Fatigue in fluctuating Parkinson's disease patients: possible impact of safinamide.

Fatigue is a common non-motor symptom in Parkinson's disease (PD). Among other pathophysiological mechanisms, neuroinflammation, a pathological PD hallmark associated with changes in glutamatergic transmission in basal ganglia, has been proposed as a crucial factor closely related to fatigue. To test the hypothesis that safinamide could represent an effective treatment of fatigue in PD patients, given its dual mechanism of action (it selectively and reversibly inhibits MAOB and modulates glutamate release), we administered the validated versions of fatigue severity scale (FSS) and Parkinson fatigue scale-16 (PFS-16) to 39 fluctuating PD patients with fatigue before and after a 24-week treatment period with safinamide as add-on therapy. An assessment of secondary variables such as depression, quality of life (QoL), and motor and non-motor symptoms (NMS) was conducted. After 24 weeks of treatment with safinamide, both FSS (p < 0.001) and PF-S16 (p = 0.02) scores were significantly lower than at baseline. Moreover, 46.2% and 41% of patients scored below the cut-off for the presence of fatigue according to FSS and PFS-16, respectively (responders). At follow-up, a significant difference emerged between responders and non-responders in mood, QoL, and NMS. Fatigue improved in fluctuating PD, and more than 40% of patients were "fatigue-free" after a 6 month treatment with safinamide. Patients without fatigue at follow-up displayed significantly better scores in QoL domains, such as mobility or activities of daily living, although disease severity remained stable, supporting the hypothesis that fatigue could considerably affect QoL. Drugs that interact with multiple neurotransmission systems, such as safinamide, could be useful in reducing this symptom.

DNA methylation of the 5'-UTR DAT 1 gene in Parkinson's disease patients.

OBJECTIVES: The involvement of epigenetics mechanisms in the transcriptional regulation of key genes has been investigated in the initiation and progression of neurodegenerative disorders, including Parkinson's disease (PD). Among others, we, here, focused the attention on the dopamine transporter (DAT) gene playing a critical role in maintaining the integrity of dopaminergic neurons. MATERIALS AND METHODS: We performed bisulfite pyrosequencing to examine DNA methylation levels of six CpG sites in the 5'-UTR of DAT1 gene in human peripheral blood mononuclear cells (PBMCs) obtained from 101 sporadic PD patients and 59 healthy controls. RESULTS: We selectively report for CpG5 an increase in DNA methylation levels in PD subjects respect to controls, that almost reaches statistical significance (30.06 ± 12.4 vs 26.58 ± 7.6, P = .052). Of interest, a significantly higher methylation at specific CpG sites (ANOVA: P = .029) was observed in PD subjects with advanced stage of illness. Namely, a multivariate regression analysis showed that a higher methylation level at specific CpG sites in the group of PD patients was associated with increased methylation at CpG2, CpG3, and with H&Y stage but not with age and gender. This regression model explains the 38% of the variance of methylation at CpG5. CONCLUSION: Our results do seem to suggest that the methylation level of CpG5 is different between PD patients and controls. Moreover, this methylation level for CpG5 may be associated also with the stage of disease.

Attention in Parkinson's disease with fatigue: evidence from the attention network test.

Fatigue is a non-specific symptom that is common in chronic diseases and represents one of the most disabling symptoms in Parkinson's disease. PD patients often experience cognitive deficits related above all to executive functions. The relationship between cognitive changes and fatigue in PD patients has not been explored in depth. The Attention Network Test (ANT) is a rapid, widely used test to measure the efficiency of three attentional networks, i.e., alerting, orienting, and executive, by evaluating reaction times (RTs) in response to visual stimuli. To assess the association between fatigue and the efficiency of the attentional networks, according to the Posnerian view, ANT was administered to 15 parkinsonian patients with fatigue (PFS-16 > 2.95), 17 parkinsonian patients without fatigue, and 37 age- and sex-matched healthy controls. Anxiety, depression, quality of sleep, and quality of life were also assessed. Parkinsonian patients displayed significantly longer RTs and lower executive network efficiency than controls. Patients with fatigue displayed significantly lower executive network efficiency than patients without fatigue. Moreover, patients with fatigue exhibited a lower accuracy than either patients without fatigue or controls. Finally, patients without fatigue displayed a more efficient alerting network than either patients with fatigue or controls. Although the pathogenesis of fatigue is multifactorial, our results indicate that fatigue may be closely related to an alteration of the striato-thalamo-cortical loop connecting the neostriatum to the prefrontal cortex, which is also responsible for the executive dysfunction that is typical of Parkinson's disease.

Idiopathic pes cavus in adults is not associated with neurophysiological impairment in the lower limbs.

The nerve conduction characteristics of adults with idiopathic pes cavus/hammer toes have not been studied extensively. Among 2048 out-patients (59.5 ± 13.9 years) referring to a laboratory of Neurophysiology in Rome, we recruited 18 patients with idiopathic pes cavus (61.3 ± 12.5 years). Fifty-four age/sex-matched controls were also studied. No nerve conduction differences were observed between patients with and without cavus foot (p > 0.05). The absence of deep tendon reflexes and slight muscle weakness and hypotrophy in the lower limbs were more common in subjects with cavus foot deformity than in controls (p < 0.001). Adult patients with idiopathic pes cavus/hammer toes do not differ from healthy controls from a neurophysiological standpoint, but they could show minor signs of clinical impairment, such as lower limb weakness, hypotrophy and areflexia.

The Role of the Right Dorsolateral Prefrontal Cortex in Phasic Alertness: Evidence from a Contingent Negative Variation and Repetitive Transcranial Magnetic Stimulation Study.

Phasic alertness represents the ability to increase response readiness to a target following an external warning stimulus. Specific networks in the frontal and parietal regions appear to be involved in the alert state. In this study, we examined the role of the right dorsolateral prefrontal cortex (DLPFC) during the attentional processing of a stimulus using a cued double-choice reaction time task. The evaluation of these processes was conducted by means of Event-Related Potentials (ERPs), in particular by using the Contingent Negative Variation (CNV), and repetitive 1-Hz Transcranial Magnetic Stimulation (rTMS). Transient virtual inhibition of the right DLPFC induced by real 1-Hz rTMS stimulation led to a significant decrease in total CNV and W1-CNV areas if compared with the basal and post-sham rTMS conditions. Reaction times (RTs) did not decrease after inhibitory rTMS, but they did improve after sham stimulation. These results suggest that the right DLPFC plays a crucial role in the genesis and maintenance of the alerting state and learning processes.

A Systematic Review on Drugs Acting as Nicotinic Acetylcholine Receptor Agonists in the Treatment of Dementia.

Acetylcholine signaling is attenuated in early Alzheimer's disease (AD) and other dementias. A significant reduction in the expression of nicotinic acetylcholine receptors (nAChRs) in the brain of AD patients has also been reported in several molecular biological and in situ labeling studies. The modulation of the functional deficit of the cholinergic system as a pharmacological target could therefore have a clinical benefit, which is not to be neglected. This systematic review was conducted to identify clinical trials, which evaluated the safety and efficacy of nicotinic acetylcholine receptor agonists using Clinicaltrial (CT) and EudraCT databases. Structured searches identified 39 trials, which used 15 different drugs designed to increase the function of the nAChRs. Most of the identified clinical trials were phase II trials, with some of them classified as ongoing for several years. The systematic screening of the literature led to the selection of 14 studies out of the 8261 bibliographic records retrieved. Six trials reported detailed data on adverse events associated with the intervention, while twelve trials reported data on efficacy measures, such as attention, behavior and cognition. Overall, smost of the physical side effects of cholinergic agonists were reported to be well tolerated. Some trials also reported improvements in attention. However, the efficacy of these drugs in other cognitive and behavioral outcomes remains highly controversial.

The Profile of the Italian Centers for Cognitive Disorders and Dementia in the Context of New Drugs in Alzheimer's Disease.

Background: The wait for the upcoming disease-modifying therapies (DMT) for Alzheimer's disease in Europe is raising questions about the preparedness of national healthcare systems to conduct accurate diagnoses and effective prescriptions. In this article, we focus on the current situation in Italy. Objective: The primary goal is to propose a profile of the Italian Centers for Cognitive Disorders and Dementias (CCDDs) that could be taken into consideration by regional and autonomous provincial authorities when deciding on the prescribing centers for DMT. Methods: Based on responses to a national survey on CCDDs in Italy, we identified the CCDDs that meet the requirements for effective prescription: 1) Multidisciplinary team; 2) Minimum Core Test for the neuropsychological assessment; 3) PET, CSF, and Brain MRI assessments. Univariate and multivariate comparisons were conducted between CCDDs that met the criteria and the others. Results: Only 10.4% of CCDDs met the requirements for effective DMT prescription, mainly located in Northern Italy. They are also characterized by longer opening hours, a higher number of professionals, a university location, and a higher frequency of conducting genetic tests, and could potentially result in prescribing centers. Conclusions: The findings suggest that the Italian national healthcare system may benefit from further enhancements to facilitate the effective prescription of DMTs. This could involve initiatives to reduce fragmentation, ensure adequate resources and equipment, and secure sufficient funding to support this aspect of healthcare delivery.

Development of a prediction model of conversion to Alzheimer's disease in people with mild cognitive impairment: the statistical analysis plan of the INTERCEPTOR project.

BACKGROUND: In recent years, significant efforts have been directed towards the research and development of disease-modifying therapies for dementia. These drugs focus on prodromal (mild cognitive impairment, MCI) and/or early stages of Alzheimer's disease (AD). Literature evidence indicates that a considerable proportion of individuals with MCI do not progress to dementia. Identifying individuals at higher risk of developing dementia is essential for appropriate management, including the prescription of new disease-modifying therapies expected to become available in clinical practice in the near future. METHODS: The ongoing INTERCEPTOR study is a multicenter, longitudinal, interventional, non-therapeutic cohort study designed to enroll 500 individuals with MCI aged 50-85 years. The primary aim is to identify a biomarker or a set of biomarkers able to accurately predict the conversion from MCI to AD dementia within 3 years of follow-up. The biomarkers investigated in this study are neuropsychological tests (mini-mental state examination (MMSE) and delayed free recall), brain glucose metabolism ([18F]FDG-PET), MRI volumetry of the hippocampus, EEG brain connectivity, cerebrospinal fluid (CSF) markers (p-tau, t-tau, Aß1-42, Aß1-42/1-40 ratio, Aß1-42/p-Tau ratio) and APOE genotype. The baseline visit includes a full cognitive and neuropsychological evaluation, as well as the collection of clinical and socio-demographic information. Prognostic models will be developed using Cox regression, incorporating individual characteristics and biomarkers through stepwise selection. Model performance will be evaluated in terms of discrimination and calibration and subjected to internal validation using the bootstrapping procedure. The final model will be visually represented as a nomogram. DISCUSSION: This paper contains a detailed description of the statistical analysis plan to ensure the reproducibility and transparency of the analysis. The prognostic model developed in this study aims to identify the population with MCI at higher risk of developing AD dementia, potentially eligible for drug prescriptions. The nomogram could provide a valuable tool for clinicians for risk stratification and early treatment decisions. TRIAL REGISTRATION: ClinicalTrials.gov NCT03834402. Registered on February 8, 2019.

Advances in amyloid-targeting monoclonal antibodies for Alzheimer's disease: clinical and public health issues.

INTRODUCTION: Alzheimer's disease (AD) is a major global public health challenge. To date, no treatments have been shown to stop the underlying pathological processes. The cerebral accumulation of amyloid-beta (Ab) is still considered as the primum movens of AD and disease-modifying treatments targeting Ab are reaching - or have already reached - clinical practice. AREAS COVERED: The authors explore the main advancements from Aß-targeting monoclonal antibodies (mAbs) for the treatment of AD. From a public health perspective, they address ethically relevant issues such as the benevolence and non-maleficence principles. They report on the potential biological and clinical benefits of these drugs, discussing minimal clinically important differences (MCID) and other relevant outcomes. They examine the short- and long-term effects of amyloid-related imaging abnormalities (ARIA), and explore the differences between eligibility criteria in clinical trials, appropriate use recommendations, and prescribing information content. In doing so, they contextualize the discussion on the disagreements among different regulatory authorities. EXPERT OPINION: Although anti-ß-amyloid monoclonal antibodies may be effective in selected scenarios, non-negligible knowledge gaps and implementation limits persist. Overcoming these gaps can no longer be postponed if we are to ensure the principles of Quality of Care for patients with cognitive impairment who would be eligible for this class of drugs.

Role of Functional Neuroimaging with 123I-MIBG and 123I-FP-CIT in De Novo Parkinson's Disease: A Multicenter Study.

BACKGROUND: Parkinson's disease is a progressive neurodegenerative disorder, with incidence and prevalence rates of 8-18 per 100,000 people per year and 0.3-1%, respectively. As parkinsonian symptoms do not appear until approximately 50-60% of the nigral DA-releasing neurons have been lost, the impact of routine structural imaging findings is minimal at early stages, making Parkinson's disease an ideal condition for the application of functional imaging techniques. The aim of this multicenter study is to assess whether 123I-FP-CIT (DAT-SPECT), 123I-MIBG (mIBG-scintigraphy) or an association of both exams presents the highest diagnostic accuracy in de novo PD patients. METHODS: 288 consecutive patients with suspected diagnoses of Parkinson's disease or non- Parkinson's disease syndromes were analyzed in the present Italian multicenter retrospective study. All subjects were de novo, drug-naive patients and met the inclusion criteria of having undergone both DAT-SPECT and mIBG-scintigraphy within one month of each other. RESULTS: The univariate analysis including age and both mIBG-SPECT and DAT-SPECT parameters showed that the only significant values for predicting Parkinson's disease in our population were eH/M, lH/M, ESS and LSS obtained from mIBG-scintigraphy (p < 0.001). CONCLUSIONS: mIBG-scintigraphy shows higher diagnostic accuracy in de novo Parkinson's disease patients than DAT-SPECT, so given the superiority of the MIBG study, the combined use of both exams does not appear to be mandatory in the early phase of Parkinson's disease.

An electrophysiological approach to tinnitus interpretation.

INTRODUCTION: Serotonin seems to play a central role in tinnitus. The intensity dependence of auditory evoked potential (IDAP) is considered an index of central serotonergic activity in the auditory cortex. The higher the steepness of the N1/P2 component amplitude-stimulus function slope (N1/P2 ASF slope as calculated by IDAP), the lower the central serotonergic activity. Similarly, the N1 amplitude-stimulus function slope (N1 ASF slope) was investigated. Auditory brainstem responses (ABR) examine the auditory system functionality from the periphery and through the brainstem, where serotonergic projections have been identified. OBJECTIVES: Assessing whether tinnitus perception neurotransmitters activity inbalance could be investigated by an electrophysiological approach. MATERIALS AND METHODS: Ten normoacousic tinnitus patients and 14 healthy controls were included in the study. Subjects underwent EEG (IDAP) recording, ABR recording and psychometric questionnaires administration. RESULTS: N1/P2 ASF slope and N1ASF slope tended to have a greater steepness in patients. N1ASF slope was significantly correlated with ABR wave V and interpeak III-V latencies in patients. ABR wave V and interpeak III-V latencies were significantly longer in patients than in controls. CONCLUSION: N1/P2 ASF slope, N1 ASF slope and ABR components appear to be useful electrophysiologic methods to study possible functional alterations related to the serotonergic activity.

Serotonergic central tone in Parkinson's disease with fatigue: Evidence from the loudness dependence of auditory evoked potentials (LDAEP).

Central fatigue in Parkinson's disease (PD) is a common and disabling symptom that further worsens the patients' quality of life. A deficit in the serotonergic system may be implicated in the occurrence of fatigue in patients with PD as well as in those with other chronic conditions characterized by fatigue. The loudness dependence of auditory evoked potentials (LDAEP) is a neurophysiological tool that has proved to be effective in measuring the serotonergic central function in vivo. The aim of the present study was to assess central serotonergic activity in PD patients and to explore its possible association with the presence of fatigue. LDAEP was recorded in 38 PD patients (26 without fatigue - PDnF and 12 with fatigue - PDF) and 34 healthy controls. A significant difference between parkinsonian patients and controls emerged, with patients displaying stronger LDAEP values (which reflect a lower serotonergic central tone) than controls. By contrast, no differences in LDAEP emerged between PDF and PDnF. Our electrophysiological data confirmed the presence of a deficit in serotonergic central transmission in PD. An association between this deficit and fatigue was not demonstrated. It is likely that an altered dopamine/serotonin balance, rather than a serotonin deficit alone, is involved in the genesis of central fatigue. This complex and multifaceted symptom is related above all to a dysfunction in the striato-thalamo-cortical loop that connects the neostriatum to the frontal lobe and is strongly affected by motivation.

Bladder symptoms assessed with overactive bladder questionnaire in Parkinson's disease.

In Parkinson's disease (PD) the urinary dysfunction manifests primarily with symptoms of overactive bladder (OAB). The OAB questionnaire (OAB-q) is a measure designed to assess the impact of OAB symptoms on health-related quality of life. In this study, we quantified the urinary symptoms in a large cohort of PD patients by using the OAB-q short form. Possible correlations between the OAB-q and clinical features were tested. Three hundred and two PD patients were enrolled in the study. Correlations between the OAB-q and sex, age, Unified Parkinson's Disease Rating Scale part III (UPDRS-III), Hoehn-Yahr (H-Y) staging, disease duration, and treatment were analyzed. Data were compared with a large cohort of 303 age-matched healthy subjects. The OAB-q yielded significantly higher scores in PD patients than in healthy subjects. In the group of PD patients, all the variables tested were similar between men and women. Pearson's coefficient showed a significant correlation between mean age, disease duration, mean OAB-q scores, UPDRS-III scores, and H-Y staging. A multiple linear regression analysis showed that OAB-q values were significantly influenced by age and UPDRS-III. No statistical correlations were found between OAB-q scores and drug therapy or the equivalent levodopa dose, whilst the items relating to the nocturia symptoms were significantly associated with the equivalent levodopa dose. Our findings suggest that bladder dysfunction assessed by OAB-q mainly correlates with UPDRS-III scores for severity of motor impairment, possibly reflecting the known role of the decline in nigrostriatal dopaminergic function in bladder dysfunction associated with PD and patients' age. Our study also suggests that the OAB-q is a simple, easily administered test that can objectively evaluate bladder function in patients with PD.

Diffusion MRI Findings in Encephalopathy Induced by Immunosuppressive Therapy after Liver Transplantation.

Neurological complications are common after liver transplantation, as they affect up to one-third of the transplanted patients and are associated with significant morbidity. The introduction of calcineurin inhibitors, cyclosporine A and tacrolimus, in immunosuppressive regimens significantly improved the outcome of solid-organ transplantation even though immunosuppression-associated neurotoxicity remains a significant complication, particularly occurring in about 25% of cases after liver transplantation. The immunosuppressant cyclosporine A and tacrolimus have been associated with the occurrence of major neurological complications, diffuse encephalopathy being the most common. The biochemical and pathogenetic basis of calcineurin inhibitors-induced neurotoxicity are still unclear although several mechanisms have been suggested. Early recognition of symptoms could help reduce neurotoxic event. The aim of the study was to evaluate cerebral changes through MRI, in particular with diffusion-weighted images (DWI) and apparent diffusion coefficient (ADC) maps, in two patients undergoing liver transplantation after immunosuppressive therapy. We describe two patients in which clinical pictures, presenting as a severe neurological condition, early after orthotopic liver transplantation during immunosuppression therapy, showed a different evolution in keeping with evidence of focal-multifocal lesions at DWI and ADC maps. At clinical onset, DWI showed hyperintensity of the temporo-parieto-occipital cortex with normal ADC values in the patient with following good clinical recovery and decreased values in the other one; in the latter case, MRI abnormalities were still present after ten days, until the patient's exitus. The changes in DWI with normal ADC may be linked to brain edema with a predominant vasogenic component and therefore reversible, while the reduction in ADC is due to cytotoxic edema and linked to more severe, nonreversible, clinical picture. Brain MRI and particularly DWI and ADC maps provide not only a good and early representation of neurological complications during immunosuppressant therapy but can also provide a useful prognostic tool on clinical outcome of the patient.

Neuroimaging in Vascular Cognitive Impairment and Dementia: A Systematic Review.

Cerebrovascular diseases are well established causes of cognitive impairment. Different etiologic entities, such as vascular dementia (VaD), vascular cognitive impairment, subcortical (ischemic) VaD, and vascular cognitive disorder, are included in the umbrella definition of vascular cognitive impairment and dementia (VCID). Because of the variability of VCID clinical presentation, there is no agreement on criteria defining the neuropathological threshold of this disorder. In fact, VCID is characterized by cerebral hemodynamic alteration which ranges from decreased cerebral blood flow to small vessels disease and involves a multifactorial process that leads to demyelination and gliosis, including blood-brain barrier disruption, hypoxia, and hypoperfusion, oxidative stress, neuroinflammation and alteration on neurovascular unit coupling, cerebral microbleeds, or superficial siderosis. Numerous criteria for the definition of VaD have been described: the National Institute of Neurological Disorders and Stroke Association Internationale pour Recherche'-et-l'Enseignement en Neurosciences criteria, the State of California Alzheimer's Disease Diagnostic and Treatment Centers criteria, DSM-V criteria, the Diagnostic Criteria for Vascular Cognitive Disorders (a VASCOG Statement), and Vascular Impairment of Cognition Classification Consensus Study. Neuroimaging is fundamental for definition and diagnosis of VCID and should be used to assess the extent, location, and type of vascular lesions. MRI is the most sensible technique, especially if used according to standardized protocols, even if CT plays an important role in several conditions. Functional neuroimaging, in particular functional MRI and PET, may facilitate differential diagnosis among different forms of dementia. This systematic review aims to explore the state of the art and future perspective of non-invasive diagnostics of VCID.

Central fatigue and attentional processing in Parkinson's disease: An event-related potentials study.

OBJECTIVE: To verify whether central fatigue in patients with Parkinson's disease (PD) is associated with the presence of a more severe selective cognitive impairment. METHODS: Twenty-four PD patients without fatigue-PDnF, 11 with fatigue-PDF and 32 healthy volunteers underwent a P300 novelty task that elicits both the P3a and the P3b components. RESULTS: P3b latency was significantly longer in both PDF and PDnF than in controls. P3b amplitudes were comparable between groups. P3a latency and P3a amplitude were respectively significantly longer and lower in PDF than in either PDnF or controls. CONCLUSION: The ability to discriminate the significant target stimulus, which requires the integrity of the dorsal attentional network and top-down control mechanisms, is compromised in parkinsonian patients irrespective of the presence of fatigue. PDF exhibited a difficulty in attentional orienting to salient novel stimuli, a bottom-up attentional control mechanism that is related to the functioning of the ventral attention network. SIGNIFICANCE: Fatigue seems to be specifically related to an impairment in the processing of novel stimuli, which is an essential part of adaptive decision-making behavior.

On the Role of Adenosine A2A Receptor Gene Transcriptional Regulation in Parkinson's Disease.

Adenosine A2A receptors (A2ARs) have attracted considerable attention as an important molecular target for the design of Parkinson's disease (PD) therapeutic compounds. Here, we studied the transcriptional regulation of the A2AR gene in human peripheral blood mononuclear cells (PBMCs) obtained from PD patients and in the striatum of the well-validated, 6-hydroxydopamine (6-OHDA)-induced PD mouse model. We report an increase in A2AR mRNA expression and protein levels in both human cells and mice striata, and in the latter we could also observe a consistent reduction in DNA methylation at gene promoter and an increase in histone H3 acetylation at lysine 9. Of particular relevance in clinical samples, we also observed higher levels in the receptor gene expression in younger subjects, as well as in those with less years from disease onset, and less severe disease according to clinical scores. In conclusion, the present findings provide further evidence of the relevant role of A2AR in PD and, based on the clinical data, highlight its potential role as disease biomarker for PD especially at the initial stages of disease development. Furthermore, our preclinical results also suggest selective epigenetic mechanisms targeting gene promoter as tool for the development of new treatments.

Selective attentional deficit in essential tremor: Evidence from the attention network test.

INTRODUCTION: The traditional view of essential tremor (ET) as a monosymptomatic and benign disorder has been reconsidered after patients with ET have been shown to experience cognitive deficits that are also related to attention. The Attention Network Test (ANT) is a rapid, widely used test to measure the efficiency of three attentional networks, i.e. alerting, orienting and executive, by evaluating reaction times (RTs) in response to visual stimuli. The aim of this study was to investigate attentional functioning in ET patients by means of the ANT. METHODS: 21 non-demented patients with ET and 21 age- and sex-matched healthy controls performed the ANT. RESULTS: RT was significantly longer in ET patients than in controls (p < 0.001). Moreover, a significant difference in alerting and executive efficiency (p = 0.003 and p = 0.01 respectively) was found between groups, while the difference in the orienting efficiency only bordered on significance. CONCLUSION: Our results point to a difficulty in the alerting and executive domains of attention in ET patients, probably owing to a dysfunction in the cerebello-thalamo-cortical loop. These selective attentional deficits are not related to clinical motor symptoms, contributing to shed further light on the clinical picture of ET.

Early diagnosis in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): the role of MRI.

The aim of our work was to evaluate the early presence of white matter changes on magnetic resonance imaging (MRI) in young asymptomatic children of patients with full-blown cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in whom DNA analysis revealed a Notch3 Cys146Tyr missense mutation on chromosome 19. Brain MRI was performed in all subjects using axial and coronal spin-echo proton density and T2-weighted images, axial fluid-attenuated inversion recovery (FLAIR) and sagittal and axial T1-weighted images. In asymptomatic subjects with Notch3 gene mutation, MRI showed small T2 hyperintense foci in periventricular and subcortical white matter. Routine use of MRI in the initial phases of a CADASIL diagnostic work up and the subsequent recognition of early abnormal findings in asymptomatic subjects may lead to prompt diagnosis of the disease in these patients. Moreover, these findings suggest that genetic screening is warranted in the presence of a suspect clinical history with specific MRI abnormalities.