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In 2003, we conducted a sensitisation campaign on migraine in the Casilino district of Rome, by sending a letter with the ID Migraine test to all the households and placing posters in the GPs' waiting room. Out of 195 headache patients recruited, 92% had migraine while 73% had never consulted a physician for headache. The aim of this study was to evaluate the long-term impact of this campaign. The follow-up was performed by a telephone interview. The questionnaire considered the characteristics of headache, quality of life, preventive and acute treatments, drug efficacy, comorbidity and subjective usefulness of the campaign. Of the 179 migraineurs, 90.5% (mean age 40.7 +/- 16.5, 139 females) were included in the follow-up. An improvement was observed in mean pain intensity (-13.9%; p < 0.0001) and mean HIT-6 score (-6.1%; p = 0.0003). The campaign was considered to be useful by 63.6% of cases, while 66.1% reported an improvement in their clinical status. Improved patients showed a decreased mean number of days with headache per month (-51.7%; p < 0.0001), pain intensity (-21.8%; p < 0.0001), headache duration (-18.1%; p = 0.0008)and HIT-6 score (-11.7%; p < 0.0001). Our data suggest that the effects of a "single shot" campaign are beneficial not only in a short-term perspective, but even in the longterm. Moreover, the lack of benefit in more severe cases suggests that such patients should not be treated by GPs alone: patients in whom the HIT-6 score, frequency,severity or duration of headache worsen should be promptly referred to the headache clinic.

Alzheimer's disease (AD) is characterized by accumulation of toxic amyloid-beta (Abeta) in the brain, with neuronal death, and an associated increased Abeta(42/40) ratio. Several mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid-beta precursor protein are involved in the etiology of familial AD (FAD); these mutations alter the Abeta(42/40) ratio and promote apoptosis. We describe an Italian pedigree linked to a novel mutation (S175C) at the third transmembrane domain of PSEN2. Clinical phenotype in these individuals is characterized by fast cognitive decline with progressive memory impairment, early involvement of executive functions, behavioral disturbances, and extrapyramidal signs.

Objective: Transcranial Doppler (TCD) is a sensitive technique for circulatory arrest diagnosis in brain death when patterns such as reverberant flow and short systolic spikes are observed. In infants, the nonossified fontanelles compensate for intracranial hypertension. We describe TCD patterns in infants with brain death, different from adults, with the hemodynamic modifications induced by anterior fontanelle compression., Method: TCD was performed in 2 infants with diagnosed brain death admitted to the neonatal intensive care unit., Results: TCD showed a large peak 'reverberant' flow, with a high peak systolic velocity and a consistent retrograde component, away from the brain. Compression of the anterior fontanelle induced, at first, a reduction in systolic flow with the subsequent appearance of the characteristic short systolic spikes. Upon compression removal, a brief increase in the systolic flow was observed before the prompt reappearance of the reverberant flow., Conclusion: TCD for brain death diagnosis should be done cautiously in infants. In these cases, reverberating flow may be indicative of circulatory arrest even if with a large peak and with a high peak systolic velocity. Heavy fontanelle compression may reproduce the classical adult TCD patterns of brain death, thus supporting the diagnosis of cerebral circulatory arrest., (Copyright 2010 S. Karger AG, Basel.)

Objectives: To evaluate whether contrast ultrasonography can be used to distinguish asymptomatic from symptomatic carotid plaques and provide insight into underlying pathophysiological differences., Design: Contrast carotid ultrasound was performed in both symptomatic and asymptomatic patients referred for carotid endarterectomy., Materials and Methods: Of 77 consecutive patients referred for carotid artery evaluation, 64 underwent carotid endarterectomy for asymptomatic cerebrovascular disease and 9 underwent urgent surgery for acute neurological deficits with hemiparesis. The endarterectomy specimens were assessed immunohistologically., Results: In all 9 patients undergoing urgent surgery, contrast ultrasonography showed the accumulation of diffuse microbubble contrast at the base of the carotid plaque. This pattern was observed only in 1/64 of the patients undergoing surgery for asymptomatic carotid disease. Immunohistologically staining of the endarterectomy specimens showed that the area of microbubble contrast at the base of the symptomatic plaques was associated with an increased number of small diameter (20-30 microm) microvessels staining for vascular endothelial growth factor (VEGF)., Conclusions: Contrast carotid ultrasonography may allow the identification of microvessels with neoangiogenesis at the base of carotid plaques, and differentiate symptomatic from asymptomatic plaques.

Currently, characterization of the vulnerable plaque is a hot research topic as a more adequate strategy for preventing cerebrovascular events is being sought. Histological studies have recognized that plaque inflammation and the presence of adventitial vasa vasorum, intimal angiogenesis and plaque neovascularization are strong predictors of instability in atheromatous lesions of cerebrovascular and cardiovascular patients. The in vivo study of these features has been the focus of development of several new radiological imaging methods. Carotid ultrasound, with ultrasound contrast agents, is not only able to provide an enhanced assessment of the arterial lumen and plaque morphology with an improved resolution of the carotid intima-media thickness, but also to directly visualize adventitial vasa vasorum and plaque neovascularization. This technique and its future clinical implications are discussed in the present review., (Copyright 2009 S. Karger AG, Basel.)

Post-stroke depression (PSD) is the most frequent psychiatric complication of stroke. Its prevalence has been estimated to be around 30-35%, ranging from 20 to 60%. Despite the extensive literature on this topic, there is no agreement on causal mechanisms, risk factors and consequences of PSD. Stroke patients with PSD suffer higher mortality rates and show a minor improvement in rehabilitation programs in comparison to non depressed stroke patients. Consequently, they have worse functional outcomes and quality of life. The available evidence supports PSD as being multifactorial in origin, and consistent with the biopsychosocial model of mental illness. Nonetheless, the stroke itself poses the risk of depression. Stroke survivors are more predisposed to PSD compared to physically ill patients with similar levels of disability, even quite a long time after the stroke, regardless of other risk factors. Early effective treatment of depression may have a positive effect not only on depressive symptoms but also on the rehabilitation outcome of stroke patients. On the other hand, there is no definitive evidence that antidepressants or psychotherapy are useful to prevent depression. Implementing preventive and therapeutic strategies to reduce the risk of mood alteration and thus improve rehabilitation outcomes would appear important in the organization of stroke services.

Objective: The role of vascular risk factors in atherosclerosis development is well established, whereas risk factors involved in determining plaque vulnerability are still a matter of debate. We investigated the vascular risk factor distribution in patients with carotid plaques., Methods: We consecutively assessed sonographic plaque morphologic characteristics, the degree of stenosis, and the common carotid artery intima-media thickness (IMT) in 1655 patients. Demographic data, a documented history of symptomatic cerebrovascular disease (CVD), and the presence of vascular risk factors were collected. According to literature, heterogeneous hypoechoic plaques with an irregular surface or ulcerations and those with a severe degree of stenosis (>or=70%) have been considered "complex" plaques at "major" risk of stroke; homogeneous hyperechoic plaques with smooth surface lesions have been considered "simple" plaques at minor risk., Results: Univariate analysis showed that all vascular risk factors were associated with the presence of carotid atherosclerotic lesions. Multiple logistic regression showed an independent association of hypertension and diabetes with complex plaques, which also had a thicker IMT. A history of CVD was observed more frequently in complex plaques, which had a higher stenosis percentage even after patients with a severe degree of stenosis (>or=70%) and indications for carotid surgery were excluded., Conclusions: Hypertension and diabetes are related to a thicker IMT and more severe complex plaques, which may reflect the instability of atherosclerotic process. Because two-thirds of the patients with complex plaques were asymptomatic for CVD, this raises the importance of surveillance sonography to monitor plaque evolution for prevention of symptomatic CVD.

Visual Imagery is the ability to generate mental images in the absence of perception, that is, We describe a patient, IM, who suffered from an acute ischemic stroke in the right anterior choroidal artery who appeared to demonstrate relatively isolated impairment in visual imagery. Her cognitive function, including her performance on tests of semantic function, was at ceiling, apart from a deficit in visual memory. IM failed in tasks involving degraded stimuli, object decision involving reality judgments on normal animals, and drawings from memory. By contrast, she was able to match objects seen from an unfamiliar viewpoint and to perform tasks of semantic and visual association. We hypothesize that IM has a visual working memory deficit that impairs her ability to generate full visual representations of objects given their names, individual feature, or partial representations. The deficit appears to be the result of damage to connections between the right thalamus and the right temporal lobe. Our findings may help to clarify the role of the thalamus in the cortical selective engagement processes that underlie working memory.

Objective: The aim of this study was to investigate the prevalence of alexithymia in a sample of patients with multiple sclerosis (MS) and to further evaluate the association between alexithymia and the occurrence of common disabling MS-related symptoms such as fatigue and depression., Methods: Fifty-eight relapsing-remitting MS patients treated with interferon (IFN)-beta-1a underwent a complete neurological evaluation, including Expanded Disability Status Scale score assessment. Alexithymia, depressive symptoms and fatigue were assessed using the 20-item Toronto Alexithymia Scale, Beck Depression Inventory and Fatigue Severity Scale., Results: Prevalence of alexithymia was 13.8%, with 27.6% of patients presenting borderline alexithymia. Sixty-seven per cent of the patients complained of fatigue while 29.3% of them were depressed. Higher levels of fatigue and depression were found in alexithymic patients when compared with non-alexithymic patients. Results from logistic regressions showed that alexithymia significantly contributes to the severity of fatigue and depression., Conclusions: Alexithymia was associated with increased severity of fatigue and depression.

Background and Purpose: Frontotemporal dementia (FTD) is a degenerative disorder characterized, in its frontal variant, by psychiatric onset, deficits in executive functions and sparing of memory and visuo-spatial abilities. Studies on visuo-spatial abilities in FTD and Alzheimer's disease (AD) have mainly focused on constructional abilities (CA) and have yielded contrasting data, often depending either on the task used or biases in the clinical selection of patients. The aim of our study was to evaluate the frequency of the CA impairment in FTD-fv and AD patients at the early stage of the disease, and to verify if some distinctive features of this impairment can characterize each pathology., Methods: The copy-drawing task (Rey Complex Figure, RCF) of 41 patients with probable mild AD and 15 patients with probable mild FTD-fv were analysed by means of quantitative and qualitative indices., Results: Data showed that both AD and FTD patients displayed similar RCF scores, as well as execution strategies, type of errors and global analysis. The FTD group only had a significant deficit in the analysis of inner details.

Objective: Transcranial Duplex ultrasound imaging with ultrasound contrast agents is an emerging technique for evaluating brain perfusion. The aim of this study was to evaluate cerebral perfusion with ultrasound in brain space-occupying lesions to identify different perfusion patterns., Methods: Twenty patients with brain space-occupying lesions underwent ultrasound assessment of brain perfusion with a contrast pulse sequencing nonharmonic ultrasound technique and an ultrasound contrast agent bolus. Data were analyzed with software for semiquantitative analysis., Results: Contrast pulse sequencing imaging with the semiquantitative analysis software allowed identification of qualitative and semiquantitative brain perfusion. Brain hemorrhages showed lower or absent perfusion compared with normal tissue. Meningiomas and glioblastomas without large necrotic areas showed higher perfusion compared with normal tissue. Glioblastomas with large necrotic areas showed overall reduced perfusion compared with normal tissue but higher than that of brain hemorrhages. In glioblastomas with large necrotic areas, it was possible to distinguish between solid and necrotic tissue., Conclusions: This bedside ultrasound technique, if validated by larger-scale studies, may add helpful information in noninvasive staging of brain tumors. Further potential applications may be in follow-up imaging to evaluate postoperative tumor recurrence or the presence of radionecrosis.

Background: Erectile dysfunction (ED) is not only evidence of diffuse atherosclerosis but also an index of early endothelial damage. We investigated cerebrovascular reactivity, expression of early arterial damage, in patients with isolated ED (ED+) and controls (ED-)., Materials and Methods: Fifteen ED+ and 15 ED- subjects, matched for age (ED+: 58+/-6, ED-: 59 +/- 4 years) and vascular risk factors, were submitted to carotid duplex ultrasound and transcranial Doppler. Cerebrovascular reactivity was assessed on both middle cerebral arteries simultaneously calculating (a) the total vasomotor range (VMR) measured after breath holding and hyperventilation and (b) the rate of change (VMR/CO(2)) after breath holding., Results: Carotid Duplex scanning showed a light carotid stenosis only in 3 (2 in the ED+ and 1 in the ED- group). No differences were observed in intima-media thickness between ED+ and ED-. Slightly slower mean middle cerebral artery flow velocities were observed in ED+ with respect to ED-. ED+ patients showed a reduced VMR (p < 0.001) and a slower VMR/CO(2) rate of change (p < 0.001) compared to ED-., Conclusions: The reduced reactivity in patients with isolated ED may represent a marker of early cerebral vasomotor dysfunction due to subclinical endothelial damage., ((c) 2008 S. Karger AG, Basel.)

Background: In neurally mediated syncope a 'typical' EEG pattern during hyperventilation (HV) may be observed. This study aimed to investigate transcranial Doppler (TCD) and EEG variations in response to hyper- and hypocapnia using simultaneous recording., Methods: Syncope patients with a typical EEG pattern during HV (SEEG+, n = 15) and those without abnormalities (SEEG-, n = 16) were compared with healthy controls (n = 20). Simultaneous TCD and EEG recordings were performed at rest (baseline), during 2 apnea tests and during HV. Cerebrovascular vasoreactivity, index for hypocapnia, total vasomotor reserve and time to flow velocity normalization after HV (t-norm) were recorded., Results: With TCD, a reduction in Vasomotor reserve was observed in SEEG+ compared with the other 2 groups (control: 67 +/- 8%; SEEG-: 67 +/- 10%; SEEG+: 57 +/- 8%; p < 0.0001). t-norm was longer in all syncopal patients and in particular in SEEG+ (control: 20.2 +/- 3 s; SEEG-: 40 +/- 7 s; SEEG+: 123 +/- 45s; p < 0.0001). Quantitative EEG showed an increase in slow bands in all subjects during HV, small and nonsignificant in controls and SEEG-, higher and significant in SEEG+, related with flow reduction., Conclusions: Changes in the sympathetic modulation of cerebral vasoconstriction may explain both the pathophysiology of vasovagal syncope and the typical paroxysmal EEG findings., (Copyright 2008 S. Karger AG, Basel.)

Background/aim: The lateral sinus (LS) is composed of the transverse sinus (TS) and sigmoid sinus (SiS)., Methods: We studied the clinical pattern of complete or isolated LS thrombosis in 22 consecutive patients., Results: Isolated LS thrombosis patients had a more severe clinical presentation, and more frequent intracranial hemorrhages and seizures., Conclusion: These data suggest that partial involvement of the LS in the thrombotic process may cause more severe clinical symptoms., (Copyright 2007 S. Karger AG, Basel.)

The intensity dependence of the auditory-evoked potentials (IDAP) is inversely related to serotonergic tone. Depression is frequently observed after stroke, associated with cognitive impairment and increased mortality. Aim of this study was to investigate the serotonergic tone in acute stroke patients by IDAP. Consecutive patients with an acute stroke admitted in our stroke unit were evaluated using clinical and instrumental examinations and compared with healthy controls. The IDAP was calculated as the linear amplitude/stimulus intensity function (ASF) slope, by measuring the peak-to-peak amplitude of Nl-P2 on four blocks of different stimulus intensities. Twenty patients were enrolled; 11 had a right brain infarction; nine had depressive symptoms (DS). The ASF slope of the auditory-evoked potentials was markedly increased in stroke patients compared with controls (P = 0.021). Stroke patients with DS had a significant steeper ASF slope than controls (P = 0.017). There was no statistical difference in ASF slope between stroke patients without DS and controls. Post-stroke depression pathophysiology is still debated. Our study suggests that in acute stroke patients with DS, there is a direct involvement of the serotonergic system, regardless the degree of disability and the site of the lesion.

Background and Purpose: Adventitial vasa vasorum and plaque vascularization have been established as predictors of unstable atheromasic lesions in cerebro- and cardiovascular patients. Ultrasound contrast agents provide reliable information on tissue perfusion and microcirculation. We used contrast ultrasound duplex scanning to identify carotid plaque vascularization., Methods: Contrast carotid duplex scanning was performed in 23 patients with plaques of different degree of stenosis and echogenicity., Results: Plaque vascularization was detected in the fibrous and fibro-fatty tissue and not observed in the calcific nor in the necrotic and hemorrhagic tissue. Constantly, a small vessel was observed under ulcerations., Conclusions: Carotid contrast ultrasound imaging appears to be an emerging technique for identifying plaque angiogenesis. Further studies are needed to clarify the role of plaque angiogenesis for assessing cerebrovascular risk and to monitor effects of therapies aimed to plaque remodelling.

The diagnosis of vascular dementia (VaD) remains a controversial issue in many aspects and concepts. These nosologic problems are caused both by the methods, insufficient to ascertain the diagnosis, as well as by the weak consistency of the clinical concept of VaD itself. One of the most intriguing issues on VaD, and in particular on post-stroke dementia (PSD), is related to the time of development of cognitive decline. In clinical practice, the 3-month time threshold is usually chosen to enable resolution of a possible acute post-stroke delirium, and to obtain a more reliable cognitive assessment with a complete regression of acute neuropsychological stroke-related deficits. Another relevant issue is the possibility to predict which patient will develop PSD. In this regard, recent data indicate an overlap between Alzheimer's disease (AD) and PSD, which seems to share risk factors and neuropathology. In most population samples these two disorders appear together, and the consensus is growing that a degenerative component has a more important role in determining PSD onset shortly after stroke than previously recognized. Therefore, anamnestic data have a fundamental role in this prognostic approach.

Objective: Common carotid artery (CCA) intima-media thickness (IMT) is considered an atherosclerosis risk marker. Thickening of the intima-media complex is accelerated by vascular risk factors, in particular, by age and elevated blood pressure. Nonetheless, it also reflects intimal hyperplasia and intimal fibrocellular hypertrophy provoked by nonatherosclerotic mechanisms such as tensile wall stress. The aims of our study were to investigate the relationship between CCA IMT and the presence of vascular risk factors and to correlate CCA IMT with the degree of distal internal carotid artery (ICA) stenosis and the proximal CCA resistive index (RI), representative of wall stress., Methods: We assessed CCA IMT, the CCA RI, and the presence of carotid plaques in 1655 consecutive patients. Demographic features and vascular risk factors were collected., Results: A positive linear relationship between mean IMT and age was observed (R(2) = 0.27; P < .001). In the multiple stepwise regression model, the presence of ICA plaques and vascular risk factors were all independently associated with higher IMT. When considering IMT values for left and right sides separately, there was an independent relationship between CCA IMT and the lateralized percentage of ICA stenosis (right IMT-right ICA percentage, R(2) = 0.10; P < .0001; left IMT-left ICA percentage, R(2) = 0.16; P < .0001) and the CCA RI, even after correcting for age and vascular risk factors., Conclusions: Risk factors for atherosclerosis and the percentage of ICA stenosis were independently associated with higher IMT values and an increase in the RI. The synergic action of risk factors may cause further deterioration of mechanical forces independent of carotid atherosclerosis.

Factors involved in atherosclerotic plaque progression are still a topic of hot debate. With the advance of new ultrasound techniques it has been possible to identify atherosclerotic plaque characteristics that may reflect a higher risk of vulnerability. Among the various proposed mechanisms, one of the least investigated is plaque motion, i.e. plaque stability in respect to the arterial wall. We report here two asymptomatic patients with internal carotid stenosis that showed differences in plaque motion, a finding that could determine a change in their future treatment.

Background: An impairment of cerebral microvessels is reported both in normal ageing and in senescence-associated processes, as well as in Alzheimer's disease (AD) and vascular dementia (VaD). The aim of this study was to explore cerebral hemodynamics by transcranial Doppler in VaD and AD, compared with age-matched control subjects., Methods: Transcranial Doppler was investigated in all patients in the basal condition. Cerebral vasoreactivity to hyper- and hypocapnia was evaluated with CO2 mixture inhalation followed by hyperventilation., Results: We studied 60 AD and 58 VaD patients and 62 nondemented controls. Both AD and VaD subjects showed lower flow velocities (FV) and higher pulsatility indices (PI) as compared with controls. Lower total vasomotor reactivity and lower response to hypercapnia were observed in the AD and VaD groups as compared with controls. AD and VaD patients did not show significant differences in FV, PI values or cerebral vasoreactivity., Conclusions: Reduced FV and increased PI with a significant vasoreactivity reduction in VaD and AD patients are indicators of impairment of cerebral microvasculature circulation in both diseases. The identification of vascular function impairment in all kinds of dementia could be of help in identifying patients who would thus benefit more from specific therapeutic approaches., (Copyright 2007 S. Karger AG, Basel.)

Stroke is the first cause of disability in industrialized countries. Thus, understanding the mechanisms of poststroke recovery appears to be crucial in improving motor performance and reducing disability in stroke patients. Strategies through which brain restores lost functions after ischemic lesions are numerous. The mechanisms underlying poststroke recovery, known as cerebral plasticity, are so far hypothetical. However, functional magnetic resonance imaging (fMRI) studies recently have provided new insights in to stroke recovery. This article sketches out the mechanisms that are thought to underly recovery and focuses on fMRI experimental studies that have investigated the influence of a number of drugs on functional recovery. Functional MRI is a valuable tool in understanding functional recovery and may help to disclose new therapeutical approaches.

Purpose of Review: This review highlights the progress achieved in stroke during the last year, and emphasizes recent controversies concerning its pathophysiology, therapy and secondary complications., Recent Findings: Studies published in 2004 provided new insights into the therapeutic window and ischemic penumbra, thrombolysis therapy, uncommon risk factors for stroke, and neuropsychological post-stroke complications. Despite the diffusion-perfusion mismatch remaining the most widely used technique to identify thresholds for ischemic penumbra and irreversible brain tissue damage, new imaging such as arterial spin-labeling perfusion and computed tomographic perfusion may define this impaired tissue more accurately. New studies assessed the relation of the interval from stroke onset to start intravenous thrombolysis treatment (tissue plasminogen activator) on favorable 3-month outcome, and on the occurrence of clinically relevant parenchymal hemorrhage: the benefit of tissue plasminogen activator could extend beyond 3 h, but with a few risks. Systemic inflammations and infections have been found to be associated with a substantial increase in the risk of developing vascular events, supporting the concept that systemic inflammation itself alters the probability of stroke occurrence. Recent literature concerning neuropsychological post-stroke complications focused mainly on the concept of mixed dementia and confirmed that mood disorders are common after stroke, and interfere with its long-term outcome., Summary: Significant advances have been made during the last year in determining more accurately the therapeutic window, using new strategies and clinical markers. Moreover, new light has been thrown on less common stroke risk factors, and neuropsychological post-stroke complications.

Objectives: To evaluate the time course of motor recovery in a poststroke period ranging from 2 to 6 months and its correlation with both the severity of motor deficit and the muscle tone disturbances (flaccidity or spasticity) of the affected limbs., Design: Prospective cohort study., Setting: A comprehensive rehabilitation hospital., Participants: Forty consecutive stroke patients (21 men, 19 women) with first ischemic stroke who met the inclusion criteria., Interventions: Not applicable., Main Outcome Measure: Change in motor deficit as evaluated by the Adams Hemispheric Stroke Scale., Results: Stepwise regression analysis indicated that the most significant factors influencing motor recovery were the time elapsed since stroke and muscle tone., Conclusions: Rehabilitation of stroke patients is more effective in the first months after the event rather than later, considering the significant correlation observed between motor recovery and time elapsed since stroke. Flaccid patients appear to need 3 months or more before reaching the final plateau, because motor recovery occurs later and/or proceeds more slowly, whereas outcomes for spastic patients with spasticity appears to occur in the first months after stroke.

There is emerging evidence that psychosis in Alzheimer Disease (AD) represents a clinically relevant phenotype with a distinct biological process. It has been reported that a functional polymorphism of the catechol-O-methyltransferase (COMT) gene predisposes to an increased risk for schizophrenia and likely to psychosis susceptibility. Aim of this study was to evaluate functional COMT genetic variation as a risk factor for psychosis in Alzheimer Disease. One hundred eighty-one AD patients and 208 age-matched controls underwent clinical and neuropsychological examination, behavioural and psychiatric disturbances evaluation, and ApoE and COMT genotyping. The distribution of COMT genotypes did not significantly differ in AD compared to controls. Among patients with psychosis (32.6%), 88.1% were COMT*H carriers (COMT H/H or COMT H/L, p < .01). The Odds Ratio (OR) for risk of psychosis in COMT*H carriers was 2.66 (confidence interval, CI 95%: 1.6-6.62), taking into account possible confounding factors. A comparable influence of COMT polymorphism on psychosis over the course of the disease was reported. These findings suggest that COMT polymorphism influences on the risk of psychosis since the early stages, and claims for the possibility to identify distinct phenotypes on genetic basis among AD patients.

Background: The adverse effects of the antiepileptic drugs (AEDs) originally developed are well known, while those of the newer AEDs remain unclear., Objective: To investigate clinical, cognitive, and neurophysiologic effects of carbamazepine, oxcarbazepine, and levetiracetam in healthy volunteers., Methods: A double-blind crossover study was conducted in 10 volunteers. Eight-day treatment with carbamazepine, oxcarbazepine, levetiracetam, or placebo was administered in random order. Drug doses were titrated gradually to the daily target doses on day 7: carbamazepine 800 mg, oxcarbazepine 1200 mg, and levetiracetam 1500 mg. At baseline and at the end of each treatment period, participants underwent cognitive and neurophysiologic assessment. A washout period of 14 days between treatment periods was conducted., Results: More adverse events were self-reported with carbamazepine (63%) than the other treatments (oxcarbazepine 12%, levetiracetam 20%, placebo 5%; p < 0.001 between the 4 groups). Carbamazepine induced the greatest motor slowing (p = 0.002), followed by oxcarbazepine (p = 0.01). Levetiracetam left baseline motor speed unchanged. All AEDs increased attention span from baseline values as shown on the Stroop test. Quantitative electroencephalogram (EEG) analysis showed that carbamazepine significantly increased the delta-theta power and reduced the frequency of alpha rhythm; oxcarbazepine induced smaller changes than carbamazepine. Levetiracetam did not change any EEG measurements. On color visually evoked potential (VEP) tests, carbamazepine induced a constant slowing of P1 latency, while oxcarbazepine induced changes only after the blue-black pattern. All color VEP measures for volunteers receiving levetiracetam were almost unchanged., Conclusions: After short-term treatment in healthy volunteers, carbamazepine induced major clinical and neurophysiologic changes. Oxcarbazepine was better tolerated than carbamazepine. Levetiracetam interfered least with clinical and neurophysiologic test results.

Objective: To assess patients who have had a stroke for the subsequent development of poststroke dementia (PSD) and to determine if the characteristics of delayed PSD (dPSD) vary in the long-term follow-up., Methods: Nondemented patients were followed from 6 months after stroke onset for 4 years. Dementia was diagnosed by International Classification of Diseases-10 criteria; dementia etiology was diagnosed by the National Institute of Neurological and Communication Disorders and Stroke/Alzheimer's Disease and Related Disorders Association and National Institute of Neurologic Disorders and Stroke/Association Internationale pour la Recherche et l'Enseignement en Neurosciences criteria. Neuroimaging and neuropsychological tests were repeated annually., Results: During a 2-year period, 191 stroke patients were enrolled. By the end of the follow-up period, 41 (21.5%) patients had developed dementia. At the Cox regression analysis, dPSD was associated with cortical atrophy (hazard ratio [HR] = 3.4, 95% CI 1.5 to 7.9), age (HR = 3.3, 95% CI 1.4 to 7.8), and multiple ischemic lesions (HR = 2.5, 95% CI 1.2 to 4.8). The Kaplan-Meier analysis showed a significant difference between the incidence of dPSD subtypes (log-rank test; p = 0.002)., Conclusions: During the 4-year follow-up, the incidence of dementia increased gradually, shifting from an Alzheimer disease-type picture in the first years to a vascular dementia type later in years 2 to 4.

Objective: To examine the relationship between inflammation and brain atrophy in patients with a clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS)., Methods: Monthly triple-dose gadolinium (Gd/DTPA)-enhanced MRI scans over 6 months were obtained in 62 consecutive CIS patients with an abnormal baseline MRI scan. Subsequently MRI was performed at months 12 and 18. Patients who developed a clinically definite MS (i. e., a second clinical episode) ended the study at the time of the relapse. For each scan, the number and volume of newly active lesions (Gd-enhancement/new or newly enlarging T2 lesion that did not enhance), and the number and volume of T2 hyperintense lesions (T2-LL) and T1-black holes (T1-LL) were calculated. The percentage of brain volume changes (PBVC) was assessed using a fully automated technique (SIENA; Structural Image Evaluation using Normalization of Atrophy)., Results: Twenty-four (39%) developed clinically definite MS by month 18. Thirty-eight (61%) were relapsefree and completed the MRI follow-up. Relapse-free patients showed a progressive median increase between baseline and month 18 in T1-LL (25%, p<0.001), but not in T2-LL (8.5%, p=ns). PBVC decreased by 1.1% (p<0.001) in a time-dependent pattern (Kendall coefficient of concordance=0.85). Exploratory subgroup analyses showed a trend towards progressive decreases in brain volume in active patients (i. e., those with at least one newly active lesion during monthly MRI scanning; Spearman's R=-0.61; p<0.001), but not among inactive patients (Spearman's R=-0.10; p=0.53). Significant differences in median brain volume changes between the active and inactive patient groups were found at months 12 and 18; the difference detected at month 6 was not significant. The cumulative number and volume of new Gd-enhancing lesions developed during the 6 months of frequent MRI scanning were highly correlated with PBVC over the 18-month period (Spearman R values were 0.73 and 0.85, respectively). The strongest predictor of PBVC at 18 months was the cumulative volume of newly active lesions during frequent MRI scanning [ss=-0. 83, standard error (SE)=0.07, p<0.001]., Conclusions: This study shows that visible inflammation as detected by monthly, triple-dose Gd-enhanced MRI is an important factor in the pathogenesis of brain tissue loss in CIS patients. However, inflammation and brain atrophy do not proceed in parallel: atrophy appeared only after a delay of months following acute inflammation. Frequent MRI scanning allows for the detection of CIS patients who will develop brain atrophy in the short-term.

Purpose of Review: The most recent reports on emotional consequences of stroke are hereby reviewed and analyzed. In particular the interpretation of some neurological presentations found in stroke patients, such as athymormia, dysprosody, emotional incontinence and emotional blunting is discussed. As current theories on mental functions do not provide satisfactory explanations for the above syndromes, a novel interpretative framework is proposed, based on neuropsychological experimental data on the 'mirror system'., Recent Findings: Recent findings support both the fundamental role of the mirror system in imitative processes as well as the relevance of imitation for the emotional part of human personality and behavior., Summary: The mirror system appears to be of paramount relevance for empathy and social behavior. The model of analysis-by-synthesis is here discussed, together with neurological presentations resulting from stroke induced impairments of the mirror system. Speculations for further researches are also proposed.

Increased levels of the gliofibrillar S100b protein can be detected during carotid endarterectomy (CEA). Whether the S100b protein increase is marker of brain ischemic sufferance and predictor of cognitive decline is controversial. Twenty-eight patients underwent clinical assessment and cranial computed tomography (CT) 24-48 hours before and 3 months after CEA. S100b serum levels were evaluated before surgery, at cross-clamping, 10 minutes later, at declamping, and 24-48 hours and 10-12 weeks after CEA. Increased S100b levels were detected in 11 patients (39%); eight (73%) of these patients had symptomatic carotid artery disease. Increased S100b level correlated with history of TIA or stroke ( p=0.005), low mini-mental state examination score ( p=0.02), and ischemic infarctions at preoperative CT ( p=0.03). Slight and transient increased S100b levels were detected in 39% of patients during CEA. The protein levels increased despite the absence of clinical events during surgery. Our findings suggest a failure of compensatory hemodynamic or metabolic mechanisms in peri-ischemic tissue, whose longterm effects on cognition remain to be investigated.

Alzheimer disease (AD) is characterised by a decrease of platelet Amyloid Precursor Protein forms ratio (APPr), which parallels symptoms' severity. Recent studies have suggested that cholesterol might play a role in the pathophysiology of AD by modulating Abeta production. Aim of this study was to evaluate the relationship between serum cholesterol levels and platelet APP processing in controls and AD. Sixty AD patients and 45 age-matched controls (CTRL) were investigated. Neuropsychological assessment, cholesterol dosage and APP forms' evaluation were performed on each subject. CTRL showed lower serum cholesterol levels compared to AD (P<0.01) and higher mean APPr scores (P<0.0001). Hypercholesterolaemic AD patients showed lower APPr scores compared to normocholesterolaemic AD patients matched for disease severity (0.31+/-0.16 versus 0.45+/-0.28; P<0.05), since the early stage of the disease. In AD, cholesterol levels influence APPr independently of disease severity. These findings confirm the association between cholesterol and AD, and suggest that in vivo cholesterol affects APP processing by interfering with its maturation.

How do we empathize with others? A mechanism according to which action representation modulates emotional activity may provide an essential functional architecture for empathy. The superior temporal and inferior frontal cortices are critical areas for action representation and are connected to the limbic system via the insula. Thus, the insula may be a critical relay from action representation to emotion. We used functional MRI while subjects were either imitating or simply observing emotional facial expressions. Imitation and observation of emotions activated a largely similar network of brain areas. Within this network, there was greater activity during imitation, compared with observation of emotions, in premotor areas including the inferior frontal cortex, as well as in the superior temporal cortex, insula, and amygdala. We understand what others feel by a mechanism of action representation that allows empathy and modulates our emotional content. The insula plays a fundamental role in this mechanism.

Previous findings demonstrated an altered pattern of amyloid precursor protein (APP) forms in platelets of Alzheimer disease (AD) patients, compared both with healthy control subjects or patients with non-Alzheimer-type dementia. The present study aims to evaluate whether platelet APP form ratio (APPr) is altered in patients with early stage AD. We selected 40 patients with early stage AD and 40 age-matched healthy controls. Compared with controls (mean+/-SD=0.91+/-0.3), mean APPr was decreased in AD (mean+/-SD=0.46+/-0.26, p<0.0001). Sixteen very mild AD patients (clinical dementia rating=0.5), identified among the AD group, showed a significant decrease of APPr values (mean+/-SD=0.50+/-0.3, p<0.0001). These findings indicate that alteration of APP processing in platelets is an early event and suggest that this assay might be of diagnostic value in differentiating mild AD from normal ageing.

The objectives of this study were to assess whether cortical motor reorganization in the early phase of multiple sclerosis (MS) is correlated with the clinical presentation and with specific damage to the corticospinal tract. Twenty patients with clinically isolated syndrome (CIS) and serial MR findings indicative of MS were selected. In 10 patients the CIS was hemiparesis (group H), and in 10 patients the CIS was optic neuritis (group ON). There were no significant differences in age, disease duration, total T2 lesion load (LL), and total T1 LL between group H and group ON. Ten age-matched healthy subjects served as controls (group C). All subjects were submitted to fMRI during a sequential finger-to-thumb opposition task of the right hand. Group H showed a significantly higher EDSS score and T1 LL calculated along the corticospinal tract than group ON. Three-group comparison by ANOVA showed significantly higher activation in group H than in the other two groups (P < 0.001). Significant foci were located in the sensory-motor cortex (BA 1-4), the parietal cortex (BA 40), the insula of the ipsilateral hemisphere, and the contralateral motor cortex (BA 4/6). Group ON showed, although at a lower level of significance (P < 0.01), higher activation of the contralateral motor-related areas than group C. Multiple regression analysis showed that T2 and T1 LL along the corticospinal tract and time since clinical onset positively correlated with activation in motor areas in both cerebral hemispheres (P < 0.005). Total T2 LL positively correlated with activation in motor areas in the contralateral hemisphere (P < 0.005). Total T1 LL and EDSS did not show any significant correlation. More severe specific damage to the motor pathway in patients with previous hemiparesis may explain the significantly higher involvement of ipsilateral motor areas observed in group H than in group ON. Furthermore, the significant correlation between the time since clinical onset and activation in motor areas suggests that cortical reorganization develops gradually in concomitance with the subclinical accumulation of tissue damage.

Accumulating evidence from epidemiological and clinical studies suggests that vascular risk factors may be involved in Alzheimer disease (AD). Although the precise contribution of vascular disturbances to the pathogenesis of AD is still unclear, various biochemical and neuropathological data strengthen the view that cerebrovascular deficiencies such as reduced blood supply to the brain and disrupted microvascular integrity in brain parenchyma play a direct or intermediate role in the chain of events ending with a dementia syndrome. The present review focuses on platelet abnormalities and hemostatic alterations in AD. In particular, data from our group, along with current literature, are discussed with regard to the evidence of platelets amyloid precursor protein (APP) processing disturbances in early AD as well as to the recent observations of increased serum levels of thrombomodulin and sE-selectin, which are sensitive markers of endothelial dysfunction. These findings strongly indicate that platelet dysfunction and microvasculature deficiencies occur rather early during the course of AD, thus suggesting a further link between AD-related processes and vascular disorders.

The ischaemic penumbra was described for the first time in the late 1970s as a ring of hypoperfused zone surrounding the region of complete infarction. The penumbral zone is a functionally silent tissue which is able to regain its function if promptly reperfused. This implies that the ischaemic penumbra is not a static but a "dynamic" and "time-dependent" concept. In this paper we describe the role of neuroimmaging tecniques such as single photon emission tomography (SPET), positron emission tomography (PET), and diffusion-weighted and perfusion-weighted magnetic resonance imaging (DWI and PWI) in the study of ischaemic penumbra. These functional imaging techniques have the advantage of giving "in vivo" quantitative estimate of cerebral blood flow (CBF) as well as information on how the ischaemic tissue metabolic changes develop. It follows that, as therapeutic options for treating acute stroke evolve, neuroimaging strategies are assuming an increasingly important role in the initial evaluation and management of the acute ischaemic patient. In this regard, a wide range of therapeutic approaches have been investigated for either ameliorating the perfusion, or interfering with the pathobiochemical cascade leading to ischaemic neuronal damage, or improving endogenous neuroprotection pathways. The "time windows" required for these treatments to be effective varies being rather short for reperfusion and longer for neuroprotection. Salvaging more penumbra would enhance recovery and thereby allow the most appropriate candidate for therapeutic trials to be selected.

In order to evaluate whether cortical motor reorganization occurs in the earliest phase of multiple sclerosis, we studied patients after a first clinical attack of hemiparesis. From a consecutive series of 70 patients enrolled in a study of patients with clinically isolated syndrome and serial MRI findings indicative of multiple sclerosis, we retrospectively selected 10 patients with hemiparesis as the onset symptom and no further clinical episode [mean age 32 +/- 9 years, disease duration 24 +/- 14 months, median Expanded Disability Status Score (EDSS) 1.25]. Ten age-matched, healthy subjects served as controls. Each subject was submitted to two functional MRI trials (one per hand) using a 1.5 T magnet during a sequential finger-to-thumb opposition task. Image analysis was performed using SPM99 software. Movements of both the 'affected' and the 'unaffected' hand activated significantly larger areas in patients than in controls in both the contralateral and ipsilateral cortical motor areas. Patients activated a greater number of foci than controls during both the right-hand and the left-hand movement. Most of these foci were located in cortical areas which were less or not at all activated in controls, such as the lateral premotor cortex [Brodmann area (BA) 6], the insula and the inferior parietal lobule (BA 40). Between-group analysis of patients versus controls showed significant (P < 0.001) foci in these areas, principally located in the ipsilateral hemisphere during right-hand movement and in both the cerebral hemispheres during left-hand movement. Time since clinical onset showed a significant positive correlation with the extent of activation in the ipsilateral motor areas (P = 0.006) during the right-hand movement and with the extent of activation in both the ipsilateral (P = 0.02) and contralateral (P = 0.006) motor areas during the left-hand movement. The T(1) lesion load along the motor pathway showed a significant positive correlation (P = 0.007) with the extent of activation in the contralateral motor areas during right-hand movement. Our study shows functional adaptive changes that involve both the symptomatic and asymptomatic hemisphere during a simple motor task in patients who had suffered a single clinical attack of hemiparesis. The extent of these changes increased with the time elapsed since disease onset and the severity of brain damage.

We investigated the effects on cerebral blood flow (CBF) of pure oxygen breathing exposure during dives in a group of professional divers, in both the normobaric (NBO) and the hyperbaric oxygen (HBO) breathing conditions. Using single photon emission computerized tomography (SPECT) and Tc-99m hexamethylpropylenamine oxime (HM-PAO), we studied 10 young divers and six normal volunteers. Divers were studied by SPECT in the NBO and HBO conditions, in two different sessions. The HBO state was obtained in a hyperbaric chamber at 2.8 ATA for 15 min. By ANOVA, we did not observe any significant difference in CBF distribution between controls and divers in both NBO and HBO conditions. By individual analysis, divers showed a decreased CBF in a total of 33 regions of interest (ROIs) during NBO and 46 ROIs during HBO with respect to control values. In particular, two divers showed a remarkable increase in the number of hypoperfused ROIs during HBO (+7 and +5 ROIs, respectively). Pure oxygen breathing exposure in young divers is associated with a patchy distribution of brain areas of hypoperfusion. This phenomenon is more pronounced in the HBO state than in the NBO state. Further studies on CBF are needed to help identify divers potentially prone to harmful oxygen effects.

Background and Purpose: The stage at which normal appearing white matter (NAWM) abnormalities first appear in multiple sclerosis (MS) is not clear. The aim of our study was to monitor water diffusion changes over time in NAWM of patients with early MS., Methods: Out of a consecutive series of patients enrolled in a MR study on clinically isolated syndrome (CIS), we selected 19 subjects who had completed a one year follow-up. The MR scans obtained at baseline and at 12 months were reviewed according to the new criteria on the diagnosis of MS. Lesion load on T2 and T1 weighted images and the trace of the apparent diffusion coefficient in NAWM were measured both at baseline and at 12 months in patients and in 12 healthy controls., Results: In three patients the diagnosis of MS was done at baseline based on MR. Thirteen patients developed MS during the study and in three patients the diagnosis remained "possible MS." TADC in NAWM in patients was significantly higher than in controls at the 12 months' follow-up but not at baseline (controls mean tADC +/- sd = 0.745 +/- 0.02 mm(2)/sec x 10(-3); patients mean tADC(12) +/- sd = 0.767 +/- 0.02 mm(2)/sec x 10(-3); p < 0.02). TADC and T2 lesion load at 12 months were significantly correlated (p < 0.01). Patients exhibiting tADC(12) above a confidence interval had a significantly greater EDSS score at the same time period (EDSS(12) +/- sd = 1.9 +/- 0.5 and = 1.1 +/- 0.4 respectively; p < 0.01)., Conclusions: This study suggests that diffusion MR cannot detect alterations in NAWM of patients with a CIS suggestive of MS. After one year, when most patients develop MS, diffusion MR abnormalities in NAWM become apparent. These abnormalities are correlated with T2 lesion load and may contribute to neurological impairment.