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Background The cerebellum now it has not considered a dopaminergic region. Despite, is traditionally reported only the presence of dopaminergic afferents to the cerebellum. Currently, studies attribute to the cerebellum a critical role in motor and cognitive functions and suggest a cerebellar involvement in dopamine related neurologic and psychiatric disorders. In several studies has been demonstrated mainly in the cerebellum of rodents a widely distribution of all dopaminergic receptor subtypes (DRD1-DRD5), a poor number of dopaminergic Purkinje neurons, and the presence of several dopaminergic neurons in the deep cerebellar nuclei. Data on an intrinsic dopaminergic neuronal system in the human cerebellum are lacking. Methods The aim of the present study of chemical neuroanatomy was to investigate in human cerebellum on the presence of a dopaminergic neuronal system, through an immunohistochemical approach based on the use of specific antibodies against the dopamine membrane transporter (DAT) and the dopamine receptor subtype 2 (DRD2). Results The immunoreactions revealed the presence of DAT and DRD2 positive neuronal cell bodies and processes of all the layers of the cerebellar cortex and in the dentate nucleus. These results are in agreement with previous studies, and suggest which the intrinsic cerebellar neuronal dopaminergic system may be involved in intrinsic and extrinsic (projective) cerebellar circuits. Conclusions This study open a new scenario on the interpretation of the cerebellar role in dopaminergic related brain disorders. Finally, this study may be an innovative critical element for the development of pharmacologic and non-pharmacologic therapeutic strategies for neurologic and psychiatric disorders related to dopamine.

Objective To assess body distribution and timing of appearance of rest tremor in Parkinson's disease. Methods Information was obtained by a computerized database containing historical information collected at the first visit and data collected during the subsequent follow-up visits. Information on rest tremor developed during the follow-up could be therefore obtained by our own observation in a proportion of patients. Results Among 289 patients, rest tremor was reported at disease onset in 65.4% of cases and detected at last follow-up examination in 74.4% of patients. Analysis of patients who did not report rest tremor at disease onset indicated that 26% of such patients (9% in the overall population) manifested rest tremor over the disease course. Rest tremor spread to new sites in 39% of patients who manifested rest tremor at disease onset. Regardless of tremor presentation at disease onset or during the follow-up, upper limb was the most frequent tremor localization. Over the follow-up, rest tremor developed faster in the upper limb than in other body sites. The risk of developing rest tremor during the follow-up was not affected by sex, side of motor symptom onset and site of tremor presentation. However, age of disease onset > 63 years was associated with an increased risk of rest tremor spread. Conclusions This study provides new information about body distribution and timing of rest tremor appearance during the course of early stages of Parkinson's disease that may help clinicians in patients' counselling.

Objectives Few studies have addressed central sensitization symptoms and pain processing in childhood migraine. Our aims were to examine pain sensitivity and responses, including habituation, evoked by CO2 laser stimuli (laser-evoked potentials (LEPs)) in a cohort of children with migraine compared to non-migraine controls and to determine the correlation between LEP features and signs of central sensitization. Methods Thirty-five patients 8–15 years of age with migraines without aura were evaluated during the inter-critical phase and were compared to 17 controls. LEPs were analyzed, and their main features were correlated with clinical symptoms including allodynia and pericranial tenderness. Results The laser-evoked pain threshold was lower and the N2P2 vertex complex amplitude was higher in children with migraines. Furthermore, habituation of vertex waves of LEPs clearly showed a tendency toward progressive amplitude enhancement in the migraine group. Acute allodynia and inter-critical pericranial tenderness correlated with trigeminal LEP features, particularly with the abnormal habituation pattern. Discussion Abnormalities of pain processing and symptoms of central sensitization appear to be characteristics of children with migraine. Reduced habituation and progressive amplification of cortical responses to laser stimuli indicate an overactive nociceptive system at the onset of migraine, and this hyperactivity may subtend allodynia and pericranial tenderness. Future prospective trials may aid in the early identification of clinical phenotypes that display a tendency to develop into the chronic form of migraine, warranting a timely therapeutic approach.

Background The average headache visit lasts only 15 minutes in the health care environment and is generally preceded by a long time spent by patients in the waiting room. Patients entering the doctor’s room need to be listened to as much as possible but do not know what details might be useful for diagnosis. Doctors focus on obtaining specific clinical information, performing a physical examination, formulating the correct diagnosis and prescribing the most appropriate therapy within as little time as possible. The compilation of a self-administered questionnaire during the waiting time might concentrate a patient’s attention on crucial headache features, reduce the tension concerning the visit and break the ice in meeting the doctor. The ID-Migraine, a self-administered questionnaire, consisting of only 3 items, is a valid and reliable screening instrument for migraine and was validated in Italy, but it does not provide information concerning headache course [1].

Despite increasing evidence suggesting the cerebellum works in concert with the cortex and basal ganglia, the nature of the reciprocal interactions between these three brain regions remains unclear. This consensus paper gathers diverse recent views on a variety of important roles played by the cerebellum within the cerebello-basal ganglia-thalamo-cortical system across a range of motor and cognitive functions. The paper includes theoretical and empirical contributions, which cover the following topics: recent evidence supporting the dynamical interplay between cerebellum, basal ganglia, and cortical areas in humans and other animals; theoretical neuroscience perspectives and empirical evidence on the reciprocal influences between cerebellum, basal ganglia, and cortex in learning and control processes; and data suggesting possible roles of the cerebellum in basal ganglia movement disorders. Although starting from different backgrounds and dealing with different topics, all the contributors agree that viewing the cerebellum, basal ganglia, and cortex as an integrated system enables us to understand the function of these areas in radically different ways. In addition, there is unanimous consensus between the authors that future experimental and computational work is needed to understand the function of cerebellar-basal ganglia circuitry in both motor and non-motor functions. The paper reports the most advanced perspectives on the role of the cerebellum within the cerebello-basal ganglia-thalamo-cortical system and illustrates other elements of consensus as well as disagreements and open questions in the field.

Objectives Cognitive frailty, a condition describing the simultaneous presence of physical frailty and mild cognitive impairment, has been recently defined by an international consensus group. We estimated the predictive role of a “reversible” cognitive frailty model on incident dementia, its subtypes, and all-cause mortality in nondemented older individuals. We verified if vascular risk factors or depressive symptoms could modify this predictive role. Design Longitudinal population-based study with 3.5- and 7-year of median follow-up. Setting Eight Italian municipalities included in the Italian Longitudinal Study on Aging. Participants In 2150 older individuals from the Italian Longitudinal Study on Aging, we operationalized reversible cognitive frailty with the presence of physical frailty and pre-mild cognitive impairment subjective cognitive decline, diagnosed with a self-report measure based on item 14 of the Geriatric Depression Scale. Measurements Incidence of dementia, its subtypes, and all-cause mortality. Results Over a 3.5-year follow-up, participants with reversible cognitive frailty showed an increased risk of overall dementia [hazard ratio (HR) 2.30, 95% confidence interval (CI) 1.02–5.18], particularly vascular dementia (VaD), and all-cause mortality (HR 1.74, 95% CI 1.07–2.83). Over a 7-year follow-up, participants with reversible cognitive frailty showed an increased risk of overall dementia (HR 2.12, 95% CI 1.12–4.03), particularly VaD, and all-cause mortality (HR 1.39, 95% CI 1.03–2.00). Vascular risk factors and depressive symptoms did not have any effect modifier on the relationship between reversible cognitive frailty and incident dementia and all-cause mortality. Conclusions A model of reversible cognitive frailty was a short- and long-term predictor of all-cause mortality and overall dementia, particularly VaD. The absence of vascular risk factors and depressive symptoms did not modify the predictive role of reversible cognitive frailty on these outcomes.

Objective Cognitive frailty is a condition recently defined by operationalized criteria describing the simultaneous presence of physical frailty and mild cognitive impairment (MCI). Two subtypes for this clinical construct have been proposed: "potentially reversible" cognitive frailty (physical frailty plus MCI) and "reversible" cognitive frailty (physical frailty plus pre-MCI subjective cognitive decline). Here the prevalence of a potentially reversible cognitive frailty model was estimated. It was also evaluated if introducing a diagnosis of MCI in older subjects with physical frailty could have an additive role on the risk of dementia, disability, and all-cause mortality in comparison with frailty state or MCI condition alone, with analyses separately performed for inflammatory state. Methods In 2,373 individuals from the population-based Italian Longitudinal Study on Aging with a 3.5-year-follow-up, we operationally categorized older individuals without dementia into four groups: non-frail/non-MCI, non-frail/MCI, frail/non-MCI, and frail/MCI. Results The prevalence of potentially reversible cognitive frailty was 1%, increasing with age and more represented in women than in men, and all groups were associated with significant increased incident rate ratios of dementia, disability, and mortality. A significant difference in rates of disability has been found between the MCI and non-MCI groups (contrasts of adjusted predictions: 0.461; 95% confidence interval: 0.187–0.735) in frail individuals with high inflammatory states (fibrinogen >339 mg/dL). Conclusion In older individuals without dementia and with elevated inflammation, a potentially reversible cognitive frailty model could have a significant additional predictive effect on the risk of disability than the single conditions of frailty or MCI.

Background and purpose Action tremor may occur in patients with Parkinson's disease and cause misdiagnosis with other movement disorders such as essential tremor and dystonia. Data on the frequency of action tremor in Parkinson's disease and on the relationships with other motor and non-motor signs are limited. Methods A cross-sectional study of 237 patients with Parkinson's disease staging 1–2 on the Hoehn−Yahr scale was conducted. Data on action tremor and other motor and non-motor signs were collected using the Unified Parkinson's Disease Rating Scale part III and the Non-Motor Symptoms Scale. Results Action tremor was found in 46% of patients and was associated with both severity of rest tremor (adjusted odds ratio 3.0, P

Background Adult-onset primary dystonia is thought to be a purely motor disorder. Nevertheless, several studies provided evidence that sensory and psychiatric disturbances may contribute to the clinical spectrum of of dystonia, whereas evidence supporting cognitive impairment is still limited. Methods A set of neuropsychological tests was administered to non depressed, non demented patients with cranial-cervical dystonia and healthy control subjects. The test battery included n -Back Task, Wechsler Memory Scale, Trail Making Test version A and B, and Wisconsin Card Sorting Test. Results As compared with healthy control subjects of similar age, sex and socio-economic status, patients with cranial-cervical dystonia showed deficit on working memory functions revealed by n -Back task, impairment of mental control and visual reproduction subtests of Wechsler memory scale, deficit on information processing speed and set-shifting capacity revealed by Trail Making Test A and B. Conclusion Patients with cranial-cervical dystonia may have impairment in specific cognitive domains relative to working memory, processing speed, visual motor ability and short term memory. Probably, these deficits are not dependent on the clinical expression of dystonia but might rather reflect the cortical and subcortical changes highlighted by functional and VBM imaging studies in patients with different forms of dystonia.

The aim of our study was to analyze morphological and functional aspects of cerebral veins by means of ecocolor-Doppler in young (i.e., ≤ 30 years old) and older (i.e.,30 years old) patients suffering from multiple sclerosis. 552 multiple sclerosis patients were evaluated by means of a dedicated Echo-Color-Doppler support (MyLab Vinco echocolor Doppler System, Esaote), in both supine and sitting positions. 458 (83%) showed alterations in their morphological and functional structures of cerebral veins and were divided in two different groups: 1) ≤ 30 (110 patients) and 2)30 years old (348 patients). Young patients showed a statistically significant higher number of both hemodynamically (44% vs. 35%, p0.01) and non-hemodynamically (51% vs. 45%, p0.05) significant stenosis in the internal jugular veins as compared to older patients. A lower percentage of young patients showed blocked outflow in the cervical veins (50% vs. 65%, p0.01) as compared to older ones. Patients30 years old outlined a significantly higher disability degree (Expanded Disability Status Scale score: 5 vs. 3, p0.01) as well as higher disease duration (12 vs. 5 months, p0.01) than younger. No differences could be outlined about multiple sclerosis clinical form of the disease. It was evidenced that young and adult groups are different kind of patients, the former showing much more cerebral veins stenosis and blocked flow in internal jugular veins and vertebral veins than the latter. Duration of disease could explain such differences: the higher the diseases duration, the higher the degree of vascular alterations and, therefore, the disability degree. This could be due to the complex venous hemodynamic impairments induced by alterations in vascular walls: the blocked or difficult blood flow through stenosis could increase the hydrostatic pressure in the skull and this could induce damages to cerebral cells leading to the genesis of more advanced morphological abnormalities. Furthermore, the vessels' alterations could impair venous endothelial functions which could turn in a possible alteration of the controls of cerebral vein return which could worsen the cerebral vascular outflow. It may be possible that early clinical, pharmacological and/or invasive vascular interventions could exert a possible role in the natural history of multiple sclerosis. Nevertheless, further trials are needed in order to confirm such considerations.

Adult-onset dystonia (AOD) may manifest in focal forms (as blepharospasm, oromandibular dystonia, cervical dystonia, laryngeal dystonia, and hand dystonia) or in segmental forms. Time from onset of dystonia to diagnosis can be an indicator of the quality of care received during the diagnosis of AOD, likely reflecting factors associated with both the patient and their health system. Three previously reported single-center studies showed that diagnosis of AOD may be delayed for several years. Here, we examined the time lapse between onset and diagnosis in patients with different forms of AOD from an Italian movement disorder center. We found the time lapse between dystonia onset and diagnosis was very long for patients who developed AOD before 1980; and even in the most recent years reaching a correct diagnosis required more than year in almost half of cases. Our results suggest that the delay in diagnosis of adult-onset focal and segmental dystonia has improved over time, but remains unacceptable. The findings are a promising indicator of improvements in care of this uncommon disorder. However, education of patients and doctors is still needed.

Background β-Site amyloid precursor protein (APP)–cleaving enzyme 1 (BACE1) activity determines the rate of APP cleavage and is therefore the main driver of amyloid β production, which is a pathological hallmark of Alzheimer's disease (AD). Methods The present study explored the correlation between BACE1 activity and cerebrospinal fluid (CSF) markers of APP metabolism and axonal degeneration in 63 patients with mild AD and 12 healthy control subjects. Results In the AD group, positive correlations between BACE1 activity and soluble APP β, the APP sorting receptor sortilin-related receptor with A-type repeats (also known as SorLA or LR11), and tau were detected. BACE1 activity was not associated with amyloid β 1–42 or soluble APP α concentrations in the AD group, and no associations between BACE1 activity and any of the protein concentrations were found in the control group. Conclusion Our results confirm the relevance of BACE1 and sortilin-related receptor with A-type repeats within the amyloid cascade and also provide a further piece of evidence for the link between amyloid and tau pathology in AD.

Background To date there are no biomarkers with proven reliability as a measure of disease burden in amyotrophic lateral sclerosis (ALS). The aim of our study is to assess the neurofilament light chain (NFL) in cerebrospinal fluid (CSF) samples as a measure of disease activity and progression in ALS. Methods Thirty-seven consecutive patients with ALS, 25 with chronic inflammatory demyelinating polyneuropathy and 21 with other neurodegenerative diseases were evaluated. CSF NFL levels were assayed by two-site solid-phase sandwich ELISA. In patients with ALS, neurological status was assessed by the revised ALS Functional Rating Scale (ALSFRS-r) and the Medical Research Council scale, and the progression of the disease was evaluated using the ‘diagnostic delay’ and the ‘progression rate’. Results Cerebrospinal fluid NFL levels were higher in ALS cases than in controls (P

Elevated homocysteine (Hcy) levels exert several neurotoxic actions and vascular dysfunctions that may be involved in pathogenesis and progression of multiple sclerosis (MS). The effective role of Hcy in MS however remains to be determined. The aim of this work was to compare plasma Hcy levels in MS patients and neurological disease controls (NDC) and to evaluate their relationships with clinical and demographic variables. In this cross-sectional study, we examined plasma Hcy levels in 217 patients with MS [53 clinically isolated syndromes (CIS) suggestive of MS, 134 relapsing remitting (RR), 23 secondary progressive (SP) and seven primary progressive (PP) MS], recruited among patients attending a tertiary clinical center in southern Italy and in 219 age/sex-matched controls. Median Hcy levels were slightly higher in MS patients compared to NDC (9.1 μmol/l; range, 3.4–35.9 vs. 8.6, range 3.5–27.4; p = 0.02). Median Hcy concentrations were increased in males more than in females in the MS population (10.4 vs. 8.4; p < 0.0001), whereas no differences across genders were found in NDC (9.1 vs. 8.5). Hcy levels were higher in male MS patients compared to the male NDC patients (p = 0.001). Patients with CIS had lower Hcy (7.5 μmol/l; p = 0.004) compared to patients with RR (9.5 μmol/l), SP (10.1 μmol/l) and PP (9.9 μmol/l). Median Hcy concentration was higher in patients with disease duration longer than 22 months (9.7 vs. 8.6 μmol/l; p = 0.02). Plasma Hcy levels are increased in patients with definite MS. Higher Hcy levels are associated with male sex, suggesting a role of Hcy in neurodegenerative processes of MS, which are prominent in male patients.

Objective: We investigated dopaminergic inhibition of CD4+CD25high regulatory T lymphocytes (Treg) in relapsing-remitting multiple sclerosis (MS) patients treated with interferon (IFN)-β. Methods: MS patients were prospectively studied at baseline and during 1 year of IFN-β, and compared with healthy controls (HCs). Treg were separated by immunomagnetic sorting and the effect of dopamine (DA) on Treg was assessed in coculture experiments with homologous effector T lymphocytes (Teff). Tyrosine hydroxylase (TH), dopaminergic receptors (DR) D3 and D5, and forkhead box protein P3 (FoxP3) mRNA were assessed by real-time PCR. Circulating CD4+ T cell subsets were assessed by flow cytometry. Results: In coculture experiments, Treg inhibition of Teff proliferation was reduced by DA in HCs and completely abolished in MS patients at baseline. However, in patients after 12 months of IFN-β, Teff proliferation was impaired and DA had no more effect on Treg. In comparison to cells from HCs, Treg from MS patients at baseline had increased mRNA for DR D5 and TH (but not for DR D3). During treatment with IFN-β, both DR D5 and TH mRNA decreased down to values lower than those of cells from HCs. In comparison to HCs, MS patients had a higher frequency of circulating Treg, both at baseline and after IFN-β, while FoxP3 mRNA levels in Treg were similar in patients and HCs and did not show major changes during IFN-β. Conclusions: Dopaminergic inhibition of Treg in MS patients is suppressed during IFN-β treatment. Treg play a key role in the suppression of autoimmunity, thus the effect may have a therapeutic repercussion.

Background According to a widely accepted hypothesis, the amyloid precursor protein (APP) is processed by two competing pathways: the amyloidogenic β-secretase–mediated pathway or the nonamyloidogenic α-secretase–mediated pathway. APP is cleaved preferentially through the nonamyloidogenic pathway in normal brain, whereas the balance shifts to the amyloidogenic pathway in Alzheimer's disease (AD). The levels of the α-secretase–cleaved soluble APP (sAPPα) and β-secretase–cleaved soluble APP (sAPPβ) in cerebrospinal fluid (CSF) are likely to reflect these competing mechanisms. Methods We investigated the levels and the relationship between sAPPα and sAPPβ in the CSF of 64 patients with mild AD, 76 patients with mild cognitive impairment, and 12 cognitively healthy control subjects, as well as the effect of apolipoprotein E genotype and sex on soluble APP levels. Results There was a significant positive correlation between sAPPα and sAPPβ levels in all three groups. sAPPα and sAPPβ concentrations were higher in patients with mild cognitive impairment compared with patients with AD. In the AD group, females exhibited higher sAPPα and sAPPβ levels than males. No influence of the apolipoprotein E genotype on soluble APP concentrations was detected. Discussion The positive correlation between sAPPα and sAPPβ challenges the hypothesis that AD is caused by an imbalance of the α- and β-secretase APP proteolysis through competing mechanisms. Moreover, the differences in CSF levels of sAPPα and sAPPβ between male and female patients with AD may reflect a "sexual dimorphism" in the activity of the two APP processing pathways in AD.

Our previous study assessed the prevalence of fibromyalgia (FM) syndrome in migraine and tension-type headache. We aimed to update our previous results, considering a larger cohort of primary headache patients who came for the first time at our tertiary headache ambulatory. A consecutive sample of 1,123 patients was screened. Frequency of FM in the main groups and types of primary headaches; discriminating factor for FM comorbidity derived from headache frequency and duration, age, anxiety, depression, headache disability, allodynia, pericranial tenderness, fatigue, quality of life and sleep, and probability of FM membership in groups; and types of primary headaches were assessed. FM was present in 174 among a total of 889 included patients. It prevailed in the tension-type headache main group (35%, p

Previous voxel-based morphometry studies of patients with primary blepharospasm documented gray matter volumetric differences of the striatum, cerebellum, thalamus, and parietal lobe areas. However, these results were inconsistent across studies, which recruited relatively small samples and did not always provide detailed clinical information on patients with blepharospasm. The objective of this study was to analyze whole-brain gray matter volume in a larger sample of patients with blepharospasm and to expand on previous works by evaluating whether clinical features of blepharospasm correlate to whole-brain gray matter changes. Voxel-based morphometry was performed on 25 patients with primary adult-onset blepharospasm and 24 healthy subjects (controls) matched for age, sex, and handedness. Clinical data were collected through a standardized interview. Severity of blepharospasm was measured using the Jankovic Rating Scale. Patients with blepharospasm had greater gray matter volume than controls in the right middle frontal gyrus, whereas patients with blepharospasm had smaller gray matter volume than controls in the left postcentral gyrus and left superior temporal gyrus. Spearman correlation analysis with Bonferroni correction failed to show significant correlations between gray matter volume and the explored clinical variables, comprising age at onset, disease duration, blepharospasm severity, presence of an effective geste antagoniste, and dose and duration of botulinum toxin treatment. Patients with blepharospasm exhibited gray matter volume differences exclusively in cortical regions highly relevant to sensory processing and cognitive modulation of motor behavior. Gray matter changes in the primary sensory cortex may represent a common trait of primary dystonias, including blepharospasm. © 2011 Movement Disorder Society

Abnormalities of central pain processing play an important role in the pathophysiology of fibromyalgia (FM). The aims of the present study were to: 1) evaluate habituation of laser-evoked potentials (LEP) to repeated painful stimulation of 1 tender and 2 nontender points; and 2) determine correlations between LEP abnormalities and major clinical features of FM. Fourteen consecutive FM outpatients and 13 normal controls were included. LEP were recorded from scalp designations Fz, Cz, Pz, T3, and T4. The dorsum of the right hand, the right supra-orbital zone, and the right knee (a tender point in all patients) were subjected to repeated CO2 laser stimuli. For each stimulation site, recordings were obtained for 3 consecutive series of 20 stimuli. The 3 main findings in FM patients were: 1) an increased amplitude of vertex LEP and subjective laser pain; 2) decreased habituation of vertex LEP and subjective laser pain; and 3) a correlation between reduced N2 wave habituation and the severity of self-reported depressive symptoms. As with other chronic pain syndromes, the pathophysiology of FM may involve a generalized increase in the perception of painful stimuli and reduced habituation of the sensory cortex. Perspective Reduced habituation of cortical responses to laser stimuli in FM patients suggests alterations in the pattern of cortical excitability. This is facilitated by depressive symptoms and abnormalities in central neurotransmission. These findings provide further support for the use of medications with effects on the central nervous system in the management of FM.

Introduction The mechanisms underlying functional movement disorders are poorly known. We examined whether experience of a movement disorder model in the family and/or the friendships contributes to functional movement disorders. Methods The hypothesis was tested in a case–control study including 33 patients with functional movement disorders and 66 age- and sex-matched patients with organic movement disorders and using a conditional logistic multivariable analysis (adjusted by age, education, disease duration, chronic medical illnesses and clinical phenotype). Results Case-control comparison yielded a significant association between functional movement disorders and exposure to phenotypically congruent movement disorder models (Odds ratio, 3.9, p = 0.01), mainly when disease model came from friendships (Odds ratio, 5.9, p = 0.04). By contrast no association was found between functional movement disorders and phenotypically different neurological or non neurological disease models. A significant inverse relationship between exposure to a phenotypically concordant movement disorder model and age of disease onset was also observed. Conclusions These findings support disease modeling as a factor contributing to the phenomenology of functional movement disorders.

SPECT imaging is widely used for the differential diagnosis of degenerative parkinsonisms by exploiting the high affinitiy of the radiotracer (123)I-FP-CIT for the dopamine transporter. Reduced levels of DAT are found in Parkinson Disease (PD), Dementia with Lewy Bodies (DLB), and Progressive Supranuclear Palsy (PSP) compared to in Essential Tremor (ET) and Healthy Controls (HC). However, the extent of the neurodegenerative process may extend beyond nigrostriatal system. We have exploited the affinity of the same radiotracer (123)I-FP-CIT for the serotonin transporter to investigate SERT levels in the midbrain of patients with PD, DLB, PSP, and ET compared to HC. Using MRI images as anatomical templates for midbrain uptake quantification, we found a mild decrease in SERT levels in PD compared to ET and HC, with marked inter-individual variability; on the other side, PSP and DLB patients displayed markedly reduced to undetectable levels of SERT, respectively. These findings show that the neurodegenerative process affects serotoninergic neurons in parkinsonisms, with much more severe involvement in DLB than in PD patients, despite the comparable loss of striatal DAT. SERT-dependent (123)I-FP-CIT uptake may allow a more comprehensive assessment of neurochemical disturbances in degenerative parkinsonisms and may have a value for differential diagnosis.

The geste antagoniste (GA), a relatively common feature of adult-onset primary dystonia, has been systematically evaluated only in cervical dystonia, but it is still unclear whether its frequency and phenomenology differ among the various forms of focal dystonia. We analysed the frequency, phenomenology, effectiveness, and relationship of the GA with demographic/clinical features of dystonia in a representative clinical series of patients with the two most common forms of adult-onset primary dystonia, blepharospasm (BSP) and cervical dystonia (CD). Clinical data were gathered using a standardized questionnaire, which showed substantial test-retest reliability (kappa = 0.79, P < 0.00001). The frequency of GA was similar among patients with BSP (42/59, 71.2%) and patients with CD (27/32, 84.4%), and in both groups GA showed similar effectiveness in reducing dystonia. The repertoire of GA was heterogenous in both BSP and CD patients, in whom seven BSP-related and five CD-related types of GA were recorded, and a "forcible" type of GA was present in 69% of BSP patients and in 48.1% of CD patients. In our whole patient population, age at dystonia onset was significantly lower among patients reporting a GA compared to those without GA (P = 0.01). GA features shared by BSP and CD predominate over differences, suggesting common mechanisms underlying this phenomenon in the two forms of primary adult-onset dystonia.

The pathophysiological mechanism of the pain in ALS is still unclear. The aim of the study was to evaluate the laser evoked potentials (LEPs) in ALS patients in relation to their clinical features. Twenty-four ALS patients were selected. Pain features were assessed and their intensity was measured by a 0-10 VAS. LEPs were recorded in all patients and in 23 healthy subjects. The dorsum of both hands was stimulated, at laser stimuli intensity of 7.5 W, with 10s inter-stimulus interval and 25 ms duration. Four electrodes were placed at Cz, T3, T4 and Fz positions, with the reference electrode at the nasion; T3 and T4 electrodes were referred off-line to Fz, in order to detect the N1 component. Latencies of N2, P2 and N1 waves were significantly higher in ALS than in controls. N1 amplitude was significantly increased in ALS patients compared to controls, with a similar trend for the N2-P2 complex. No correlation was found between LEP abnormalities, pain intensity and clinical features. A degeneration of subcortical structures may subtend a delay in the afferent input to the nociceptive cortex in ALS. On the other hand, an increase of pain processing at the cortical level may derive from a potential sensory compensation to motor cortex dysfunction.

Neuropsychiatric symptoms are frequent in dementia with Lewy bodies (DLB). Dopamine transporter (DAT) imaging with (123)I-labeled ligand N-delta-(fluoropropyl)-2 beta-carbomethoxy-3beta-(4-iodophenyl)tropene ((123)I-FP-CIT), which reliably measures midbrain dopaminergic dysfunction, has provided important evidence on the neurobiological substrate of some of these symptoms including apathy and depression. However, little is known on DAT levels and other distressing symptoms such as delusions and hallucinations. Therefore, (123)I-FP-CIT imaging was performed in 18 well-characterized patients with DLB, and striatal DAT levels were correlated with the frequency/severity ratings of several neuropsychiatric symptoms. A wide range of neuropsychiatric symptoms could be observed in the sample. Significant correlations were observed between decreased striatal DAT levels and visual hallucinations. Although there were no correlations between striatal DAT levels and other neuropsychiatric symptoms, when considering the putamen and the caudate nucleus separately, delusions, depression, and apathy were inversely correlated to decreased caudate DAT levels. The seresults provide intriguing evidence on the involvement of the mesocortical dopaminergic pathways in neuropsychiatric symptoms in DLB.

Background and purpose: Multiple sclerosis (MS) patients are often emotionally disturbed. We investigated anger in these patients in relation to demographic, clinical, and mood characteristics. Patients and methods: About 195 cognitively unimpaired MS patients (150 relapsing–remitting and 45 progressive) were evaluated with the State Trait Anger Expression Inventory, the Chicago Multiscale Depression Inventory, and the State Trait Anxiety Inventory. The patients’ anger score distribution was compared with that of the normal Italian population. Correlation coefficients among scale scores were calculated and mean anger scores were compared across different groups of patients by analysis of variance. Results: Of the five different aspects of anger, levels of withheld and controlled Anger were respectively higher and lower than what is expected in the normal population. Although anger was correlated with anxiety and depression, it was largely independent from these mood conditions. Mean anger severity scores were not strongly influenced by individual demographic characteristics and were not higher in more severe patients. Conclusions: The presence of an altered pattern of anger, unrelated to the clinical severity of MS, suggests that anger is not an emotional reaction to disease stress. An alteration of anger mechanisms might be a direct consequence of the demyelination of the connections among the amygdale, the basal ganglia and the medial prefrontal cortex.

Objective: Recent findings support greater efficacy of early vs. delayed interferon beta (IFN) treatment in patients with a first clinical event suggestive of multiple sclerosis (MS). We aimed to evaluate the effectiveness of early IFN treatment in definite relapsing-remitting MS (RRMS) and to assess the optimal time to initiate IFN treatment with regard to the greatest benefits on disability progression. Methods: A cohort of 2,570 IFN-treated RRMS patients was prospectively followed for up to 7 years in 15 Italian MS Centers. A Cox proportional hazards regression model adjusted for propensity score (PS) quintiles was used to assess differences between groups of patients with early vs. delayed IFN treatment on risk of reaching a 1-point progression in the Expanded Disability Status Scale (EDSS) score, and the EDSS 4.0 and 6.0 milestones. A set of PS-adjusted Cox hazards regression models were calculated according to different times of treatment initiation (within 1 year up to within 5 years from disease onset). A sensitivity analysis was performed to assess the robustness of findings. Results: The lowest hazard ratios (HRs) for the three PS quintiles–adjusted models were obtained by a cutoff of treatment initiation within 1 year from disease onset. Early treatment significantly reduced the risk of reaching a 1-point progression in EDSS score (HR 0.63; 95% CI 0.48 – 0.85; p 0.002), and the EDSS 4.0 milestone (HR 0.56; 95% CI 0.36 – 0.90; p 0.015). Sensitivity analysis showed the bound of significance for unmeasured confounders. Interpretation: Greater benefits on disability progression may be obtained by an early IFN treatment in RRMS. Ann Neurol 2009;66:513–520

Objective To test whether higher education accelerates Alzheimer's Disease (AD) progression rate through an effect on the cognitive reserve capabilities of an individual. Methods We investigated the influence of schooling and other demographic and clinical conditions (including age, sex, diabetes, arterial hypertension, and acetyl cholinesterase inhibitor – AcheI – therapy) on Mini Mental Status Examination (MMSE) score changes over time in 162 AD patients as well as the interaction of schooling with the above conditions using the Generalized Estimated Equation procedure. Results Generalized Estimated Equation procedure yielded an overall progression rate of 0.24 MMSE points per month. Patients with education ≥8 years showed a faster cognitive decline. Male sex, occurrence of arterial hypertension and type II diabetes, and lack of AcheI therapy were associated to faster decline. Stratifying by gender, vascular risk factors, and AcheI therapy, we observed a significant interaction between education and time in the subgroup of patients who had vascular risk factors, and in those who were not treated with AcheI. Conclusion These results confirm that schooling may be a significant predictor of cognitive decline as measured by MMSE in persons with AD and provide epidemiological support to “cognitive reserve” model.

Dementia is a frequent non-motor feature of Parkinson's disease (PD). Elevated plasma homocysteine (Hcy) levels have been associated with both cognitive impairment and dementia. Increased Hcy levels have been observed in levodopa-treated patients with PD. The objective of our study was to evaluate the association between plasma Hcy levels and dementia in PD. We performed a multicenter cross-sectional study on patients with PD with (PDD) and without (PDnD) dementia and age- and sex-matched healthy controls. We compared Hcy levels in patients with PDD and PDnD and healthy controls, and we performed logistic regression analysis to search for an association between the presence of dementia and increased Hcy levels in PD. Patients with PD (121), PDD (42), and PDnD (79), and age- and sex-matched controls (154) were enrolled. Hcy levels were higher in patients with PD compared to controls (17.5 micromol/L +/- 10.2 vs. 11 +/- 4.1; P 18.9 micromol/L) with the bottom tertile (

Objectives The aim of this study was to evaluate the function of Aδ fibers at the hand level in patients with clinical symptoms of Carpal Tunnel Syndrome (CTS) using CO 2 laser evoked potentials (LEPs), in light of the intensity and distribution of sensory symptoms and pain. Methods Thirty-four CTS outpatients (62 hands) were compared to 23 sex- and age-matched control subjects (46 hands). The periungueal skin of the first, second, third and fifth fingers, and the dorsum of the hands were stimulated in random order. The latency and amplitude of the N2, P2 and N1 components were evaluated with respect to the Nerve Conduction Study (NCS) data, clinical scales, pain intensity and glove-like symptoms distribution. Results The amplitude of the N2–P2 complex was significantly reduced in CTS hands compared to normal hands after stimulation of the second and third fingers, even in patients with mild nerve conduction impairment. No significant fifth finger LEP abnormalities were found in patients with glove-like distribution symptoms. The N2–P2 amplitude at the second and third fingers was positively correlated with the severity of sensory symptoms. Conclusions The involvement of median nerve Aδ fibers in CTS seems to be an early phenomenon, which concurs with the impairment of large motor and sensory afferents and is linked to the severity of the disease. Significance The finding of reduced sensory symptoms in patients with severe thin afferents damage, may suggest a slight expression of central sensitisation phenomena in the advanced stage of CTS syndrome.

The effects of Glatiramer Acetate (GA) in combination with Minocycline (MIN), a second-generation tetracycline, have been investigated on the course of EAE in mice, resulting in a significant reduction in disease severity and burden with attenuation of the inflammation, axonal loss and demyelination. Here we investigate the effects of combination therapy with GA and MIN on the induction, maturation and phenotyping of blood monocyte-derived dendritic cells (DCs) in Multiple Sclerosis (MS) patients. Hence the expressions of HLA-DR, CD11c, CD83 and CD1a were studied by flow cytometric analysis on immature (iDCs) and mature DCs (mDCs) from untreated and GA treated MS patients. Thirteen relapsing–remitting MS patients and 13 healthy controls (HCs) were included in the study. Ten of the MS patient group were re-tested after a 2 month period of GA treatment. The marker expressions on DC from untreated MS and HCs were studied in vitro in the absence or presence of GA and GA + MIN; and on DCs from GA treated MS patients without and with the in vitro addition of MIN. We found that in vitro GA alone or in combination with MIN downregulated DCs antigen presentation capability (HLA-DR), whereas the combination treatment only affected also myeloid DCs activation (CD83) in both MS and HCs. Prolonged GA treatment ( in vivo for 2 months) affected antigen presentation capability by DCs, whereas when treated in vitro with MIN these cells also tended to reduce activation marker expression and myeloid phenotype acquisition (CD11c). The present data demonstrate possible combination effects of GA and MIN on peripheral blood monocyte-derived DCs in MS patients.

BACKGROUND Hypertension and diabetes are significantly associated with insulin resistance (IR), which could affect the vasodilatory capacity and microcirculation. The aim of the study was to verify whether IR is associated with a reduced microvascular blood flow in normoglycemic mild hypertensives. METHODS Eighty-four untreated grade-1 hypertensives were equally divided, according to the IR homeostasis model assessment (HOMA) index, into three groups: IR-Low = 2.16 +/- 0.09 vs. IR-Medium = 3.77 +/- 0.09 vs. IR-High = 7.08 +/- 0.68 (P < 0.001) with similar sex distribution, office systolic blood pressure (SBP)/diastolic blood pressure (DBP) and history of hypertension. They underwent ambulatory blood pressure monitoring (ABPM) and a laboratory stress session, during which blood pressure (BP), heart rate (HR), and skin blood flow (Laser Doppler) were taken on the forehead (LDF) and the hand (LDH), where the neuroadrenergic control of the microvascular blood flow is higher. Reactivity was calculated as "area-under-the-curve" (AUC) during arithmetic and cold pressor tests. Postischemic LDH served as the index of endothelial microcirculatory damage. RESULTS ABPM confirmed the diagnosis of hypertension, but IR-High patients showed a reduced nighttime BP fall. They also demonstrated reduced LDH-AUC and LDF-AUC although BP-AUC and HR-AUC reactivity were similar. Postischemic LDH was lower in the IR-High group (P < 0.05), and the postischemic LDH change was progressively impaired in both IR-Medium and IR-High patients (P < 0.001). LDH-AUC (-0.305, P = 0.007) and postischemic LDH at 30 s (-0.217, P = 0.059) and 60 s (-0.248, P = 0.030) during hyperemia were associated with HOMA. Multiple regression analysis, with HOMA as the dependent variable, showed that BMI (beta = 0.336, P < 0.001) and LDH (beta = -0.239, P < 0.001), LDH-AUC (beta = -0.296, P < 0.01) and postischemic LDH change (beta = -0.321, P < 0.001) entered the equation. CONCLUSIONS The findings suggest that IR is associated with functional microvascular constrictive impairment in normoglycemic mild hypertensives.

The aim of this study was to test the function of the diffuse noxious inhibitory control system (DNIC) in chronic and episodic migraine, exploring the blink reflex (BR) modifications induced by topical application of capsaicin on the hand. We evaluated 11 migraine without aura (MA) and nine chronic migraine (CM) patients during the not symptomatic phase; they were compared with 14 non-headache subjects (N). The BR was elicited by weak electrical stimuli delivered to the right supraorbital nerve; it was obtained 10 min and 20 min after the application of 1 ml of 3% capsaicin in a cream base (Teofarma) on the skin of the dorsum of the right hand, and 60 min after capsaicin removal. The subjective pain sensation induced by capsaicin was significantly increased in CM with respect to both MA patients and normal subjects; the R2 area was increased in CM patients during capsaicin application, with respect to controls and MA patients, who did not exhibit any reflex alterations. These results may suggest a failure of DNIC and a disturbed control of the trigeminal reflex at the central level, linked with migraine frequency.

The present study aimed to evaluate heat pain thresholds and evoked potentials following CO(2) laser thermal stimulation (laser-evoked potentials, LEPs), during remote application of capsaicin, in migraine patients vs. non-migraine healthy controls. Twelve outpatients suffering from migraine without aura were compared with 10 healthy controls. The LEPs were recorded by 6 scalp electrodes, stimulating the dorsum of the right hand and the right supraorbital zone in basal condition, during the application of 3% capsaicin on the dorsum of the left hand and after capsaicin removal. In normal subjects, the laser pain and the N2-P2 vertex complex obtained by the hand and face stimulation were significantly reduced during remote capsaicin application, with respect to pre-and post-capsaicin conditions, while in migraine LEPs and laser pain were not significantly modified during remote painful stimulation. In migraine a defective brainstem inhibiting control may coexist with cognitive factors of focalised attention to facial pain, less sensitive to distraction by a second pain.

Objective To investigate the impact of interferon-beta (IFNβ) on disease progression in relapsing-remitting multiple sclerosis patients. Methods A cohort of 1,504 relapsing-remitting multiple sclerosis (1,103 IFNβ–treated and 401 untreated) patients was followed for up to 7 years. Cox proportional hazards regression adjusted for propensity score inverse weighting was used to assess the differences between the two groups for three different clinical end points: secondary progression (SP) and irreversible Expanded Disability Status Scale (EDSS) scores 4 and 6. Times from first visit and from date of birth were used as survival time variables. Results The IFNβ–treated group showed a highly significant reduction in the incidence of SP (hazard ratio [HR], 0.38, 95% confidence interval [CI], 0.24–0.58 for time from 1st visit; HR, 0.36, 95% CI, 0.23–0.56 for time from date of birth; p < 0.0001), EDSS score of 4 (HR, 0.70, 95% CI, 0.53–0.94 for time from first visit; HR, 0.69, 95% CI, 0.52–0.93 for time from date of birth; p < 0.02), and EDSS score of 6 (HR, 0.60, 95% CI, 0.38–0.95 for time from first visit; HR, 0.54, 95% CI, 0.34–0.86 for time from date of birth; p ≤ 0.03) when compared with untreated patients. SP and EDSS scores of 4 and 6 were reached with significant delays estimated by times from first visit (3.8, 1.7, and 2.2 years) and from date of birth (8.7, 4.6, and 11.7 years) in favor of treated patients. Sensitivity analysis confirmed findings. Interpretation IFN-β slows progression in relapsing-remitting multiple sclerosis patients. Ann Neurol 2007;61:300–306

The contingent negative variation (CNV) is a neurophysiological pattern related to planning of external — paced, voluntary movements. The aim of the study, was to examine the CNV in a cohort of mild demented and non-medicated HD patients, evaluating the CNV amplitude modifications in the light of clinical features and performing Low Resolution Brain Electromagnetic Tomography (LORETA) analysis in order to show the CNV multiple generators. Fourteen HD patients and 25 sex and age-matched controls were studied. All subjects were evaluated by the motor section of UHDRS, MMSE and WAIS. The CNV was recorded by 19 scalp electrodes, with a red light flash as visual warning stimulus (S1), followed by a blue light flash (S2) after a fixed interval of 3 s. The amplitude of early CNV was significantly reduced in HD, compared to controls: the amplitude reduction was significantly correlated with the bradikinesia score. LORETA analysis of early CNV significantly discriminated patients from controls, for a prevalent activation of the posterior part of anterior cingulate cortex in HD. An abnormal activation of the associative cortex devoted to the processing of attention preceding voluntary movement may be supposed in HD, probably mediated by the altered basal ganglia modulation.

Objective To assess whether cigarette smoking interferes with dopaminergic transmission in current- and never-smoking patients with Parkinson's disease. Materials and methods Striatal [123I]FP–CIT single photon emission computed tomography was performed in 67 patients with Parkinson's disease (35 women and 32 men aging 60.8 ± 10.1 years and staging 1.76 ± 0.5 on the Hoehn and Yahr scale). At study time, there were 13 current-smokers and 54 never-smokers. Results Current-smokers showed a significantly lower putamen/occipital [123I]FP–CIT ratio and a non-significant trend to a lower caudate/occipital [123I]FP–CIT ratio uptake. Current-smokers were also characterized by a lower off UPDRS-III motor score. A logistic regression analysis adjusted for age, sex, disease duration, Hoehn and Yahr staging, and medication indicated a significant lower [123I]FP–CIT uptake not only in the putamen (odds ratio, 0.1; 95% confidence interval, 0.01 to 0.65; P = 0.02) but also in the caudate (odds ratio, 0.2; 95% confidence interval, 0.04 to 0.71; P = 0.015) as well as a lower UPDRS-III motor score (odds ratio, 0.9; 95% confidence interval, 0.81 to 0.99; P = 0.04) in current-smokers. Conclusions The lower [123I]FP-CIT uptake together with the lower UPDRS-III motor score observed in our current-smokers patients with Parkinson's disease (even taking into account variables that are probably expression of dopaminergic neuron decline and treatment) would support an effect of smoking on dopaminergic synaptic mechanisms.

Influenza vaccination has been implicated in Guillain Barre Syndrome (GBS) although the evidence for this link is controversial. A case–control study was conducted between October 2010 and May 2011 in seven Italian Regions to explore the relation between influenza vaccination and GBS. The study included 176 GBS incident cases aged ≥18 years from 86 neurological centers. Controls were selected among patients admitted for acute conditions to the Emergency Department of the same hospital as cases. Each control was matched to a case by sex, age, Region and admission date. Two different analyses were conducted: a matched case–control analysis and a self-controlled case series analysis (SCCS). Case–control analysis included 140 cases matched to 308 controls. The adjusted matched odds ratio (OR) for GBS occurrence within 6 weeks after influenza vaccination was 3.8 (95 % CI: 1.3, 10.5). A much stronger association with gastrointestinal infections (OR = 23.8; 95 % CI 7.3, 77.6) and influenza-like illness or upper respiratory tract infections (OR = 11.5; 95 % CI 5.6, 23.5) was highlighted. The SCCS analysis included all 176 GBS cases. Influenza vaccination was associated with GBS, with a relative risk of 2.1 (95 % CI 1.1, 3.9). According to these results the attributable risk in adults ranges from two to five GBS cases per 1,000,000 vaccinations.

Aims: Questions regarding perception of pain in non-communicating patients and the management of pain continue to raise controversy both at a clinical and ethical level. The aim of this study was to examine the cortical response to salient visual, acoustic, somatosensory electric non-nociceptive and nociceptive laser stimuli and their correlation with the clinical evaluation. Methods: Five Vegetative State (VS), 4 Minimally Conscious State (MCS) patients and 11 age- and sex-matched controls were examined. Evoked responses were obtained by 64 scalp electrodes, while delivering auditory, visual, non-noxious electrical and noxious laser stimulation, which were randomly presented every 10 s. Laser, somatosensory, auditory and visual evoked responses were identified as a negative-positive (N2-P2) vertex complex in the 500 ms post-stimulus time. We used Nociception Coma Scale-Revised (NCS-R) and Coma Recovery Scale (CRS-R) for clinical evaluation of pain perception and consciousness impairment. Results: The laser evoked potentials (LEPs) were recognizable in all cases. Only one MCS patient showed a reliable cortical response to all the employed stimulus modalities. One VS patient did not present cortical responses to any other stimulus modality. In the remaining participants, auditory, visual and electrical related potentials were inconstantly present. Significant N2 and P2 latency prolongation occurred in both VS and MCS patients. The presence of a reliable cortical response to auditory, visual and electric stimuli was able to correctly classify VS and MCS patients with 90% accuracy. Laser P2 and N2 amplitudes were not correlated with the CRS-R and NCS-R scores, while auditory and electric related potentials amplitude were associated with the motor response to pain and consciousness recovery. Discussion: pain arousal may be a primary function also in vegetative state patients while the relevance of other stimulus modalities may indicate the degree of cognitive and motor behavior recovery. This underlines the importance of considering the potential experience of pain also in patients in vegetative state and to appropriately assess a possible treatment also in those patients.

Amyloid-β (Aβ) has been implicated in memory loss and disruption of synaptic plasticity observed in early-stage Alzheimer's disease. Recently, it has been shown that soluble Aβ oligomers target synapses in cultured rat hippocampal neurons, suggesting a direct role of Aβ in the regulation of synaptic structure and function. Postsynaptic density-95 (PSD-95) is a postsynaptic scaffolding protein that plays a critical role in synaptic plasticity and the stabilization of AMPA (AMPARs) and NMDA (NMDARs) receptors at synapses. Here, we show that exposure of cultured cortical neurons to soluble oligomers of Aβ1-40reduces PSD-95 protein levels in a dose- and time-dependent manner and that the Aβ11-40-dependent decrease in PSD-95 requires NMDAR activity. We also show that the decrease in PSD-95 requires cyclin-dependent kinase 5 activity and involves the proteasome pathway. Immunostaining analysis of cortical cultured neurons revealed that Aβ treatment induces concomitant decreases in PSD-95 at synapses and in the surface expression of the AMPAR glutamate receptor subunit 2. Together, these data suggest a novel pathway by which Aβ triggers synaptic dysfunction, namely, by altering the molecular composition of glutamatergic synapses.