Prestroke dementia in patients with atrial fibrillation. Frequency and associated factors.

BACKGROUND AND PURPOSE: Prestroke dementia is frequent but usually not identified. Non-valvular atrial fibrillation (NVAF) is independently associated with an increased risk for dementia. However, the frequency and determinants of prestroke dementia in patients with NVAF have never been evaluated. OBJECTIVE: The aim of this study was to determine the frequency of prestroke dementia and associated factors in patients with a previously known NVAF. METHODS: This is an ancillary study of Stroke in Atrial Fibrillation Ensemble II (SAFE II), an observational study conducted in patients with a previously known NVAF, consecutively admitted for an acute stroke in French and Italian centers. Prestroke dementia was evaluated by the IQCODE in patients with a reliable informant. Patients were considered as demented before stroke when their IQCODE score was > or = 104. RESULTS: of 204 patients, 39 (19.1%; 95% confidence interval [CI]: 13.7%-24.5%) patients met criteria for prestroke dementia. The only variable independently associated with prestroke dementia was increasing age (adjusted odds ratio for 1 year increase in age: 1.10; 95 % CI: 1.04-1.17), and there was a nonsignificant tendency for previous ischemic stroke or TIA and arterial hypertension. CONCLUSION: One fifth of stroke patients with a previously known NVAF were already demented before stroke. The main determinant of prestroke dementia is increasing age. A large cohort is necessary to identify other determinants.

Placebo-controlled comparison of effervescent acetylsalicylic acid, sumatriptan and ibuprofen in the treatment of migraine attacks.

Acetylsalicylic acid (ASA) in combination with metoclopramide has been frequently used in clinical trials in the acute treatment of migraine attacks. Recently the efficacy of a new high buffered formulation of 1000 mg effervescent ASA without metoclopramide compared to placebo has been shown. To further confirm the efficacy of this new formulation in comparison with a triptan and a nonsteroidal anti-inflammatory drug (ibuprofen) a three-fold crossover, double-blind, randomized trial with 312 patients was conducted in Germany, Italy and Spain. Effervescent ASA (1000 mg) was compared to encapsulated sumatriptan (50 mg), ibuprofen (400 mg) and placebo. The percentage of patients with reduction in headache severity from moderate or severe to mild or no pain (primary endpoint) was 52.5% for ASA, 60.2% for ibuprofen, 55.8% for sumatriptan and 30.6% for placebo. All active treatments were superior to placebo (P < 0.0001), whereas active treatments were not statistically different. The number of patients who were pain-free at 2 h was 27.1%, 33.2%, 37.1% and 12.6% for those treated with ASA, ibuprofen, sumatriptan or placebo, respectively. The difference between ASA and sumatriptan was statistically significant (P = 0.025). With respect to other secondary efficacy criteria and accompanying symptoms no statistically significant differences between ASA and ibuprofen or sumatriptan were found. Drug-related adverse events were reported in 4.1%, 5.7%, 6.6% and 4.5% of patients treated with ASA, ibuprofen sumatriptan or placebo. This study showed that 1000 mg effervescent ASA is as effective as 50 mg sumatriptan and 400 mg ibuprofen in the treatment of migraine attacks regarding headache relief from moderate/severe to mild/no pain at 2 h. Regarding pain-free at 2 h sumatriptan was most effective.

Platelet-activating factor (PAF) in internal jugular venous blood of migraine without aura patients assessed during migraine attacks.

The aim of the study was to verify the production of PAF and the activity of PAF acetyl-hydrolase (PAF-AH), the enzyme involved in the catabolism of this phospholipid mediator, in migraine attacks. Their levels were determined during migraine crises in serial samples of internal jugular venous blood taken from five migraine patients without aura, who were admitted to the hospital during the crises. Internal jugular venous blood samples were taken immediately after catheter insertion at 1, 2, and 4 h after attack onset, and within 2 h from its cessation. PAF was purified by high-performance liquid chromatography (HPLC) and determined by radioimmunoassay method. The enzymatic activity of PAF-AH was measured by reverse-phase HPLC, based on the derivatization with 7-diethylaminocoumarin-3-carbonylazide. In the internal jugular venous blood of migraine patients without aura (MO), an increase was observed in PAF levels, which was already evident at the time of catheter insertion (885.6 +/- 82.8) and at the first hour (868.4 +/- 65.24) (ANOVA: P < 0.0001). PAF levels remained elevated through the second (746.8 +/- 82.95), fourth (700.6 +/- 34.93) and sixth hours (644.4 +/- 42.85), and then decreased at the end of the attack, reaching levels significantly lower than those measured at the time of catheter insertion (565.5 +/- 38.34). The activity of PAF-AH showed an opposite trend with higher values at the first hour and significantly lower values at the second and fourth hours from the beginning of the migraine attack (ANOVA: P < 0.02). The increased production of PAF may account for persistent platelet activation during migraine crises, even in the presence of an increased production of nitric oxide (NO) end-products which, on the other hand, should instead intervene in counteracting and limiting platelet activation. Potential sources of PAF production are the endothelial cells from cerebral vessels, stimulated by trigeminal neuropeptides, platelets themselves, and mast cells, as suggested by the neurogenic inflammation model.

Different cytokine levels in thrombolysis patients as predictors for clinical outcome.

Thrombolytic therapy not always improves clinical outcome in ischemic stroke patients. This could cause lymphomonocyte accumulation in the infarcted brain area. These produce an excessive amount of proinflammatory cytokines, such as IL-1 beta, IL-6 and TNF-alfa. The aim of our study was to determine ILs levels in fibrinolytic therapy treated patients, compared with healthy controls and to evaluate if the varying levels can predictors of neurological outcome. Eighteen patients underwent thrombolytic treatment with t-PA within 3 h. Plasma levels of IL-1 beta, IL-6, TNF-alfa and IL-10 were determined by ELISA method before and within 24 h after t-PA infusion and compared with controls. Significantly higher levels of IL-1 beta and Il-6 emerged in stroke patients before treatment compared with the control group (P < 0.05 and 0.04, respectively). Slightly higher plasma levels of TNF-alfa and lower plasma levels of IL-10 were also found at base line in stroke patients. After thrombolytic treatment no significant variations were observed in the levels of TNF-alfa and IL-6, whereas a trend toward lower values for IL-1 beta and higher levels for IL-10 was observed. Positive correlations among the values of IL-6, TNF-alfa and National Institute of Health Stroke Scale (NIHSS) at discharges were observed. A similar correlation with modified Rankin scale score at 3 month was found. Pre-treatment cytokine status seems to influence pre-and long-term clinical outcome. Therefore an investigation into the possible predictor of cytokines seem worthy.

Assessment of tremor: a new computerised tool for clinical practice.

The quantitative assessment of tremor represents the main difficulty in clinical evaluation. We developed a software package - T-Lab - for the biomechanical analysis of hyperkinetic movement disorders. This software can receive and elaborate data from an electronic device interfaced with a personal computer. The aim of our study was to verify the validity of the PC-aided method proposed in the routine assessment of tremor. We did this by a correlation (regression) analysis between the scores obtained by Webster's Amplitude Clinical Scale and the amplitude data by T-Lab and between EMG data and frequency measures of T-Lab. Forty-seven patients presenting with upper limb tremor were enrolled. Four series of data were obtained: two series for frequency and two for amplitude. A significant correlation between all sets of data compared was found. T-Lab represents a valid, objective and useful device of quantifying tremors in clinical practice.

Relevance of protein nitration in brain injury: a key pathophysiological mechanism in neurodegenerative, autoimmune, or inflammatory CNS diseases and stroke.

This review has focused on the evidence for the involvement of nitrative oxidation in certain neurodegenerative disorders (Parkinson's Disease, Alzheimer's Disease, Amyotrophic Lateral Sclerosis), stroke, and inflammatory and autoimmune disorders (with particular attention devoted to multiple sclerosis). The relationship between protein peroxidation and pathological changes observed in the above disorders has been reported. Whereas many of the findings are from studies with animal models and autoptic specimens from human patients, few data are available from cerebrospinal fluid and blood samples of the patients at different times and disease stages. The participation of nitrative oxidation to the direct and indirect injury of neurons and other cells of the brain (i.e., oligodendrocytes, for multiple sclerosis) is clear; less evident is their relevance for the development and progression of these disorders.Further studies should be aimed to establish the clinical and prognostic value of peroxidative markers for the CNS diseases considered. This is fundamental for the development of therapeutic interventions antagonizing nitric oxide-related species damage.

Cerebrospinal fluid biochemical markers in early detection and in differential diagnosis of dementia disorders in routine clinical practice.

Measurement of total tau and amyloid beta1-42 (Ab42) in cerebrospinal fluid (CSF) improves diagnostic accuracy of Alzheimer's disease (AD). We examined a consecutive patient sample referred to our center for diagnostic assessment of cognitive decline. CSF tau and Abeta42 were assayed each week as routine neurochemical analyses. There were 119 patients investigated. These included 61 with probable AD (35 mild AD, 26 severe AD), 24 with mild cognitive impairment (MCI), 14 with vascular dementia, 11 with Lewy body dementia, and 9 with fronto-temporal dementia. Mild AD showed significantly lower CSF Abeta42 levels and significantly higher CSF tau levels than the other diagnostic groups; 79% of MCI patients had pathological values for both biomarkers. We confirm that these biomarkers have a role in the clinical work-up of patients with cognitive deficits.

Neurovascular territory involved in different etiological subtypes of ischemic stroke in the Perugia Stroke Registry.

UNLABELLED: We studied the correlation between the potential causes of stroke (TOAST etiological groups) and the involvement of different vascular territories seen on computed tomography (CT) scans in patients with ischemic stroke. Information from consecutive patients with a first-ever stroke have been prospectively coded and entered into a computerized data bank (Perugia Stroke Registry). A population of 1,719 patients were evaluated: 1,284 patients (74.7%) had ischemic stroke. Large artery disease was the main cause of entire middle cerebral artery (MCA) territory infarcts (40.9%), superficial MCA territory infarcts (35.7%), and watershed infarcts (68.2%). The highest presence of emboligenic heart disease was found in the entire MCA territory infarcts (28.8%) or superficial (29.4%) supratentorial infarcts and in cerebellar infarcts (36.8%). Small artery disease was the most common presumed cause of deep MCA infarcts (75.0%) and posterior cerebral artery (PCA) territory infarcts (52.1%). IN CONCLUSION: stroke location could depend on its etiology. Lacunar infarcts are the most prevalent (36.7%), being mostly localized in the deep MCA territory; large artery disease includes more than two-thirds of watershed infarcts; the most prevalent territories involved in cardioembolic stroke are the entire MCA and posterior fossa.

Glycosylation of acetylcholinesterase and butyrylcholinesterase changes as a function of the duration of Alzheimer's disease.

The identification of biochemical markers of Alzheimer's disease (AD) may help in the diagnosis of the disease. Previous studies have shown that Abeta(1-42) is decreased, and tau and phospho-tau are increased in AD cerebrospinal fluid (CSF). Our own studies have identified glycosylated isoforms of acetylcholinesterase (Glyc-AChE) and butyrylcholinesterase (Glyc-BuChE) that are increased in AD CSF. Glyc-AChE is increased in APP (SW) Tg2576 transgenic mice prior to amyloid plaque deposition, which suggests that Glyc-AChE may be an early marker of AD. The aim of this study was to determine whether Glyc-AChE or Glyc-BuChE is increased in CSF at early stages of AD and to compare the levels of these markers with those of Abeta(1-42), tau and phospho-tau. Lumbar CSF was obtained ante mortem from 106 non-AD patients, including 15 patients with mild cognitive impairment (MCI), and 102 patients with probable AD. Glyc-AChE, tau and phospho-tau were significantly increased in the CSF of AD patients compared to non-neurological disease (NND) controls. Abeta(1-42) was lower in the AD patients than in NND controls. A positive correlation was found between the levels of Glyc-AChE or Glyc-BuChE and disease duration. However, there was no clear correlation between the levels of tau, phospho-tau or Abeta(1-42) and disease duration. The results suggest that Glyc-AChE and Glyc-BuChE are unlikely to be early markers of AD, although they may have value as markers of disease progression.

Magnetization transfer changes of grey and white matter in Parkinson's disease.

Since the attempt to evidence structural brain damage in Parkinson's disease (PD) by conventional magnetic resonance imaging (MRI) is usually disappointing, we have investigated whether the magnetization transfer ratio (MTR) can reflect changes in grey and white matter of PD patients. MTR was quantified in 44 regions of interest (ROIs) in both grey and white matter of 11 non-demented PD patients, ranging from 2 to 4 on the Hoehn and Yahr Scale, and eight age-matched healthy subjects. MTR differences between patients and controls were found in the supratentorial white matter and in the brainstem. In particular, lower MTR values were found in the paraventricular white matter of PD patients (p<0.05) while no differences were observed in corpus callosum, frontal, parietal, occipital lobes or centrum semiovalis. Lower MTR values were found in substantia nigra (p<0.001), red nucleus (p<0.05) and pons (p<0.05) of the patient group. No differences were discovered in basal ganglia and thalamus. These findings suggest that MTR measurements in the paraventricular white matter and brainstem may help to recognize a marker for probable PD.

Glutamate and nitric oxide pathway in chronic daily headache: evidence from cerebrospinal fluid.

A central sensitization has been advocated to explain chronic daily headache (CDH) due to sustained peripheral sensitization of allogenic structures responsible for sustained trigeminovascular system activation. Several mechanisms have been suggested to underlie central sensitization, but have been poorly investigated in CDH. They involve N-methyl-D-aspartate (NMDA) receptor activation and nitric oxide (NO) production and supersensitivity and increased and maintained production of sensory neuropeptides. The present study supports the above pathogenic mechanisms demonstrating a significant increase in glutamate and nitrite levels in the CSF of CDH patients, without a significant difference between patients without and those with analgesic overuse headache (P < 0.0001 and P < 0.002). The increase in CSF nitrites was accompanied by a significant rise in the CSF values of cyclic guanosine monophosphate (cGMP) in patients in comparison with controls (P < 0.0001). A statistically significant correlation emerged between visual analogic scale (VAS) values and glutamate, nitrites and cGMP. Although substance P (SP) and calcitonin gene-related peptide (CGRP), and to a lesser extent neurokinin A, were significantly increased in CSF compared with control subjects, their values did not correlate with glutamate, nitrites and cGMP levels in CSF in the patient group. The present study confirms the involvement of glutamate-NO-cGMP-mediated events underlying chronic head pain that could be the target of a new therapeutic approach which should be investigated.

Characteristics of migraine in an out-patient population over 60 years of age.

One hundred and sixty-three consecutive patients (129 females and 34 males) over 60 years of age attending the Headache Centre of the University of Perugia in the period January 2000-December 2001 were included in the study. One hundred and fifty-two (93.3%) were affected by a primary headache disorder. According to the 1988 IHS Criteria, their prevailing attacks could be diagnosed as migraine without aura (MwoA) in 57.2% of cases (n = 87) and as migraine with aura (MwA) in 11.8% of cases (n = 18). Attacks both in MwoA and MwA were unilateral and of severe-to-moderate intensity in 45% and 50% of cases. Head pain was referred as pulsating by 56% and 38.9% of MwoA patients MwA patients, respectively. Aggravation with routine daily activities was present in 72.4% and 61.1% in MwoA and MwA patient groups. The most frequent accompanying symptoms were photophobia and phonophobia. Headache attacks were of shorter duration in MwA patients, but in 3.4% of MwoA patients attacks lasted between 2 and 4 h. Of patients affected by MwA, 55% referred, together with the typical attacks, symptoms of aura not followed by headache. A worsening of headache in the last 5 years was reported by 67.8% and 44.4% of MwoA and MwA patients, respectively. Of the patients with MwoA, 86.2% (n = 75), and 83.3% (n = 15) of those with MwA used symptomatic drugs for their attacks. In the majority of cases they took more than one analgesic or non steroidal anti-inflammatory drug. A total of 51.7% of patients with MwoA and 55.5% of patients with MwA were under prophylactic treatment. Preventive drugs included antidepressants, beta-blockers, calcium channel antagonists and antiepileptic drugs. The choice of symptomatic or prophylactic drugs was made, in the majority of cases, on the basis of concomitant diseases.

Localized (1)H magnetic resonance spectroscopy in mainly cortical gray matter of patients with multiple sclerosis.

The brain water fraction (R), the brain water transverse relaxation time (T2), the atrophy index (alpha) and the absolute concentration of the principal brain metabolites (NAA, Cho and Cr) were measured by localized proton magnetic resonance spectroscopy in the occipito-parietal cortex (mainly gray matter) of 15 relapsing-remitting (R-R) multiple sclerosis (MS) patients, 15 secondary progressive (SP) MS patients and 8 healthy subjects. Significantly lower values of N-acetylaspartate (NAA), creatine (Cr) and the NAA/Cr ratio in the occipito-parietal cortex were detected in SP MS patients than in R-R MS and control subjects (p < 0.01). Moreover, MS patients showed shorter T2 water relaxation times and reduced brain water fraction compared with controls. Higher atrophy indices were also detected in the mainly occipito-parietal gray matter of MS patients, particularly in those with the progressive form. These findings suggest that the pathological process in MS is not limited to either white matter lesions or normal-appearing white matter but extends into the cortical gray matter (occipito-parietal), particularly in the progressive form of the disease. This can involve changes in neural metabolism or neural shrinkage and neuron loss. The significant increase in atrophy indices could be the expression of the relatively higher cerebrospinal fluid signal from the occipito-parietal cortex, even in the absence of obvious cortical atrophy.

Stroke related to carotid artery dissection in a young patient with Takayasu arteritis, systemic lupus erythematosus and antiphospholipid antibody syndrome.

Autoimmune diseases are rarely the cause of stroke even in the young age group in association with cervical artery dissection and collagen vascular diseases. Takayasu arteritis is a chronic, idiopathic, inflammatory disease that primarily affects large vessels, such as the aorta and its main branches. Takayasu arteritis rarely coexists with systemic lupus erythematosus, and only few cases have been reported in association with the presence of antiphospholipid antibodies. We describe a young patient with right internal carotid artery dissection and subsequent stroke who presented with all three syndromes. Although this patient met the diagnostic criteria for each syndrome, systemic lupus erythematosus, Takayasu arteritis and the antiphospholipid antibody syndrome, it remains unlikely that the three disorders are not related. We suggest a single disimmune disorder may have led to carotid artery dissection.

Autosomal recessive early onset parkinsonism is linked to three loci: PARK2, PARK6, and PARK7.

Autosomal recessive, early onset parkinsonism (AREP) is genetically heterogeneous. Mutations in the parkin gene (PARK2 locus, chromosome 6q) account for up to 50% of AREP families. The parkin protein displays ubiquitin-ligase activity for different targets, which accumulate in the brain of patients with parkin defect and might cause neurodegeneration. Two new AREP loci (PARK6 and PARK7) have been recently mapped on chromosome 1p and confirmed in independent datasets, suggesting that both might be frequent. The three AREP forms display similar clinical phenotypes. Recruiting new families will help cloning the defective genes at PARK6 and PARK7 loci. This will contribute to unraveling the pathogenesis of AREP, and it is also expected to foster our understanding of molecular events underlying classic Parkinson's disease.

Cerebrospinal fluid levels of biomarkers and activity of acetylcholinesterase (AChE) and butyrylcholinesterase in AD patients before and after treatment with different AChE inhibitors.

In order to evaluate the biochemical effects of long-term treatment with inhibitors of acetylcholinesterase (AChE) in patients with Alzheimer's disease (AD), we measured the activities of AChE and butyrylcholinesterase (BuChe) and the concentrations of beta-amyloid (1-42), tau and phosphorylated tau proteins in the cerebrospinal fluid (CSF). A total of 91 patients suffering from probable AD of mild to moderate degree were treated for 6 months with donepezil (n=59), galantamine (n=15), rivastigmine (n=10), or placebo (n=7). AChE activity in CSF was significantly increased after treatment with donepezil and galantamine; the opposite was observed in the rivastigmine-treated group. Untreated patients did not show any AChE activity variation. BuChE did not show any change in any of the groups studied. Mean values of beta-amyloid(1-42), total tau and phosphorylated tau also did not vary significantly. We conclude that AChE inhibitors induce different effects on CSF AChE activity, while other CSF biomarkers are not significantly affected by treatment.

Normal pressure hydrocephalus and basilar artery aneurysm. Case report and pathogenetic consideration.

The authors describe the case of a 60-year-old patient with basilar artery aneurysm who in time developed normal pressure hydrocephalus (NPH). Clinical examinations and laboratory tests did not reveal other data from which the pathology could be attributed to causes other than the vascular malformation already considered. The mechanical obstruction exerted by the aneurysm lodged on the floor of the third ventricle represents, according to the authors, the physiopathogenetic mechanism by which a temporal delay is developed between the endoventricular pulsation and that of the cerebral veins so as to produce a precise pulsatile gradient in a centrifugal direction to allow the formation of an active hydrocephalus proportional to the entity of cerebrospinal fluid (CSF) pulse.

Peripheral blood lymphocytes muscarinic cholinergic receptor subtypes in Alzheimer's disease: a marker of cholinergic dysfunction?

Muscarinic M2-M5 muscarinic cholinergic receptors were investigated in peripheral blood lymphocytes of patients with mild cognitive impairment of the Alzheimer's type (MCIAT), probable Alzheimer's disease (AD) and probable vascular dementia (VaD). [3H]-N-methyl scopolamine (NMS) in the presence of muscarinic antagonists and Mamba venom to occlude different receptor subtypes was used as radioligand. Analysis of [3H]-NMS binding curves without receptor subtype assessment resulted in a slight decrease of receptor density in AD patients. Evaluation of receptor subtypes in MCIAT and AD patients revealed a decrease of M3 receptor by more than 50%, an increase of M4 receptor expression by about 20% and no changes of M2 or M5 receptors. The expression of M2-M5 receptors was unaltered in VaD patients. Strong positive and negative correlations respectively were found between the density of lymphocyte M3 and M4 receptors and MMSE score in both MCIAT (0.78 for M3 receptor and 0.80 for M4 receptor) and AD (0.82 for M3 receptor and 0.83 for M4 receptor) patients. These findings suggest that changes in the expression of peripheral blood lymphocyte M3 and M4 receptors in AD are related to the degree of cognitive impairment. Assessment of lymphocyte muscarinic receptor subtypes may contribute to characterization of cholinergic impairment in AD.

Clinical and genetic analysis of hereditary and sporadic ataxia in central Italy.

We have clinically and genetically evaluated 24 affected patients belonging to 22 Italian Friedreich ataxia (FA) families, 52 patients from 32 kindreds with proven autosomal dominant cerebellar ataxia (ADCA), 9 patients belonging to 5 families with autosomal recessive hereditary ataxia (ARCA) and 103 sporadic cases, 89 of which affected by idiopathic late onset cerebellar ataxia (ILOCA). Genotype-phenotype correlation analyses in FA patients have evidenced an inverse relationship between GAA repeat expansion length and age of onset, disease duration, and presence of cardiomyopathy. Among autosomal dominant types, spinocerebellar ataxia 2 (SCA2) genotype has been found in 31% of our ADCA families, resulting the most frequent form of ataxia. Phenotypic analysis of the various SCA subtypes evidenced a marked heterogeneity of symptoms with a substantial overlap between different syndromes.