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PURPOSE To study for the first time the incidence of adult-onset CNS tumors in Southern Sardinia, Italy. METHODS Clinical records of patients > 18 years old who were diagnosed with primary CNS tumors during 2016-2019 in the study area were reviewed. Meningiomas, cranial/paraspinal nerve tumors, lymphomas, and pituitary tumors were excluded. Cases were classified according to the 2016 WHO classification of CNS tumors and to the morphology codes from the International Classification of Diseases-Oncology, third edition. Age-adjusted incidence rates were calculated by the direct method to the 2011-2020 European standard population. Kulldorff's spatial scan statistic was used to identify geographic clusters of patients who shared increased/decreased tendency to develop CNS tumors. RESULTS CNS tumors were diagnosed in 234 incident patients, but histological diagnosis was available in 222/234 patients (95%) aged 64.3 ± 13.5 years at diagnosis. Crude incidence rate was 7.1 per 100,000 persons-year (95% CI, 6.2-8.1), 6.2 per 100,000 persons-year (95% CI, 5.4-7.0) when age-adjusted. CNS tumors were more frequent in men and after age 40. Glioblastoma accounted for 76% of the total (adjusted rate, 4.7 per 100,000 persons-year; 95% CI, 4.0-5.4). Spatial analysis revealed geographic variations of glioblastoma incidence within the study area. CONCLUSION Although the distribution of tumor diagnoses in Sardinia reflects expected age and gender-related patterns in western populations, our findings would indicate a slightly higher incidence of glial tumors, glioblastoma in particular, in Sardinia than in other European countries. The identification of spatial clusters of high/low risk will serve as a resource for etiological research.

C9orf72 mutation (C9+) is a common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis. C9+ clinical phenotype is heterogeneous and epilepsy has been recently described in few cases. We report a 47-year-old patient who developed reflex reading epilepsy (RRE) at the age of 19. After the first years with exclusive reflex seizures, afterwards the patients developed drug-resistant, unprovoked seizures and progressive cognitive deterioration. In the last years, a progressive motor impairment with spastic tetraparesis also occurred. During the hospitalization, the patient underwent an extensive workup identifying C9+ expansion and a family history suggestive for an autosomal dominant inheritance. This report, together with the few cases already described, raises the possibility that epileptic manifestations are part of the clinical phenotype of C9ORF72 mutation and reflect hyperexcitability of cortical networks involved in neurodegeneration.

In genetic prion diseases (gPrD), five genetic variants (E200K, V210I, V180I, P102L, and D178N) are responsible for about 85% of cases. The R208H is one of the several additional rare mutations and to date, only 16 cases carrying this mutation have been reported worldwide. To describe the phenotypic features of 5 affected patients belonging to apparently unrelated Sardinian (Italian) families with R208H gPrD, and provide evidence for a possible founder effect are the aims of this study. The R208H PRNP mutation has a much higher relative frequency in Sardinia than elsewhere in Italy (72% vs. 4.4% of gCJD cases). Our cohort shared similar phenotypic features to the previously described patients with R208H-129M haplotype with most patients showing the classical Creutzfeldt-Jakob disease (CJD) phenotype. The analysis of 10 controls and 5 patients by NGS sequencing identified 4 haplotypes, 3 associated with the wild type variant, and one (H1) shared by all patients carrying the 208His variant. This is the first report of a regional cluster for R208H mutation in gPrD and the first report of the presence of a common ancestor for this Sardinian R208H cluster, confirming the probable consequences of genetic isolation process even for rare diseases.

C9orf72 mutation is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) worldwide. Recently, several reports of patients with FTD who carried the C9orf72 mutation and also manifested epilepsy have been published, since seizures occur in FTD at a higher rate than in the general population, the possible association between epilepsy and C9orf72 mutation remains to be clarified. In the attempt to understand whether epilepsy contributes to the phenotype of the C9orf72 mutation, we compared epilepsy occurrence in patients with FTD who carried the C9orf72 mutation and those who did not. In our sample of 84 patients with FTD, 7.1% of cases reported epilepsy, with no significant differences between subsamples of patients with FTD stratified according to the presence of the C9orf72 mutation or to family history of FTD/parkinsonism/motor neuron disease. Our findings did not support to the possibility that epilepsy represents a characteristic feature of the C9orf72 mutation, as suggested by recent case reports published in the English literature.

Rome and São Paulo share many cultural similarities, there are in São Paulo metropolitan area (M.A.) 6 million people from Italian descendancy, being the Italian population in São Paulo M.A. bigger than Rome’s. This study develops a sustainability assessment (S.A.) to obtain a comprehensive framework to assess the sustainability performance of both cities, compare them and propose a solution. Five metrics on which based the S.A. were chosen according to the results of a survey with São Paulo and Rome residents. To validate the effectiveness of these indicators two focus groups were conducted, then the indicators were valued, and a Sustainability Solution Space was applied to identify their interactions. A Multi-Criteria Analysis was carried out to assess which of the cities has currently the highest performance in terms of sustainability. Rome had a higher sustainability ranking than Sao Paulo, nevertheless both cities should improve corruption scores to improve their ranking.

Hannu Laaksovirta konsortion jäsenenä. The Genomics England Research Consortium, The International ALS/FTD Genomics Consortium (iAFGC), The International FTD Genetics Consortium (IFGC), The International LBD Genomics Consortium (iLBDGC), The NYGC ALS Consortium, The PROSPECT Consortium,17 James B. Rowe,17 Luisa Benussi,18 Giuliano Binetti,18,19 Roberta Ghidoni,18 Edwin Jabbari,20,21 Coralie Viollet,22 Jonathan D. Glass,23 Andrew B. Singleton,24 Vincenzo Silani,25,26 Owen A. Ross,27 Mina Ryten,8,28,29 Ali Torkamani,30 Toshiko Tanaka,31 Luigi Ferrucci,31 Susan M. Resnick,32 We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered. We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer’s and Parkinson’s disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.

Background. Heparin-induced thrombocytopenia (HIT) is a transient, antibody-mediated thrombocytopenia syndrome that usually follows exposure to unfractioned heparin (UFH) or low-molecular-weight heparin (LMWH). In contrast to other pathological conditions which lead to thrombocytopenia and bleeding complications, HIT results in a paradoxical prothrombotic state. It is caused by antibodies directed to complexes containing UFH or LMWH and a self-platelet protein: the platelet factor 4 (PF4). The heparin-PF4 immune complex leads to activation of platelets, monocytes, and endothelial cells which release procoagulant proteins and tissue factor with subsequent blood coagulation activation. Case Report. We describe the case of a woman undergone to knee replacement and affected by urosepsis who developed a HIT after exposure to enoxaparin. The thrombotic burden was very impressive involving the arterial and venous cerebral vessel and the venous pulmonary, hepatic, and inferior legs vascular beds. The patient was successfully treated with fondaparinux without recurrent thrombosis or bleeding. The clinical scenario could be named “catastrophic HIT” like the catastrophic antiphospholipid syndrome since they have a similar pathogenetic mechanism involving both platelets and monocytes procoagulant activities and a similar clinical manifestation with a life-threatening multiple arterial and/or venous thromboses. Conclusion. Patients presenting with HIT could show a very impressive thrombotic burden resembling to that of the catastrophic antiphospholipid syndrome. A careful differential diagnosis should be made towards other pathological conditions which lead to thrombocytopenia to avoid an unnecessary and potentially harmful platelet transfusion. Although fondaparinux is off-label, its use in patients with HIT is simple and seems to be effective.

Dementia with Lewy body is a neurodegenerative disorder affecting both cognitive and motor domains. Motor impairment manifests predominantly as a symmetrical/mild asymmetrical parkinsonian syndrome that is only mildly responsive to Levodopa. To characterize motor dysfunction in dementia with Lewy body, we quantitatively assessed upper limb movements using a motion-capture system. Ten patients and ten healthy controls were tested while performing the hand-to-mouth movement of which speed, smoothness and accuracy features were measured. The results showed that individuals with dementia with Lewy body required a longer time to complete the task, particularly due to a prolonged duration of the adjusting phase (i.e., when approaching the target/mouth). The overall motor performance of dementia with Lewy body patients closely resembled what previously observed in patients affected by both Parkinson's disease and ataxia while performing the same task. Moreover, the severity of parkinsonian symptoms as assessed by the UPDRS-III scale impacted on the velocity of movement alone whereas impairment of executive functions correlated with variables related to the phase of targeting the mouth. This study provides new information about upper limb motor dysfunction in dementia with Lewy body.

The Capgras syndrome (CS) is a rare psychiatric disorder. CS is classified as a delusional misidentification syndrome. Initially, CS was described in paranoid schizophrenia and schizoaffective disorders. CS has also been reported in neurodegenerative diseases such as Alzheimer's disease and Lewy body dementia. To date, there are very few descriptions of the occurrence of CS in idiopathic Parkinson's disease (PD), with or without dementia. Considering the recent observation of two new cases in PD patients, a systematic overview of the literature published between 1976 and 2016 reporting CS in PD was conducted. The purpose of this article is to examine the phenomenon in people with PD with and without dementia, the psychopathologic context in which it happened, the role played by the dopaminergic medications and to define useful therapeutic strategies. Our CS cases occurred in two elderly patients with advanced PD and cognitive impairment, respectively, after an acute stressor event and after an increase of the total daily dose of levodopa. In light of our observations and the cases reported in the literature, we argue that CS is an acute or subacute psychotic disorder occurring mostly in PD with dementia. Besides, the increase in brain dopamine levels induced by acute stressful events and/or dopamine-enhancing medications should be considered as a possible causal mechanism of CS in patients with advanced stages of PD and cognitive decline.

© 2018 Elsevier Inc., To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

It has been shown that different genes could be associated with distinctive clinical and radiological phenotypes of FTD. TARDBP gene has been described worldwide in few cases of FTD so its phenotype is still unclear. The objective is to study the clinical and radiological characteristics of TARDBP-related FTD. In the present study, we report clinical, neuropsychological and radiological features of five new Sardinian non-related cases of FTD carriers of the p.A382T TARDBP mutation. Furthermore, we reviewed non-related FTD cases with TARDBP mutations previously described in literature. The p.A382T missense mutation of TARDBP was present in the 21.7 % of familial cases of our FTD cohort (5/23) and in no one of the sporadic patients. 3 of 5 patients showed a temporal variant FTD and 4/5 a predominant temporal involvement at MRI. The review of the literature of FTD cases with TARDBP mutations showed that in 5 of 16 cases, the clinical phenotype was consistent with temporal variant of FTD or semantic dementia (31 %) and in 7 of 16 cases neuroimaging showed predominant temporal lobe involvement (43.7 %). Our study further supports the pathogenetic role of TARDBP mutations in pure FTD and in the full spectrum of FTD/ALS. The presence of a predominant temporal lobe involvement in a high percentage of FTD mutated patients with a peculiar clinical pattern could be useful in the differential diagnosis with other forms of dementia/FTD both sporadic and familial.

Background Hemiplegic migraine is a rare form of migraine with aura characterized by motor aura. Although auras in hemiplegic migraine are typically complex with two or more aura symptoms, neglect has been rarely described. Case report We report the case of a 20-year-old woman with sporadic hemiplegic migraine that was investigated for the presence of unilateral spatial neglect (USN) during aura in one of her migraine attacks. Transient hemispatial neglect was observed during a right-sided migraine attack with left sensory-motor hemisyndrome; after migraine resolution there was a total recovery. Conclusions Our case demonstrates that USN may be a symptom of aura. To our knowledge, this is the first report of USN during aura in an adult with sporadic hemiplegic migraine.

Amyotrophic Lateral Sclerosis (ALS) is one of the most severe neurodegenerative diseases, which is known to affect upper and lower motor neurons. In contrast to the classical tenet that ALS represents the outcome of extensive and progressive impairment of a fixed set of motor connections, recent neuroimaging findings suggest that the disease spreads along vast non-motor connections. Here, we hypothesised that functional network topology is perturbed in ALS, and that this reorganization is associated with disability. We tested this hypothesis in 21 patients affected by ALS at several stages of impairment using resting-state electroencephalography (EEG) and compared the results to 16 age-matched healthy controls. We estimated functional connectivity using the Phase Lag Index (PLI), and characterized the network topology using the minimum spanning tree (MST). We found a significant difference between groups in terms of MST dissimilarity and MST leaf fraction in the beta band. Moreover, some MST parameters (leaf, hierarchy and kappa) significantly correlated with disability. These findings suggest that the topology of resting-state functional networks in ALS is affected by the disease in relation to disability. EEG network analysis may be of help in monitoring and evaluating the clinical status of ALS patients.

Amyotrophic Lateral Sclerosis (ALS) is a severe neurodegenerative disease, which affects domains outside of the motor system. Recent findings have suggested that scalp electroencephalography (EEG) analysis may represent a useful tool for the monitoring of the disease. Here, we investigated functional connectivity in a set of ALS patients using source-reconstructed EEG time series comparing the results to age-matched healthy controls. Source based functional connectivity was estimated using a measure of amplitude envelope correlation (AEC) after performing orthogonalisation procedure in the time domain. The results of this study show that alpha band functional connectivity at source level discloses different patterns of inter-regional synchronization in ALS patients compared to healthy subjects. These findings suggest that ALS induces a strong frequency-specific reduction of functional connectivity patterns and that these changes are not limited to motor connections.

We investigated the clinical and MRI effects of mitoxantrone (MITOX) administered to 45 patients during the first five years of highly active relapsing-remitting multiple sclerosis. Differences occurring between the end of treatment and follow-up (clinical mean: 3.6 years; brain MR: 1.8 years) with respect to baseline variables (EDSS, annualized relapse rate, active T2 lesions, new T1 lesions and number of Gd-enhancing lesions) were analysed using parametric and non-parametric tests. One patient developed leukemia four months after the end of the treatment; no other serious adverse events occurred during treatment and the follow-up period. A clinically relevant reduction in the annualized relapse rate ( P < 0.0001 at end of treatment and P < 0.0001 at follow-up) and improvement in the EDSS ( P < 0.0001 at end of treatment and P = 0.0005 at follow-up) was found. At the end of treatment, 53% of patients experienced no increase in active T2 lesions, while 73% showed no increase in the number of new T1 lesions. At follow-up, 41 out of 45 (91%) patients showed a stable MRI pattern and were active-scan free. Despite potential serious adverse events, MITOX may be considered an option in selected patients with very active early MS. Multiple Sclerosis 2007; 13: 975—980. http://msj.sagepub.com

Cerebral microbleeds (CMB) might reflect specific underlying vascular pathologies like cerebral amyloid angiopathy (CAA). In the present study we report the gradient-echo MRI pattern of two siblings with P284S PSEN1 mutation. T2* gradient-echo images of the two subjects demonstrated multiple microbleeds in lobar regions. The role and causes of CMB in sporadic Alzheimer's disease (AD) patients have not been clearly established and useful contributions could derive from familial AD studies. Furthermore, since CAA is a potential risk factor for developing adverse events in AD immunization trials, the identification in vivo of CAA through non-invasive MRI methods could be useful to monitoring side effects.

The FTD includes three main clinical syndromes: the behavioural variant (bvFTD), semantic dementia and progressive non-fluent aphasia [1]. For the BvFTD, which is characterized by a rich constellation of psychiatric and behavioural symptoms, the differential diagnosis with psychiatric disorders like schizophrenia and affective disorders, may be challenging [2, 3]. Recently a hexanucleotide repeat expansion in a noncoding region of the C9ORF72 gene has been identified as the cause of chromosome 9p21-linked ALS, FTD and ALS–FTD [4, 5]. We report the case of a man who developed from the age of 42 years an affective disorder characterized by repeated manic and hypomanic episodes. The manic phases were characterized by euphoria, racing thoughts, logorrhea, very high self-esteem, artistic hyperproductivity, little need for sleep. The patient fulfilled the DSM IV criteria for bipolar affective disorder (BPAD) type I [6] and was put on a long term lithium therapy with a good clinical response; during manic phases haloperidol was administered up to the acute episode resolution. The patient worked as a teacher until the age of 57 years. A patient’s maternal uncle developed a parkinsonism at the age of 60. The patient aged 64 presented to our neurological unit because he developed euphoria, impulsivity, logorrhea, sexual disinhibition with his wife, delusional fixed ideas with repetitive behaviours. He was obsessed by the idea of cleaning or putting petrol in his car and spent all day watching sport TV shows. As many of these symptoms were present in the past BPAD episodes, the patient underwent a new psychiatric examination; low doses of haloperidol were started without any improvement, so the therapy was stopped. Later a progressive cognitive impairment appeared. Neuropsychological assessment showed marked attention and executive functions troubles, working memory impairment, anomia and verbal fluency dysfunction. Neurologic examination revealed mild parkinsonism with postural tremor, camptocormia, diffuse bradykinesia and rigidity. Extrapyramidal symptoms arose when the patient was not under antipsychotic treatment. Mutations of TARDBP and PGRN genes were excluded. The patient has been found positive for a GGGGCC hexanucleotide repeat expansion in the first intron of C9ORF72 gene ([70 repeats). Brain MRI showed bilateral frontotemporal atrophy, prominent in frontal areas (Fig. 1). The orbitofrontal cortex was more involved than the dorsolateral prefrontal cortex; moreover there was a significant involvement of the fronto-insula and anterior cingulate gyrus. Perfusion SPECT demonstrated reduction of uptake in the left frontotemporal and right frontoparietal regions (Fig. 1). Structural and functional neuroimaging findings G. Floris G. Borghero A. Cannas F. D. Stefano F. Marrosu Department of Neurology, Azienda Universitaria-Ospedaliera of Cagliari and University of Cagliari, Cagliari, Italy

Recent literature has shown that apraxia of speech (AOS) is a motor speech disorder that exists as a distinct progressive neurodegenerative disease, namely progressive AOS (pAOS) (1,2). Several stu...

In our study we analysed clinical and neuropsychological data in a cohort of 57 Sardinian patients with FTD (55 apparently unrelated and two belonging to the same family), who underwent genetic screening for the C9orf72 mutation. Eight out of 56 patients were found positive for the C9orf72 mutation representing 14% of the entire cohort and 31.6% of the familial cases (6/19). C9orf72 mutated patients differed from the other FTD cases of the cohort for a younger age of onset, higher frequency of familial history for FTD and higher prevalence of delusional psychotic symptoms and hallucinations. In the neuropsychological assessment, C9orf72 mutated patients differed from non-mutated for the high frequency of visuospatial dysfunction regarding constructional apraxia (p = 0.02). In conclusion, our study confirms that Sardinian FTD patients have peculiar genetic characteristics and that C9orf72 mutated patients have a distinctive clinical and neuropsychological profile that could help differentiate them from other FTD patients. In our cohort we found that constructional apraxia, rarely reported in FTD, can properly discriminate between C9orf72 mutated and non-mutated patients and contribute to broaden the neuropsychological profile in frontotemporal dementia associated with this mutation.

Delusional jealousy or Othello syndrome (OS) is a well-described psychiatric disorder with paranoid features reported in both organic and functional psychoses. In organic psychoses, the disorder occurs more frequently among chronic male alcoholics and in demented patients. To date, only 2 anecdotal cases of OS have been reported in Parkinson disease (PD) during dopaminergic treatment.To investigate the presence of OS in PD patients and to study the relationship between dopaminergic treatment, avoiding the possible influence of dementia.Five hundred sixty-three PD patients without dementia encountered in our movement disorders practice were included in the study. All patients who developed OS were studied. Relationships between clinical and familial history and dopaminergic therapy and OS were assessed.Six patients with OS were identified. They were all male, with a relatively recent diagnosis of PD characterized by mild-moderate motor deficit. Dopaminergic treatment had been prescribed at low dosages. Neither confusional states (including agitated confusion) nor delirium were associated with OS. The disorder became manifest mainly at time of introduction/increment of antiparkinson treatment. Invariably, OS decreased or receded after reduction/suspension of the antiparkinson drug and prescription of an atypical neuroleptic, usually clozapine or quetiapine.We hypothesize that nondemented PD patients affected by OS do not necessarily present with severe motor complications and may well have a biologic predisposition for psychiatric disorders. In our opinion this paranoid delusion is rarely considered in PD.

Pisa syndrome (PS) is a dystonic lateroflexion of the trunk with a postural disturbance resembling the leaning tower of Pisa. Initially reported as a side effect related to antipsychotic therapy, this original dystonic posture is also manifested in neurodegenerative disorders such as Alzheimer's disease and multiple system atrophy, or in rare idiopathic cases. Recent observations have described the onset of PS with subchronic course in patients affected by Parkinson's disease (PD). Here, we report on the acute development of PS in a parkinsonian patient during treatment with entacapone/levodopa/carbidopa combination. This case illustrates how, in contrast to previously well-known chronic/subchronic forms, this axial dystonic posture may occur in PD as an acute onset reversible type, related to levodopa treatment.

An 89-year-old woman developed bradykinesia, mutism, and apathy after a rapid correction of hyponatremia caused by repeated vomiting. Brain MRI showed bipallidal involvement that improved at follow-up (figure 1, figure 2). The patient’s clinical history and neuroimaging are suggestive of extrapontine myelinolysis. This disease involves basal ganglia but the globus pallidus is usually spared or not singly involved.1 A patient with bipallidal extrapontine myelinolysis has been previously described.2 Toxic, hypoxic, and metabolic causes of bipallidal involvement were excluded in our patient. Extrapontine myelinolysis should be included in the differential diagnosis of patients with a history of hyponatremia, subacute parkinsonism, and bipallidal lesions on MRI.

Dear Sirs, From 2006, a locus on chromosome 9p21 has been associated with a large proportion of ALS and FTD [1–3]. Recently, two independent groups have identified a hexanucleotide repeat expansion in noncoding region of the C9ORF72 gene as the cause of chromosome 9p21-linked ALS-FTD [4, 5]. We report the case of a 64-year-old man who presented with a 3-year history of delusional mystic thoughts, auditive, visual, and olfactory hallucinations, and hyperreligiosity. The patient later developed progressive apathy, dysphoric mood, hyperphagia, self-care reduction, and progressive cognitive decline with motor retardation. The man's father had died at age 68 after committing suicide, and his older brother developed parkinsonism associated with behavioral disturbances at age 60 and died 2 years later. Neuropsychological assessment of this patient, performed 3 years after the onset of neurological symptoms, demonstrated bradyphrenia, marked impairment of attention and executive functions, marked constructional apraxia, mild visual and verbal long-term memory deficit, mild anomia, emotional lability, fatuity, and mild utilization behavior. Blood exams, thyroid antibodies and hormones, vitamin B12, folic acid, and TPHA were all normal. Neurological examination revealed symmetric akinetic-rigid syndrome characterized by hypomimia, dysarthria, camptocormia with anterocollis, and diffuse bradykinesia. Brain MRI documented atrophy mainly frontotemporal but with consistent posterior region involvement (Fig. 1). Perfusion SPECT with 99Tc-ethylene cystine dimer (ECD) showed a marked reduction of the uptake in the frontotemporal and parietal regions bilaterally (Fig. 1). A few months after the first neurological assessment, the patient had a rapid progression to a severe dementia and developed marked pyramidal involvement of upper and lower limbs with an inability to walk. The patient became anarthric, dysphagic, and developed constipation. The nature of the dysarthria was both pseudobulbar and extrapyramidal. Lower motor neuron signs or symptoms were not present. Later the patient was admitted to a surgical department for intestinal sub-occlusion; during the hospitalization, a pulmonary embolism (PE) occurred. The patient died 4 years after the first neurological manifestations. Mutations of TARDBP, MAPT, and PGRN genes were excluded. The patient has been found positive for a GGGGCC hexanucleotide repeat expansion in the first intron of C9ORF72 gene (>50). Our patient developed a dementia with prominent behavioral disturbances at presentation, characterized mostly by psychosis with mystic themes. The neuropsychological evaluation demonstrated a marked cognitive impairment with predominant frontal syndrome. An important involvement of visuo-spatial functions was also found (Fig. 2). This cognitive impairment, associated with multimodal hallucinations and parkinsonism, which presented before the onset of upper motor neuron signs, raised a differential diagnosis between FTD and dementia with Lewy bodies (DLB). A few cases have been reported with similar diagnostic difficulties [6]. The parkinsonism was not drug-induced. The dementia profile of our patient was consistent with a behavioral variant of FTD. He presented a positive family history for similar disturbances. Some features of our case are atypical for FTD, like psychosis, constructional apraxia associated with the frontal syndrome, atrophy, and perfusional deficit extended to posterior cortical areas. Hallucinations are possible but not common in FTD [7], whereas they are a core clinical feature in the diagnostic criteria of DLB [8]. Of note, some clinical aspects of our case have been reported in patients with ALS-FTD linked to the locus 9p21, such as the presence of parkinsonism, psychosis, visuo-spatial impairment, and brain atrophy with parietal and occipital lobe involvement [9, 10]. We propose that delusions with multimodal hallucinations at presentation, visuo-spatial dysfunction, and frontotemporal brain atrophy also involving posterior areas could be aspects of a possible distinctive phenotype of FTD-parkinsonism-upper motor neuron disease linked to the C9ORF72 gene hexanucleotide expansions. Fig. 1 a–c Brain MRI T1-weighted transversal scans showing bilateral frontotemporal and posterior cerebral areas atrophy. d–f Perfusion single-photon emission computed tomography (SPECT) with 99Tc-ethylene cystine dimer (ECD). The transversal ... Fig. 2 Severe constructional apraxia demonstrated by the copy of a simple drawing

Few studies have examined the use of a short cognitive screening of ALS patients in order to establish which patients should undergo a more comprehensive neuropsychological assessment. We tested 20 patients with early ALS with four cognitive screening instruments and subsequently with an extensive neuropsychological assessment. Sixty percent of patients showed a deficit in at least two scores of tests administered, while 40% had three abnormal tests. Dysexecutive syndrome was the most common neuropsychological impairment. The Frontal Assessment Battery (FAB) proved a useful indicator of the presence of cognitive dysfunction to complete neuropsychological evaluation. In conclusion, the FAB can be considered a sensitive cognitive screening tool in these patients. These data will be verified on a larger sample of patients.

Peroxidases (E.C. 1.11.1.7., hydrogen donor oxidoreductase) utilize hydrogen peroxide or substituted peroxides for the oxidation of a large number of substrates. Peroxidases are widely distributed and have been isolated from many higher plants (1). The wide distribution of the enzyme suggests that it could be of great biological importance, but the physiological functions and metabolic control of these enzymes are still poorly understood. The simultaneous presence of amine oxidase and peroxidase in cell walls suggests that the peroxide generated on oxidation of the amines could be utilized by the peroxidase (2,3). Recently we have purified an amine oxidase from Hordeum vulgare (4) and we have attempted to purify the peroxidase in order to study in vitro the reconstituted coupled system. beta-glucosidase (beta-D-glucoside glucohydrolase E.C. 3.2.1.21.) is capable of transforming glucosides in glucose and the corresponding aglycone or disaccharides as cellobiose, sophorose, gentiobiose. This enzyme is widely distributed in plants, fungi, bacteria, yeasts and animals (5,6). In the homogenate of Hordeum vulgare seedlings we also found beta-glucosidase activity and also attempted to purify beta-glucosidase. This enzyme copurified with peroxidase up to the last step. We report here the isolation of peroxidase and beta-glucosidase from Hordeum vulgare seedlings: some molecular and kinetic properties are given.

Parkinson's disease (PD), commonly defined as a hypokinetic movement disorder, is hampered by the appearance of motor complications (MC), including dyskinesias and motor fluctuations, and non-motor symptoms such as behavioral, neuropsychiatric and cognitive disorders, which, in the last years, are gaining increasing attention. The factors affecting MC and these non-motor symptoms are still largely unknown and their interactions are not yet fully evaluated.To identify the presence of behavioral, neuropsychiatric and cognitive disorders in PD patients with and without MC and to evaluate their association with MC.Consecutive PD patients received a comprehensive structured clinical evaluation including pharmacologic treatment, MC and non-motor symptoms such as reward-seeking behaviors, neuropsychiatric symptoms (depression, anxiety, psychoses and hallucinations) and dementia.349 patients were included in this analysis. Patient with MC showed enhanced frequency of dementia (p0.001), anxiety, depression and psychoses (p0.01). A higher frequency of impulse control disorders was detected in patients with dyskinesias (22.2% - p0.001) and motor complications (12.2% - p0.05). Dyskinesias were significantly more present in patients with hypersexuality (p0.05) and compulsive shopping (p0.001), while they were not significantly associated with pathological gambling and binge eating. Patients with dyskinesias also had significantly higher frequency of dopamine dysregulation syndrome, hallucinations and delusions (p0.001), with the exception of delusional jealousy.We found a higher frequency of behavioral, neuropsychiatric and cognitive disorders in patients with MC. The lack of detection of dyskinesias in several PD patients with pathological gambling in our study represents a very interesting issue. While binge eating mainly seems to be related to the use of dopamine agonists, the significant lack of association between dyskinesias and delusional jealousy suggests the hypothesis of a possible underlying psychopathological predisposition rather than a mere pharmacologic effect in PD patients with these behavioral complications.

Mutations inLRRK2represent the most common causes of Parkinson's disease (PD) identified to date, but their penetrance is incomplete and probably due to the presence of other genetic or environmental factors required for development of the disease. We analyzed the presence ofparkinsequence variants (mutations or polymorphisms) and exon rearrangements inLRRK2mutations carriers (both PD patients and unaffected relatives) in order to detect a possible modifier effect on penetrance. Eight families with nine PD patients with heterozygousLRRK2mutations (identified within 380 Sardinian PD patients screened for the presence of the five most commonLRRK2mutations) and sixteen additional relatives were genetically investigated for the presence ofLRRK2andparkinmutations. No evidence was found for the presence of pathologicalparkinmutations or exon rearrangements in patients or not affected family members. Three single-nucleotide polymorphisms (SNPs) were identified both in patients and unaffected relatives but did not significantly differ between the two groups. These data provide no support to the hypothesis whereby suchparkingene mutations may be commonly implicated in possible effect on penetrance inLRRK2mutation carriers.

The authors describe the case of a 70-year-old male who developed a peculiar syndrome characterized by pathological gambling (PG), delusional parasitosis and adipsia with mild frontal symptoms. Onset of the syndrome followed a cerebral haematoma involving hypothalamic and bilateral ventromedial prefrontal areas. The potential manifestation of PG following a lesion in the above areas may contribute towards furthering the understanding of pathological conditions underlying this disorder.

Mutations in the LRRK2 gene are the most common known cause of familial and sporadic Parkinson's disease (PD). Few studies performed to date to assess frequency of these mutations are actually only representative of specific areas. Here we study the frequency and clinical phenotype of LRRK2 G2019S, I2020T and R1441C/G/H mutations in 356 Sardinian patients with idiopathic PD and 208 controls. Seventeen additional subjects, relatives of PD mutated probands, were enrolled. Eight patients were mutated in heterozygosis for LRRK2 gene (2.3%): six carried the G2019S (1.7%) and two the R1441C (0.6%) mutation. Three PD patients G2019S carriers (50%) were detected in two contiguous villages comprising 3921 inhabitants while the other three (50%) were identified in the remaining population of 796,079 inhabitants. Only one mutated proband had a family history of PD. LRRK2 G2019S and R1441C mutations associated with PD were not an uncommon mutation in a Sardinian population, especially in sporadic PD patients. The detection of the G2019S variant in ten unaffected relatives confirms a reduced penetrance of the underlying mutation and might explain its prevalence among patients with sporadic PD. These findings may provide new insights into the importance of studies of frequency of LRKK2 mutations in PD patients originating from small ethnically homogeneous populations.

The wide variability of dystonic postures manifested in the clinical course of Parkinson's disease (PD) represents a complicated on-going issue. Several recently published reports of Pisa syndrome (PS) in parkinsonian patients on dopaminergic therapy have described a variable means of onset and clinical course of this truncal dystonia.To describe PD patients with PS, with the aim of stressing the frequent iatrogenic origin and potential reversibility of this syndrome during the initial stages of its appearance.Eight consecutive PD patients who developed a PS after modifications of antiparkinson therapy were studied. All patients underwent detailed clinical assessment, [(123)I]FP-CIT-SPECT being performed in three cases. Four patients were videotaped.All patients developed PS within a variable time-span ranging from 15 days to 3 months after adjustment of treatment. Seven cases of PS were manifested following an increase and one a decrease of dopaminergic treatment. A marked reversal of dystonia was produced in the first seven patients by the withdrawal or dose decrease of dopaminergic PS priming drug, and in the eighth patient an increase of dopaminergic therapy was necessary.In our opinion, the recognition of reversibility of PS during the initial stages of its appearance may be of considerable clinical importance. Indeed, it may facilitate the rapid withdrawal or reintroduction of dopaminergic treatment, thus avoiding an initial veering towards the subchronic variant and, subsequently into a chronic irreversible variant.

There is still debate over the optimal dosage, frequency and route of administration of interferon (IFN) beta in multiple sclerosis (MS). A prospective, non-randomized, comparative study was performed to evaluate differences in magnetic resonance imaging and clinical outcomes of two IFN beta-1a preparations (30mcg intramuscular [im] once-weekly [qw], AVO; and 22 mcg subcutaneous [sc] three-times-weekly [tiw]; R22). Relapsing-remitting MS patients on one of the two IFN preparations (AVO, n=47; R22, n=48) were assessed at baseline and after 6 months of further treatment. There were no significant differences between the two groups at baseline. Both groups showed significantly reduced relapse rates (F=19.5; p0.001) from baseline (0.6) to 6-month assessment (0.2; p0.001). Univariate analysis showed a significant difference in favour of R22 on T2 lesion volume (F=14.4; p0.001) and T1 black hole lesion load (F=8.5; p=0.004), the latter showing a significant increase in the AVO group (p0.001). The incidence of patients with new T1 black holes was also higher for AVO than R22 (23.5% vs 8.3%; p=0.025). These results from patients receiving AVO or R22 in normal clinical practice are in line with randomized clinical studies that show the benefits of high-dose, high-frequency administration of IFN beta-1a in MS therapy.

Neuropsychological and psychopathological modifications induced by dopaminergic drugs in patients with Parkinson's disease (PD) are invariably not taken into sufficient consideration by the neurologist. Among the former, modifications of sexual urges and behaviours are of particular importance with regard to severity and variety of clinical pictures. Although rare, such modifications may assume the connotations of an aberrant sexual behaviour with criminal implications, in line with a diagnosis of paraphilia. The authors report the case of a 51-year-old male PD patient who, after a few years of dopaminergic treatment with pergolide, developed a paraphilic disorder, consistent with DSM-IV TR diagnosis of frotteurism, and delusional jealousy. The patient presented mild motor impairment and lack of or negligible cognitive deterioration, thus providing evidence that these disorders are not typical of advanced PD. Pergolide was reduced and quetiapine, an atypical neuroleptic, was introduced with subsequent subsiding of the paraphilic disorder and improvement of delusional jealousy.

The authors describe four members of a family with a novel P284S presenilin 1 mutation presenting a clinical phenotype characterized by early-onset dementia, paratetraparesis, dysarthria, dysphagia, and marked involvement of brain white matter. The distinctive clinical and MRI findings in the family studied extend the phenotypic spectrum of dementia associated with mutation of the PS1 gene.

Objective Our objective was to assess brain damage in first-degree relatives of patients with sporadic and familial multiple sclerosis (MS). Methods Asymptomatic first-degree relatives of sporadic (sMS, n = 152) and familial MS (fMS, n = 88) and healthy volunteers (NC, n = 56) underwent brain MRI and magnetization transfer (MT) imaging on a mobile MR scan. On MR examinations, we visually assessed white matter (WM) lesions and quantified WM lesion volumes, brain volumes, and MT ratio (MTr) in lesions and normal-appearing WM (NAWM). Results A lesional MR pattern similar to that of MS patients was found in 4% sMS and 10% fMS. In these WM lesions, MTr was lower (p < 0.0001) than in the WM of NC. In contrast, there was no difference in NAWM-MTr and brain volume values between the three groups. Interpretation Focal brain abnormalities indistinguishable from those of MS occur in asymptomatic first-degree relatives of MS patients. These are twice more frequent in fMS than in sMS but do not lead to the widespread tissue damage commonly found in MS patients. Although there is a genetic susceptibility to develop brain abnormalities suggestive of focal demyelination in first-degree relatives of MS patients, other factors are probably critical for the development of a diffuse, clinically relevant, pathology. Ann Neurol 2006

Although it is an undeniable fact that dopaminergic therapy has greatly improved the quality of life and prognosis of patients with Parkinson's disease, various and serious adverse events correlated to dopaminergic drugs are not uncommon. Among these, those of neuropsychological and psychopathological nature are of particular importance, being capable of causing an upheaval in the basic personality of the patient. To this regard, the authors report the actual words of a patient himself that are far more convincing that any considerations we may express. In our opinion, the overwhelming impact of dopaminergic treatment on the psychopathological and neuropsychological equilibrium of all parkinsonian patients should unfailingly be carefully evaluated and pondered, particularly in the early onset forms of the disease.

Hallervorden–Spatz disease (HSD) is a rare autosomal recessive neurodegenerative disorder associated with iron accumulation in the basal ganglia. Presumptive in vivo diagnosis is based on the combination of MRI (the “eye-of-the-tiger” sign) and heterogeneous clinical symptoms.1 The typical clinical presentation includes early onset of progressive extrapyramidal signs (dystonia, tremor, choreoathetosis) and intellectual subnormality. Common accessory symptoms are spasticity with pyramidal tract signs, optic atrophy, and retinitis pigmentosa. After the recent identification of mutations in the pantothenate kinase gene ( PANK2 ) located in chromosome 20p12.3,2 the term “pantothenate kinase–associated neurodegeneration” (PKAN) was proposed for this disorder. We previously reported two siblings of Sardinian origin who were diagnosed with HSD based on the presence of a homozygous mutation in the PANK2 gene.3 Patient 1 is a 24-year-old woman who at age 16 developed slurred speech, postural tremor in both hands (7 to 8 Hz), and progressive …

Five patients (4 women) with Parkinson's disease (PD) and primary major psychiatric disorder (PMPD) meeting DSM-IV criteria for the diagnosis of bipolar affective disorder (BAD) were studied. Four patients had early onset PD. Four developed a severe psychiatric disorder a few years after starting dopaminergic therapy in presence of a mild motor disability and a mild cognitive impairment, with no evidence of cerebral atrophy at CT or MRI. Two patients developed a clear manic episode; the other three presented a severe depressive episode (in one case featuring a Cotard syndrome). None showed previous signs of long term L-dopa treatment syndrome (LTS), hallucinosis or other minor psychiatric disorders. The two manic episodes occurred shortly after an increase of dopaminergic therapy and in one case rapid cyclic mood fluctuations were observed. At the onset of psychiatric symptoms, all patients had an unspecific diagnosis of chronic delusional hallucinatory psychosis (CDHP).

Objective: To describe a patient with a double pathogenetic mutation of C9ORF72 and TARDBP genes. Background Several genes have been found to be related to ALS; however, patients carrying two different pathogenetic genetic mutations have never been described. Design/Methods: We are performing a study of genetic determinants of familial ALS in Italy. All patients undergo mutational analysis for SOD1, FUS and TARDBP and OPTN . Repeat primer PCR to screen the presence of the hexanucleotide expansion in the first intron of C9ORF72 is performed. Results: The index case was a year-old man who at 43 developed bulbar-onset ALS with behavioural frontemporal dementia (FTD) occurring one year later. He deceased 34 months after the onset of ALS. He carried both a A382T missense mutation of the TARDBP gene and a hexanucleotide repeat expansion of C9ORF72 gene. His father, who also had a hexanucleotide repeat expansion of C9ORF72 gene, developed spinal onset ALS at 64, and behavioural FTD two years later. He deceased 78 months after the onset of ALS. His mother developed spinal onset ALS at 69 and a mild FTD six months later. She deceased at 73. She carried a A382T missense mutation of the TARDBP gene. The proband9s brother developed ALS at 33 and deceased 75 months after the onset of ALS, without cognitive impairment. No DNA is available of this patients. Conclusions: The proband had two mutations pathogenetic for ALS and FTD, one ( TARDBP ) transmitted from the maternal line, and the other ( C9ORF72 ) from the paternal line. He developed ALS with FTD at 43 years, much earlier than his parents, and had a more severe clinical course. The presence of two pathogenetic mutations in this patients indicates that multiple genetic factors should be considered in pathogenesis of ALS and are likely to modify the clinical course of the disease. Disclosure: Dr. Calvo has nothing to disclose. Dr. Borghero has nothing to disclose. Dr. Cannas has nothing to disclose. Dr. Marrosu has received personal compensation for activities with Biogen Idec and Merck Serono. Dr. Marrosu has received personal compensation in an editorial capacity for Neurological Sciences. Dr. Marrosu has received research support from Serono Foundation, Biogen Idec, Schering Italy, and Sanofi Aventis. Dr. Murru has nothing to disclose. Dr. Floris has nothing to disclose. Dr. Traynor has received personal compensation in an editorial capacity for the journal Neurology. Dr. Renton has nothing to disclose. Dr. Moglia has nothing to disclose. Dr. Canosa has nothing to disclose. Dr. Ilardi has nothing to disclose. Dr. Cammarosano has nothing to disclose. Dr. Brunetti has nothing to disclose. Dr. Ossola has nothing to disclose. Dr. Restagno has nothing to disclose. Dr. Chio has nothing to disclose.

Hedonistic homeostatic dysregulation (HHD) is a well-known neuropsychiatric complication described in patients with Parkinson's disease (PD), characterized by misuse of and addiction to dopaminergic drugs (Giovannoni et al., 2000). Previous reports have indicated HHD in approximately 3.4% of PD patients, more frequently in males with early onset of the disease (Pezzella et al., 2005).