (NA) and adrenaline (Ad). In addition to studies in the basal state, measurements also were made after the centrally acting sympatholytic agent clonidine. These were combined with haemodynamic and neurohormonal measurements. After clonidine, there was a fall in blood pressure in NS and MSA patients but not in MS and PAF patients; a rise in growth hormone (GH) in NS and PAF patients but not in MS and MSA patients; and an up-regulation in PBMCs beta-adrenoceptors in NS but not in MS, MSA and PAF patients. Up-regulation of beta-adrenoceptors on PBMCs in MS could be attributed to autonomic dysfunction but the disparity between MS and PAF patients when considering their plasma levels of NA and Ad argue against. Although the neurohormonal responses to clonidine and the physiological assessment of autonomic function in progressive MS patients, demonstrate central autonomic dysfunction resembling that of the MSA patients, the normal basal beta-adrenoceptor densities in the latter, suggests that the up-regulation of these receptors is independent of the central autonomic dysfunction in MS.

Expression of beta-adrenoceptors on circulating mononuclear cells in hypertensives and normotensives before and after reduction of central sympathetic outflow by clonidine.

We have studied beta-adrenoceptor number and affinity on peripheral blood mononuclear cells (PBMCs) in normotensives (NT) and hypertensives (HT), before and after intravenous administration of clonidine, an alpha 2-adrenoceptor agonist which lowers blood pressure predominantly by reducing central nervous system sympathetic outflow. After clonidine, there was a decrease in blood pressure and plasma noradrenaline (NA) and adrenaline (Ad) levels, with an increase in growth hormone (GH) levels, in both NT and HT. There was no difference in basal beta-adrenoceptor densities on PBMCs between NT and HT. After clonidine at 30 and 60 min, there was an increase in beta-adrenoceptor density associated with a low affinity in NT. In HT, no changes were observed. The increased beta-adrenoceptor densities on PBMCs in NT after clonidine, returned to baseline values after 2 h. Short term up-regulation of beta-adrenoceptors on PBMCs in NT after clonidine is accompanied by a fall in blood pressure (BP) and plasma levels of catecholamines. The changes may represent a compensatory mechanism reflecting a rapid externalization-activation of adrenoceptors residing on the internal surface of the membranes with a change of the coupling ability between the receptor and the catalytic component. In HT, although the haemodynamic and neurohormonal response to clonidine was similar to NT, short term upregulation of receptors did not occur. The lack of such response may mirror a form of regulatory dysfunction of beta-adrenoceptors in HT.

The relationship between blood flow and pulsatility index in the superior mesenteric artery at rest and during constrictor stimuli in normal subjects.

The relationships between superior mesenteric artery blood flow (SMABF) and pulsatility index (PI) measurement during rest (25 subjects) and stimuli constricting the SMA (16 subjects) have been studied in normal subjects. At rest and during constrictor stimuli, SMABF and PI were highly reproducible (r = 0.89, p < 0.01 for SMABF, and r = 0.97, p < 0.001 for PI) between two observers. There was significant correlation between changes in SMABF, PI, and SMA vascular resistance during the constrictor stimuli, except during head-up tilt when PI was unchanged. Both PI and SMABF measurements are reproducible and can be used to monitor physiological changes in suitable (18 of 25) subjects. PI measurement, although semiquantitative, by itself can also be used to monitor these changes. This may be also of importance in pathological situations such as intestinal ischemia, where measurement of volume blood flow may be less accurate due to irregularities of the vessel wall. PI measurement, however, ideally should not be used in studies involving postural change.

Alcohol ingestion lowers supine blood pressure, causes splanchnic vasodilatation and worsens postural hypotension in primary autonomic failure.

Patients with pure autonomic failure (PAF) and multiple system atrophy (MSA) may complain of feeling light-headed after alcohol ingestion particularly on assumption of the upright posture. The reasons for this have not been investigated. We therefore studied the effects of oral alcohol (40% vodka in sugar-free orange juice) and placebo (juice only) on the systemic and regional (including superior mesenteric artery, SMA) blood flow in nine patients with PAF and six patients with MSA. After alcohol, there was a fall in supine blood pressure (BP) and vasodilatation in the SMA but no change in cardiac output, or forearm muscle and cutaneous blood flow in either PAF or MSA; BP fell further during head-up tilt with no changes in levels of plasma catecholamines. After placebo, there were no changes while supine. We conclude that alcohol lowers supine BP and dilates the SMA with no change in muscle or cutaneous blood flow. Alcohol also enhances the fall in BP during head-up tilt. This may explain the symptoms experienced by PAF and MSA patients after alcohol.

Beta-adrenoceptor expression on circulating mononuclear cells of idiopathic Parkinson's disease and autonomic failure patients before and after reduction of central sympathetic outflow by clonidine.

There is a short-term up-regulation of beta-adrenoceptors on peripheral blood mononuclear cells (PBMC) after reduction of central sympathetic outflow by clonidine in normal individuals. We have studied beta-adrenoceptor number and affinity on PBMC in idiopathic Parkinson's disease (PD), pure autonomic failure (PAF), and multiple system atrophy (MSA; Shy-Drager syndrome) patients and age- and sex-matched normal controls (NC) before and after intravenous administration of clonidine, an alpha 2-adrenoceptor agonist which lowers blood pressure predominantly by reducing CNS sympathetic outflow. Basal beta-adrenoceptor density was high in PAF but within the normal range in PD and MSA patients. After clonidine there was a decrease in plasma levels of noradrenaline (NA) and adrenaline (Ad) in PD, MSA, and NC, and an increase in growth hormone (GH) in PD, PAF, and NC. NC. In PAF, NA and Ad remained unchanged. In MSA, there was no increase in GH levels. There was an up-regulation of beta-adrenoceptors on PBMC at 30 and 60 minutes after clonidine administration, which returned to baseline values after 2 hours, and the affinity of the receptors was decreased in NC and PD patients. Intracellular production of cAMP after isoproterenol stimulation demonstrated that the up-regulation was not functional. Up-regulation after clonidine did not occur in PAF and MSA patients. The observed correlation of plasma NA and sympathetic defect with basal and clonidine-induced up-regulation of beta-adrenoceptors on PBMC may provide insight into beta-adrenoceptor changes in other tissues and also help in differentiating subgroups of autonomic failure patients.

Cardiovascular and hormonal responses to liquid food challenge in idiopathic Parkinson's disease, multiple system atrophy, and pure autonomic failure.

We investigated the effect of a balanced liquid meal on blood pressure (BP) and heart rate (with patients supine and during head-up tilt), and on levels of plasma catecholamines, glucose, and insulin, in patients with idiopathic Parkinson's disease (IPD), multiple system atrophy (MSA), pure autonomic failure (PAF), and in healthy subjects (controls). After food, supine BP fell in IPD, but to a greater extent in MSA and PAF. In controls, BP was unchanged. Head-up tilt did not lower BP in IPD and controls, but there was a postprandial fall to lower levels in both MSA and PAF. Plasma norepinephrine levels rose in IPD pre- and postprandially during tilt, but were unchanged in MSA and PAF. These data suggest that in IPD, food causes a smaller fall in supine BP than in MSA and PAF. In IPD, as in controls, food does not induce or unmask postural hypotension, unlike in MSA and PAF, in which BP falls to even lower levels. There are therefore differences in the responses to food ingestion between these groups. This may be of value in separation of these disorders at an early stage.