Capgras syndrome in Parkinson's disease: two new cases and literature review.

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.

[Implementation of DNA-HPV primary screening in Italian cervical cancer screening programmes. Results of the MIDDIR Project]. / L'implementazione del DNA-HPV come test primario nei programmi italiani di screening del cervicocarcinoma. Risultati del Progetto MIDDIR.

OBJECTIVES: to obtain data on conversion paths to HPV testing as part of screening programmes and to harmonize the introduction of HPV testing in primary cervical cancer screening protocols of Italian programmes. DESIGN: survey by questionnaire on strategies adopted by screening programmes for transition to primary HPV testing; systematic review of the literature; discussion among experts. SETTING AND PARTICIPANT S: managers of Italian Regions' cervical cancer screening programmes. MAIN OUTCOME MEASURES: transition planning; activity volumes; modalities of centralization; criteria for dismissal; staff training; communication initiatives. RESULTS: nine cervical screening programmes responded to the survey. Most of them chose to schedule a transition of a few years to allow for adjustment of the volume of activity in the passage from the three-year screening interval to the five-year one. To select women to be given precedence, 7 programmes use the age, starting from the oldest. The liquid base is the choice by far preferred both for HPV test and for Pap test. The reading of HPV test "born" already centralized, but a centralization process is in place also for cytology. CONCLUSIONS: the survey on conversion strategies to primary HPV testing showed the opportunity to schedule a transition phase. For HPV test, cost, organization, and quality benefits of centralization are clear, thus the central organization should be preferred and managed immediately. Moreover, the need for a centralization of cytology is evident. The tariff scheme should be based on the whole process rather than on single performances. Dismissal strategies have to be tailored on peculiarities of single services, but some typologies can be outlined.

The phenotypical core of Alzheimer's disease-related and nonrelated variants of the corticobasal syndrome: A systematic clinical, neuropsychological, imaging, and biomarker study.

INTRODUCTION: The corticobasal syndrome (CBS) constitutes a neurodegenerative disease spectrum with substantial phenotypical or biological heterogeneity, requiring large or multimodal studies to identify its clinico-biological signature while disentangling Alzheimer's disease (AD)-related from non-AD-related CBS. METHODS: We analyzed a large (N = 45) monocenter expert-clinic CBS cohort, recruited in motor and/or cognitive units to avoid recruitment biases, assessed with standardized motor and/or cognitive-language tests, brain perfusion imaging, and cerebrospinal fluid biomarkers. RESULTS: CBS mainly manifests as a motor and/or language disorder incorporating a "mixed progressive aphasia" phenotype, consistent with left-lateralized damage to frontal-parietal-temporal cortices. Biomarker expression indicates in 18% underlying AD causing predominant parietal-temporal damage and Gerstmann syndrome (sensitivity 75%; specificity 75%), whereas non-AD-CBS presented with predominant prefrontal and lexical-semantic impairment. DISCUSSION: CBS is primarily a "motor-plus-aphasia" disease unfolding into AD-related and non-AD-related variants with distinctive cognitive-anatomic patterns. CBS, and notably its "Gerstmann variant", should be included in the new AD "lexicon" and categorized in the evolving diagnostic spectrum of "atypical AD"d.

The p.A382T TARDBP gene mutation in Sardinian patients affected by Parkinson's disease and other degenerative parkinsonisms.

Based on our previous finding of the p.A382T founder mutation in ALS patients with concomitant parkinsonism in the Sardinian population, we hypothesized that the same variant may underlie Parkinson's disease (PD) and/or other forms of degenerative parkinsonism on this Mediterranean island. We screened a cohort of 611 patients with PD (544 cases) and other forms of degenerative parkinsonism (67 cases) and 604 unrelated controls for the c.1144G > A (p.A382T) missense mutation of the TARDBP gene. The p.A382T mutation was identified in nine patients with parkinsonism. Of these, five (0.9 % of PD patients) presented a typical PD (two with familiar forms), while four patients (6.0 % of all other forms of parkinsonism) presented a peculiar clinical presentation quite different from classical atypical parkinsonism with an overlap of extrapyramidal-pyramidal-cognitive clinical signs. The mutation was found in eight Sardinian controls (1.3 %) consistent with a founder mutation in the island population. Our findings suggest that the clinical presentation of the p.A382T TARDBP gene mutation may include forms of parkinsonism in which the extrapyramidal signs are the crucial core of the disease at onset. These forms can present PSP or CBD-like clinical signs, with bulbar and/or extrabulbar pyramidal signs and cognitive impairment. No evidence of association has been found between TARDBP gene mutation and typical PD.

Transient unilateral spatial neglect during aura in a woman with sporadic hemiplegic migraine.

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.

Focal bilateral motor seizures precipitated by abrupt cessation of chronic lormetazepam abuse and amitriptyline overdose.

We report the case of an adult psychiatric patient who developed new-onset focal bilateral motor seizures (FBMS) in the context of a severe benzodiazepine withdrawal syndrome. The patient was forced to interrupt chronic lormetazepam abuse and overdosed on amitriptyline (800 mg in an oral solution) before the onset of seizures. Typical signs of amitriptyline intoxication such as sedation and anticholinergic effects were not observed. Video-EEG recordings revealed a stereotypical ictal motor pattern with asymmetric tonic posturing and bilateral clonic movements of the upper limbs, but there were no abnormalities identified by EEG. Seizures recurred multiple times per day but resolved simultaneously when withdrawal symptomatology subsided eight days after onset. Nonepileptic seizures (NES) were considered in the differential diagnosis because of the patient's psychiatric history including preserved awareness during the bilateral convulsions, the absence of postictal confusion, and normal EEG. The present case indicates that FBMS may occur during benzodiazepine withdrawal in patients who overdosed on amitriptyline. The diagnosis may be challenging as FBMS may mimic NES in the absence of abnormal neurophysiologic findings. This may be especially challenging in patients with an underlying psychiatric disease.

Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases.

Extensive evidence implicates activation of the lipid phosphatidylinositide 3-kinase (PI3K) pathway in the genesis and progression of various human cancers. PI3K inhibitors thus have considerable potential as molecular cancer therapeutics. Here, we detail the pharmacologic properties of a prototype of a new series of inhibitors of class I PI3K. PI103 is a potent inhibitor with low IC50 values against recombinant PI3K isoforms p110alpha (2 nmol/L), p110beta (3 nmol/L), p110delta (3 nmol/L), and p110gamma (15 nmol/L). PI103 also inhibited TORC1 by 83.9% at 0.5 micromol/L and exhibited an IC50 of 14 nmol/L against DNA-PK. A high degree of selectivity for the PI3K family was shown by the lack of activity of PI103 in a panel of 70 protein kinases. PI103 potently inhibited proliferation and invasion of a wide variety of human cancer cells in vitro and showed biomarker modulation consistent with inhibition of PI3K signaling. PI103 was extensively metabolized, but distributed rapidly to tissues and tumors. This resulted in tumor growth delay in eight different human cancer xenograft models with various PI3K pathway abnormalities. Decreased phosphorylation of AKT was observed in U87MG gliomas, consistent with drug levels achieved. We also showed inhibition of invasion in orthotopic breast and ovarian cancer xenograft models and obtained evidence that PI103 has antiangiogenic potential. Despite its rapid in vivo metabolism, PI103 is a valuable tool compound for exploring the biological function of class I PI3K and importantly represents a lead for further optimization of this novel class of targeted molecular cancer therapeutic.

[Community interventions among tobacco control strategies: coping with their definition and evaluation]. / Definizione e valutazione degli interventi di comunità nell'ambito delle strategie di contrasto al fumo di tabacco.

Community interventions represent a key component of the current anti-smoking strategies. We propose a conceptual framework for classifying these interventions, based on the concept of community utilised in different studies. We identified 5 different focuses: geographical areas (i.e. city, county, region); targets (sub-group of a population); settings (school, workplace); culture and individual attitudes; multilevel networks. These two latter views refer to functional rather than to structural aspects of a community and they represent the most promising approaches to design intervention strategies. Communities are represented as a group of organizations, systems and social networks investigating individual, environmental and cultural factors that can strongly influence behavioural changes. The great heterogeneity in what the authors mean as community interventions has in our opinion affected the evaluation of their impact. To facilitate their evaluation and to contribute to the detection of determinants, as well as of barriers, it is necessary to compare community interventions sharing similar theoretical approaches and focuses. Also, studies aimed at assessing the steps of the implementation process of community programmes may allow to identify those components related to specific levels of intervention, thus enabling the generalisation of results. To reach this goal it may be helpful to combine study designs allowing for both quantitative and qualitative assessments, such as action research and participatory evaluation research.

[Effective laws for tobacco control: EU directives and Italian legislation]. / Interventi legislativi efficaci per il controllo del tabagismo: direttive dell'Unione Europea e applicazioni in Italia.

Effective tobacco control policies include law issuing: bans/restrictions on smoking in public areas and workplaces, increasing of taxes on tobacco products, bans on advertising of tobacco products, warning labels on cigarette boxes. For some of these policies the European Union (EU) has introduced specific directives that EU member states have to put into law. This paper briefly presents literature data, EU directives and the laws consequently issued in Italy. The importance of standardizing European legislation, especially for those policies that are not enforced by EU directives is also discussed. In Italy and in some other European countries smoking is forbidden in public and work-places, despite no EU directive. The positive impact of this ban in these countries suggests that it should be considered a priority in the European policies against tobacco in order to reduce the gap between literature recommendations and actions.

EEG functional network topology is associated with disability in patients with amyotrophic lateral sclerosis.

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.

Phenotypic variability related to C9orf72 mutation in a large Sardinian kindred.

We investigated intrafamilial phenotypic variability in carriers of the C9orf72 mutation, analysing clinical, neuropsychological and imaging characteristics of various members from a large Sardinian kindred with FTD or ALS. We compared these with those of C9 + patients in our ALS and FTD cohorts. Results showed that three patients carried the C9orf72 mutation: two with ALS and one with FTD and Parkinsonism. C9 + patients in our bvFTD Sardinian cohort had a higher frequency of Parkinsonism than non-mutated patients (75% vs. 36.3%, p <0.02). Parkinsonism was present in 2.7% of our ALS cohort and 3.3% of the C9 + patients. The prevalence of Parkinsonism in C9 + patients in the bvFTD and ALS cohorts showed a statistically significant difference (p <0.006). In conclusion, Parkinsonism was frequently associated with FTD but not ALS in a large Sardinian family, a finding reflected in the wider C9orf72 associated Sardinian ALS and FTD populations.

Multiple Spontaneous Cerebral Microbleeds and Leukoencephalopathy in PSEN1-Associated Familial Alzheimer's Disease: Mirror of Cerebral Amyloid Angiopathy?

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.

Prediction of Alzheimer's Disease Dementia: Data from the GuidAge Prevention Trial.

In therapeutic trials, it is crucial to identify Alzheimer's disease (AD) at its prodromal stage. We assessed the accuracy of the free and cued selective reminding test (FCSRT) compared to other cognitive tests to predict AD dementia in subjects with subjective cognitive decline or mild cognitive impairment. Subjects from the placebo group of the GuidAge trial over 70 years old and without clinical signs of dementia at baseline who completed the 5-year follow-up free of dementia (n = 840) or developed AD dementia (n = 73) were included in our study. Among all the tests, the sum of the 3 free recall of the FCSRT (FCSRT-FR) and the sum of free and cued recall (FCSRT-TR) yielded the best results to predict AD dementia occurrence (all p values <0.05 for comparison of FCSRT-FR ROC and MMSE, CDRsb, and CVF ROCs). FCSRT-FR had an area under the ROC curve of 0.799 (95% CI 0.738-0.85) and the optimal cut-off was 20 (se 68.06% , sp 81.43% , PPV 23.90% , NPV 96,75%). Concerning FCSRT-TR, the AUC was 0.776 and the optimal cut-off was 42 (se 62.5% , sp 82.26% , PPV 23.20% and NPV 96.24%). This study sets the framework for implementing the FCSRT in clinical and therapeutic trials for efficient subject selection.

Constructional apraxia in frontotemporal dementia associated with the C9orf72 mutation: broadening the clinical and neuropsychological phenotype.

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.

Clinical phenotypes and radiological findings in frontotemporal dementia related to TARDBP mutations.

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.

C9ORF72 intermediate repeat expansion in patients affected by atypical parkinsonian syndromes or Parkinson's disease complicated by psychosis or dementia in a Sardinian population.

The hexanucleotide repeat expansion GGGGCC in the C9ORF72 gene larger than 30 repeats has been identified as a major genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent papers investigated the possible pathogenic role and associated clinical phenotypes of intermediate C9ORF72 repeat expansion ranging between 20 and 30 repeats. Some studies suggested its pathogenicity for typical Parkinson's disease (PD), atypical parkinsonian syndromes, FTD with/without parkinsonism, and ALS with/without parkinsonism or with/without dementia. In our study, we aimed to screen patients affected by atypical parkinsonian syndromes or PD complicated by psychosis or dementia for the presence of C9ORF72 repeat expansions, and in unrelated age- and sex-matched healthy controls. Consecutive unrelated patients with atypical parkinsonian syndromes and patients with PD complicated by psychosis or dementia were included in this study. Atypical parkinsonian syndromes were further divided into two groups: one with patients who met the criteria for the classic forms of atypical parkinsonism [multiple system atrophy (MSA), Lewy body disease (LBD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD)] ;and patients who did not meet the above criteria, named non-classical atypical parkinsonism with or without dementia. Ninety-two unrelated patients (48 men, 44 women) were enrolled. None of the patients was found to be carriers of C9ORF72 repeat expansions with more than 30 repeats. Intermediate 20-30 repeat expansions were detected in four female patients (4.3 %). Three of them presented clinical features of atypical parkinsonian syndromes, two with non-classical atypical parkinsonism and dementia FTD-like, and one with non-classical atypical parkinsonism without dementia. The other patient presented clinical features of typical PD complicated by psychosis. Among 121 control subjects, none presented long or short expansion for the C9ORF72 gene. Our findings seem to support the hypothesis that the hexanucleotide expansions of C9ORF72 gene with intermediate repetitions between 20 and 29 repetitions could be associated with typical PD with psychosis or dementia and atypical parkinsonisms with dementia (non-classical atypical parkinsonism with dementia FTD-like) or without dementia (non-classical atypical parkinsonism upper MND-like), although the causal relationship is still unclear. In these latter patients, parkinsonism, more or less levodopa responsive, constituted the symptomatological central core at onset.

Population based cancer screening programmes as a teachable moment for primary prevention interventions. A review of the literature.

BACKGROUND AND AIM: Unhealthy diet, physical inactivity, and smoking are key risk factors for the major non-communicable diseases such as cancer, cardiovascular diseases, and diabetes. The screening procedure may represent an ideal setting for promoting healthy lifestyles as it represents a time when subjects are probably more inclined to consider a relationship between their own habits and their effects on health. The aim of this study is to review available evidence concerning interventions combining screening and primary prevention interventions, aimed at promoting the adoption of healthy lifestyles. METHODS: We searched the MEDLINE and Cochrane library electronic databases for intervention studies of primary prevention interventions implemented in the context of established screening programmes, or of pilot screening projects, where the study design included a comparison group. RESULTS: Comprehensive interventions are acceptable for asymptomatic subjects targeted for cancer screening, can result in improvements and may be cost-effective. A positive impact of these interventions in favoring the adoption of cancer protective dietary behaviors was observed in all studies. Conflicting results were instead reported with respect to physical activity, while no impact could be observed for interventions aimed to favor smoking cessation. CONCLUSIONS: The retrieved studies suggest that the screening setting may offer valuable opportunities to provide credible, potentially persuasive life style advice, reaching a wide audience. A multiple risk factor approach may maximize the benefit of behavioral change, as the same health related habits are associated not only with cancers targeted by screening interventions, but also with other cancers, coronary artery disease, and other chronic conditions, while unhealthy behaviors may be mutually reinforcing. In order to cover a maximum number of possibilities, health education programmes should include multiple strategies, integrating and combining models of individual, social, and environmental change.