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Objectives To assess the accuracy of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes in identifying subjects with melanoma. Design A diagnostic accuracy study comparing melanoma ICD-9-CM codes (index test) with medical chart (reference standard). Case ascertainment was based on neoplastic lesion of the skin and a histological diagnosis from a primary or metastatic site positive for melanoma. Setting Administrative databases from Umbria Region, Azienda Sanitaria Locale (ASL) Napoli 3 Sud (NA) and Friuli Venezia Giulia (FVG) Region. Participants 112, 130 and 130 cases (subjects with melanoma) were randomly selected from Umbria, NA and FVG, respectively; 94 non-cases (subjects without melanoma) were randomly selected from each unit. Outcome measures Sensitivity and specificity for ICD-9-CM code 172.x located in primary position. Results The most common melanoma subtype was malignant melanoma of skin of trunk, except scrotum (ICD-9-CM code: 172.5), followed by malignant melanoma of skin of lower limb, including hip (ICD-9-CM code: 172.7). The mean age of the patients ranged from 60 to 61 years. Most of the diagnoses were performed in surgical departments. The sensitivities were 100% (95% CI 96% to 100%) for Umbria, 99% (95% CI 94% to 100%) for NA and 98% (95% CI 93% to 100%) for FVG. The specificities were 88% (95% CI 80% to 93%) for Umbria, 77% (95% CI 69% to 85%) for NA and 79% (95% CI 71% to 86%) for FVG. Conclusions The case definition for melanoma based on clinical or instrumental diagnosis, confirmed by histological examination, showed excellent sensitivities and good specificities in the three operative units. Administrative databases from the three operative units can be used for epidemiological and outcome research of melanoma.

Adverse events (AEs) of antiepileptic drugs (AEDs) affect patient compliance and dropout. No questionnaire measuring AEs of AEDs is available for Italian-speaking people with epilepsy. Moreover, no questionnaire has been shown to predict patient dropout.The aim of this study was to provide a validated Italian version of the Liverpool Adverse Events Profile (iLAEP) and to define iLAEP reliability in AE monitoring and dropout risk prediction.The original LAEP was translated and tested for internal consistency and reliability. Patients with epilepsy who are on stable AED regimen completed the questionnaire as well as a 3-month follow-up to assess dropouts.Overall, 204 patients with epilepsy were enrolled (mean age: 47.1±21.5). High internal consistency (Cronbach's α=0.88) was demonstrated, and very quick completion time was registered (mean=9min). A 3-month follow-up was performed to assess treatment discontinuation and potential predictive value of the iLAEP score. Treatment was discontinued in 33.3% of the cohort. Moreover, iLAEP scores (mean=30.71) significantly differed between patients interrupting (39.15±5.66) and those prosecuting treatment (29.4±6.54, p.001). A cutoff of 36.5 had an 85% accuracy in predicting treatment discontinuation (85% sensitivity, 79% specificity). Scores36.5 were associated with a 20.27-fold increase in dropout relative risk (RR), with a 66% positive predictive value.The iLAEP represents a reliable, quick, and inexpensive assessment tool for patient-reported AEs of AEDs. An iLAEP cutoff of 36.5 differentiates patients unlikely to interrupt treatment from those more prone to stop AEDs in the following 3months. The iLAEP might help clinicians in weighting the risk of dropout and better tailor treatment to patients.

Freezing of gait (FOG) is a common and disabling symptom in Parkinson's disease (PD) and its staging is complex because of its episodic nature. Patient-reported assessments are essential in evaluating this disabling symptom. The Freezing of Gait Questionnaire (FOG-Q) is considered a valid and reliable tool for the assessment of FOG severity. The aim of our study was to validate the Italian version of FOG-Q and to investigate for its association with several clinical aspects of PD. Fifty-one PD patients were administered the FOG-Q and the timed up and go test. Moreover, patients were evaluated for the unified PD rating scale (UPDRS), the Hoehn and Yahr Scale (HY) and the falls-efficacy scale [FES(S)]. Mean (SD) FOG-Q item scores ranged between 1.5 and 2.7 (1.0-1.4); corrected item-total correlations ranged between 0.63 and 0.86. The total FOG-Q score ranged between 0 and 24, with a mean + SD of 12.6 (6.2) and a median (q1-q3) of 12 (9-17). Reliability was 0.91. FOG-Q correlated with HY (0.36, p = 0.0091), UPDRS part III (rS = 0.27, p = 0.054), PD duration (rS = 0.35, p0.01), FES(S) (rS = 0.58, p0.001) and the timed up and go test (rS = 0.51, p = 0.001). Non-significant positive correlations were observed for dyskinesia and motor fluctuations. Our study validates the Italian version of the FOG-Q, in that it results being a reliable instrument for assessing FOG in PD patients.

Background Neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease with dementia (PDD), and dementia with Lewy bodies (DLB) share clinical and molecular features. Cerebrospinal fluid (CSF) biomarkers may help the characterization of these diseases, improving the differential diagnosis. We evaluated the diagnostic performance of five CSF biomarkers across a well-characterized cohort of patients diagnosed with AD, DLB, PDD, and Parkinson’s disease (PD). Methods A total of 208 patients were enrolled in 3 European centers. The diagnostic groups (AD, n = 48; DLB, n = 40; PDD, n = 20; PD, n = 54) were compared with cognitively healthy neurological control subjects (patients with other neurological diseases [OND], n = 46). CSF levels of fatty acid binding protein 3, heart type (FABP3), α-synuclein (α-syn), amyloid-β peptide 1–42, total tau (t-tau), and phosphorylated tau 181 (p-tau) were assessed with immunoassays. Univariate and multivariate statistical analyses were applied to calculate the diagnostic value of the biomarkers as well as their association with clinical scores. Results FABP3 levels were significantly increased in patients with AD and DLB compared with those with PD and OND (p

The Cambridge Neuropsychological Test Automated Battery (CANTAB) is a system of neuropsychological tests frequently used to track the progression of cognitive deficits in mild cognitive impairment (MCI) and Alzheimer's disease (AD). We investigated test-retest reliability in seven CANTAB tests. Twenty-five MCI patients, with either AD-like or conflicting/normal cerebrospinal fluid profiles underwent three testing sessions at 6-month intervals, including the following tests: Reaction Time and Rapid Visual Information Processing (assessing attention and reaction times); Delayed Matching-to-Sample, Paired Associates Learning, Spatial Recognition Memory and Pattern Recognition Memory (assessing memory); Spatial Working Memory (assessing executive functions). No significant difference was found when comparing the two groups. Many CANTAB measures obtained low or marginal test-retest coefficients. We observed a marked improvement in Spatial Working Memory (SWM) in both groups when comparing the baseline performance with the 6-month follow-up, but no difference in performance between 6- and 12-month follow-ups. A similar trend was documented in Paired Associates Learning (PAL), but the effect size was small. Such improvement may result from a practice effect, likely due to the learning of an effective strategy. Our evidence raised an important issue concerning the need for methodological caution when interpreting the results of longitudinal studies using SWM and PAL.

Background People with abdominal aortic aneurysm who receive endovascular aneurysm repair (EVAR) need lifetime surveillance to detect potential endoleaks. Endoleak is defined as persistent blood flow within the aneurysm sac following EVAR. Computed tomography (CT) angiography is considered the reference standard for endoleak surveillance. Colour duplex ultrasound (CDUS) and contrast-enhanced CDUS (CE-CDUS) are less invasive but considered less accurate than CT. Objectives To determine the diagnostic accuracy of colour duplex ultrasound (CDUS) and contrast-enhanced-colour duplex ultrasound (CE-CDUS) in terms of sensitivity and specificity for endoleak detection after endoluminal abdominal aortic aneurysm repair (EVAR). Search methods We searched MEDLINE, Embase, LILACS, ISI Conference Proceedings, Zetoc, and trial registries in June 2016 without language restrictions and without use of filters to maximize sensitivity. Selection criteria Any cross-sectional diagnostic study evaluating participants who received EVAR by both ultrasound (with or without contrast) and CT scan assessed at regular intervals. Data collection and analysis Two pairs of review authors independently extracted data and assessed quality of included studies using the QUADAS 1 tool. A third review author resolved discrepancies. The unit of analysis was number of participants for the primary analysis and number of scans performed for the secondary analysis. We carried out a meta-analysis to estimate sensitivity and specificity of CDUS or CE-CDUS using a bivariate model. We analysed each index test separately. As potential sources of heterogeneity, we explored year of publication, characteristics of included participants (age and gender), direction of the study (retrospective, prospective), country of origin, number of CDUS operators, and ultrasound manufacturer. Main results We identified 42 primary studies with 4220 participants. Twenty studies provided accuracy data based on the number of individual participants (seven of which provided data with and without the use of contrast). Sixteen of these studies evaluated the accuracy of CDUS. These studies were generally of moderate to low quality: only three studies fulfilled all the QUADAS items; in six (40%) of the studies, the delay between the tests was unclear or longer than four weeks; in eight (50%), the blinding of either the index test or the reference standard was not clearly reported or was not performed; and in two studies (12%), the interpretation of the reference standard was not clearly reported. Eleven studies evaluated the accuracy of CE-CDUS. These studies were of better quality than the CDUS studies: five (45%) studies fulfilled all the QUADAS items; four (36%) did not report clearly the blinding interpretation of the reference standard; and two (18%) did not clearly report the delay between the two tests. Based on the bivariate model, the summary estimates for CDUS were 0.82 (95% confidence interval (CI) 0.66 to 0.91) for sensitivity and 0.93 (95% CI 0.87 to 0.96) for specificity whereas for CE-CDUS the estimates were 0.94 (95% CI 0.85 to 0.98) for sensitivity and 0.95 (95% CI 0.90 to 0.98) for specificity. Regression analysis showed that CE-CDUS was superior to CDUS in terms of sensitivity (LR Chi2 = 5.08, 1 degree of freedom (df); P = 0.0242 for model improvement). Seven studies provided estimates before and after administration of contrast. Sensitivity before contrast was 0.67 (95% CI 0.47 to 0.83) and after contrast was 0.97 (95% CI 0.92 to 0.99). The improvement in sensitivity with of contrast use was statistically significant (LR Chi2 = 13.47, 1 df; P = 0.0002 for model improvement). Regression testing showed evidence of statistically significant effect bias related to year of publication and study quality within individual participants based CDUS studies. Sensitivity estimates were higher in the studies published before 2006 than the estimates obtained from studies published in 2006 or later (P < 0.001); and studies judged as low/unclear quality provided higher estimates in sensitivity. When regression testing was applied to the individual based CE-CDUS studies, none of the items, namely direction of the study design, quality, and age, were identified as a source of heterogeneity. Twenty-two studies provided accuracy data based on number of scans performed (of which four provided data with and without the use of contrast). Analysis of the studies that provided scan based data showed similar results. Summary estimates for CDUS (18 studies) showed 0.72 (95% CI 0.55 to 0.85) for sensitivity and 0.95 (95% CI 0.90 to 0.96) for specificity whereas summary estimates for CE-CDUS (eight studies) were 0.91 (95% CI 0.68 to 0.98) for sensitivity and 0.89 (95% CI 0.71 to 0.96) for specificity. Authors' conclusions This review demonstrates that both ultrasound modalities (with or without contrast) showed high specificity. For ruling in endoleaks, CE-CDUS appears superior to CDUS. In an endoleak surveillance programme CE-CDUS can be introduced as a routine diagnostic modality followed by CT scan only when the ultrasound is positive to establish the type of endoleak and the subsequent therapeutic management.

Reduced β-glucocerebrosidase activity was observed in postmortem brains of both GBA1 mutation carrier and noncarrier Parkinson's disease patients, suggesting that lower β-glucocerebrosidase activity is a key feature in the pathogenesis of PD. The objectives of this study were to confirm whether there is reduced β-glucocerebrosidase activity in the CSF of GBA1 mutation carrier and noncarrier PD patients and verify if other lysosomal enzymes show altered activity in the CSF.CSF β-glucocerebrosidase, cathepsin D, and β-hexosaminidase activities were measured in 79 PD and 61 healthy controls from the BioFIND cohort. The whole GBA1 gene was sequenced.Enzyme activities were normalized according to CSF protein content (specific activity). β-glucocerebrosidase specific activity was significantly decreased in PD versus controls (-28%, P0.001). GBA1 mutations were found in 10 of 79 PD patients (12.7%) and 3 of 61 controls (4.9%). GBA1 mutation carrier PD patients showed significantly lower β-glucocerebrosidase specific activity versus noncarriers. β-glucocerebrosidase specific activity was also decreased in noncarrier PD patients versus controls (-25%, P0.001). Cathepsin D specific activity was lower in PD versus controls (-21%, P0.001). β-Hexosaminidase showed a similar trend. β-Glucocerebrosidase specific activity fairly discriminated PD from controls (area under the curve, 0.72; sensitivity, 0.67; specificity, 0.77). A combination of β-glucocerebrosidase, cathepsin D, and β-hexosaminidase improved diagnostic accuracy (area under the curve, 0.77; sensitivity, 0.71; specificity, 0.85). Lower β-glucocerebrosidase and β-hexosaminidase specific activities were associated with worse cognitive performance.CSF β-glucocerebrosidase activity is reduced in PD patients independent of their GBA1 mutation carrier status. Cathepsin D and β-hexosaminidase were also decreased. The possible link between altered CSF lysosomal enzyme activities and cognitive decline deserves further investigation. © 2017 International Parkinson and Movement Disorder Society.

The Alzheimer’s disease Cooperative Study (ADCS)-Cognitive Function Instrument (CFI) is a 14-item questionnaire administered to the subject and the referent, aimed at detecting early changes in cognitive and functional abilities in individuals without clinical impairment. It is used for monitoring annual variations in cognitive functioning in prevention trials. The aim of the present study was to validate the Italian version of the CFI. A consecutive series of 257 functionally independent subjects was recruited among relatives of patients or as volunteers. They were administered CFI and global cognition measurements: Mini-Mental Status Examination (MMSE) and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The reliability and criterion validity were comparable to the original in both self- and partner-report. Similarly to what reported in the original version, we found a corrected item-total correlation ranging between 0.38 and 0.54 in self-report and between 0.33 and 0.64 in partner-report. Cronbach’s α was 0.77 (95% CI 0.72–0.83) in self-report and 0.78 (95% CI 0.73–0.84) in partner-report. Total partner- and self-report scores were significantly correlated (rS = 0.31, p

Introduction Multiple sclerosis (MS) usually presents at onset with a clinically isolated syndrome (CIS). According to 2010 McDonald criteria, a diagnosis of MS can be made if CIS patients satisfy clinical/MRI criteria of both dissemination in time (DIT) and space (DIS). Objective The aim of this study was to analyze the follow-up data and possible prognostic factors of CIS patients satisfying DIS MRI criteria. Patients and methods We performed a retrospective, multicenter study across 2 Italian centers. Clinical, MRI, and laboratory assessments were performed according to real-life clinical workup. Results Out of the 137 enrolled patients, during a median follow-up time of 3.1 years, 116 (84.7%) converted to MS with the large majority (78.4%) of the converters developing MS within 1 year. In multivariate analysis, baseline predictors of an earlier conversion were a cerebellar/brainstem CIS (HR 2.00, 95% CI: 1.3–3.0, p = 0.001) and the presence of all the Barkhof-Tintore MRI criteria (HR 1.67, 95% CI: 1.1–2.6, p = 0.028). Conclusions Patients with CIS and DIS are at very high risk of an early conversion to MS. The onset with cerebellar/brainstem symptoms and the evidence of a higher MRI lesion load at baseline are the strongest independent predictors of an early conversion to MS.

Background and purpose We assessed the prevalence and magnitude of neuropsychiatric adverse events (NPAEs) associated with antiepileptic drugs (AEDs) among patients with brain tumour-related epilepsy (BTRE). Methods This observational, prospective, multicentre study enrolled 259 patients with BTRE after neurosurgery. All patients received AED monotherapy. Efficacy was assessed through clinical diaries, whereas NPAEs were collected using the Neuropsychiatric Inventory Test-12 questionnaire at baseline and after 5 months. Results Tumour localization in the frontal lobe was associated with a higher prevalence of NPAEs (odds ratio, 7.73; P < 0.001). Independent of tumour localization, levetiracetam (LVT) treatment was associated with higher prevalence and magnitude of NPAEs (odds ratio, 7.94; P < 0.01) compared with other AEDs. Patients with oligodendroglioma reported more NPAEs than patients with other tumour types. NPAEs were not influenced by chemotherapy, radiotherapy or steroid treatment. Evaluating non-neurobehavioural adverse events of AEDs, no significant differences were found among AEDs, although patients treated with old AEDs had a higher prevalence of adverse events than those treated with new AEDs. Conclusions Both tumour localization in the frontal lobe and LVT treatment are associated with a higher risk of NPAEs in patients with BTRE. LVT is regarded as a first-line option in patients with BTRE because of easy titration and few significant drug-to-drug interactions. Thus, as NPAEs lead to poor compliance and a high dropout rate, clinicians need to accurately monitor NPAEs after AED prescription, especially in patients with frontal lobe tumours receiving LVT.

Cerebrospinal fluid (CSF) biomarkers may support the diagnosis of Alzheimer's disease (AD). We studied if the diagnostic power of AD CSF biomarker concentrations, i.e., Aβ42, total tau (t-tau), and phosphorylated tau (p-tau), is affected by differences in lateral ventricular volume (VV), using CSF biomarker data and magnetic resonance imaging (MRI) scans of 730 subjects, from 13 European Memory Clinics. We developed a Matlab-algorithm for standardized automated segmentation analysis of T1 weighted MRI scans in SPM8 for determining VV, and computed its ratio with total intracranial volume (TIV) as proxy for total CSF volume. The diagnostic power of CSF biomarkers (and their combination), either corrected for VV/TIV ratio or not, was determined by ROC analysis. CSF Aβ42 levels inversely correlated to VV/TIV in the whole study population (Aβ42: r=-0.28; p42 alone (AUC: 0.75 versus 0.81) or in combination with t-tau (AUC: 0.81 versus 0.91). In conclusion, differences in VV may be an important confounder in interpreting CSF Aβ42 levels.

Background: Decreased concentrations of amyloid-β 1-42 (Aβ42) in cerebrospinal fluid (CSF) and increased retention of Aβ tracers in the brain on positron emission tomography (PET) are considered the earliest biomarkers of Alzheimer’s disease (AD). However, a proportion of cases show discrepancies between the results of the two biomarker modalities which may reflect inter-individual differences in Aβ metabolism. The CSF Aβ42/40 ratio seems to be a more accurate biomarker of clinical AD than CSF Aβ42 alone. Objective: We tested whether CSF Aβ42 alone or the Aβ42/40 ratio corresponds better with amyloid PET status and analyzed the distribution of cases with discordant CSF-PET results. Methods: CSF obtained from a mixed cohort (n = 200) of cognitively normal and abnormal research participants who had undergone amyloid PET within 12 months (n = 150 PET-negative, n = 50 PET-positive according to a previously published cut-off) was assayed for Aβ42 and Aβ40 using two recently developed immunoassays. Optimal CSF cut-offs for amyloid positivity were calculated, and concordance was tested by comparison of the areas under receiver operating characteristic (ROC) curves (AUC) and McNemar’s test for paired proportions. Results: CSF Aβ42/40 corresponded better than Aβ42 with PET results, with a larger proportion of concordant cases (89.4% versus 74.9%, respectively, p

Background : Administrative healthcare databases are widely present in Italy. Our aim was to describe the current state of healthcare databases validity in terms of discharge diagnoses (according to the International Classification of Diseases, ICD-9 code) and their output in terms of research. Methods : A systematic search of electronic databases including Medline and Embase (1995-2013) and of local sources was performed. Inclusion criteria were: healthcare databases in any Italian territory routinely and passively collecting data; medical investigations or procedures at patient level data; the use of a validation process. The quality of studies was evaluated using the STARD criteria. Citations of the included studies were explored using Scopus and Google Scholar. Results : The search strategy allowed the identification of 16 studies of which 3 were in Italian. Thirteen studies used regional administrative databases from Lombardia, Piemonte, Lazio, Friuli-Venezia Giulia and Veneto. The ICD-9 codes of the following diseases were successfully validated: amyotrophic lateral sclerosis (3 studies in four different regional administrative databases), stroke (3 studies), gastrointestinal bleeding (1 study), thrombocytopenia (1 study), epilepsy (1 study), infection (1 study), chronic obstructive pulmonary disease (1 study), Guillain-Barre syndrome (1 study), and cancer diseases (4 studies). The quality of reporting was variable among the studies. Only 6 administrative databases produced further research related to the validated ICD-9 codes. Conclusion : Administrative healthcare databases in Italy need an extensive process of validation for multiple diagnostic codes to perform high quality epidemiological and health services research.

To assess the discriminating power of multiple cerebrospinal fluid (CSF) biomarkers for Parkinson's disease (PD), we measured several proteins playing an important role in the disease pathogenesis. The activities of β-glucocerebrosidase and other lysosomal enzymes, together with total and oligomeric α-synuclein, and total and phosphorylated tau, were thus assessed in CSF of 71 PD patients and compared to 45 neurological controls. Activities of β-glucocerebrosidase, β-mannosidase, β-hexosaminidase, and β-galactosidase were measured with established enzymatic assays, while α-synuclein and tau biomarkers were evaluated with immunoassays. A subset of PD patients (n = 44) was also screened for mutations in the β-glucocerebrosidase-encoding gene (GBA1). In the PD group, β-glucocerebrosidase activity was reduced (P

Parkinson's disease (PD) is characterized neuropathologically by the cytoplasmic accumulation of misfolded α-synuclein in specific brain regions. The endolysosomal pathway appears to be involved in α-synuclein degradation and, thus, may be relevant to PD pathogenesis. This assumption is further strengthened by the association between PD and mutations in the gene encoding for the lysosomal hydrolase glucocerebrosidase. The objective of the present study was to determine whether endolysosomal enzyme activities in cerebrospinal fluid (CSF) differ between PD patients and healthy controls. Activity levels of 6 lysosomal enzymes (β-hexosaminidase, α-fucosidase, β-mannosidase, β-galactosidase, β-glucocerebrosidase, and cathepsin D) and 1 endosomal enzyme (cathepsin E) were measured in CSF from 58 patients with PD (Hoehn and Yahr stages 1-3) and 52 age-matched healthy controls. Enzyme activity levels were normalized against total protein levels. Normalized cathepsin E and β-galactosidase activity levels were significantly higher in PD patients compared with controls, whereas normalized α-fucosidase activity was reduced. Other endolysosomal enzyme activity levels, including β-glucocerebrosidase activity, did not differ significantly between PD patients and controls. A combination of normalized α-fucosidase and β-galactosidase discriminated best between PD patients and controls with sensitivity and specificity values of 63%. In conclusion, the activity of a number of endolysosomal enzymes is changed in CSF from PD patients compared with healthy controls, supporting the alleged role of the endolysosomal pathway in PD pathogenesis. The usefulness of CSF endolysosomal enzyme activity levels as PD biomarkers, either alone or in combination with other markers, remains to be established in future studies.

Cerebrospinal fluid (CSF) is increasingly being used to detect biochemical changes that occur in different neurological conditions. In Alzheimer's disease (AD), three CSF biomarkers (Aβ42, total tau, and phosphorylated tau) are used in clinical practice to support the diagnosis in the prodromal stages of the disease. In Parkinson's disease (PD), the investigation is following the pathway of AD research and some promising markers have been identified, with the main aim to favor an early diagnosis, i.e. in the premotor phase. Some of these CSF markers have also been incorporated in AD and PD clinical trials to demonstrate target engagement of the drug and/or to enrich the patient populations. In this chapter, we will review the main CSF biomarkers for AD and PD and their potential application to clinical trials.In clinical trials assessing the efficacy of disease-modifying agents for AD, CSF biomarkers are currently used both as a diagnostic criterion for inclusion and for monitoring the biochemical impact of the drug on the upstream neurodegenerative mechanisms. Accordingly, recent trials devoted to PD are following such a procedure, although in this neurodegenerative disorder CSF biomarkers are not ready yet for routine clinical use.AD and PD are neurodegenerative disorders that share a long asymptomatic/prodromal phase in which neurodegenerative phenomena already take place in the brain. Clinical trials assessing the efficacy of disease-modifying agents should include the CSF measurement of related biomarkers as biochemical proof of the underlying pathology as well as of the impact of the drug on these pathogenic mechanisms.

The variability of Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers undermines their full-fledged introduction into routine diagnostics and clinical trials. Automation may help to increase precision and decrease operator errors, eventually improving the diagnostic performance. Here we evaluated three new CSF immunoassays, EUROIMMUNtrademark amyloid-β 1-40 (Aβ1-40), amyloid-β 1-42 (Aβ1-42), and total tau (t-tau), in combination with automated analysis of the samples. The CSF biomarkers were measured in a cohort consisting of AD patients (n = 28), mild cognitive impairment (MCI, n = 77), and neurological controls (OND, n = 35). MCI patients were evaluated yearly and cognitive functions were assessed by Mini-Mental State Examination. The patients clinically diagnosed with AD and MCI were classified according to the CSF biomarkers profile following NIA-AA criteria and the Erlangen score. Technical evaluation of the immunoassays was performed together with the calculation of their diagnostic performance. Furthermore, the results for EUROIMMUN Aβ1-42 and t-tau were compared to standard immunoassay methods (INNOTESTtrademark). EUROIMMUN assays for Aβ1-42 and t-tau correlated with INNOTEST (r = 0.83, p < 0.001 for both) and allowed a similar interpretation of the CSF profiles. The Aβ1-42/Aβ1-40 ratio measured with EUROIMMUN was the best parameter for AD detection and improved the diagnostic accuracy of Aβ1-42 (area under the curve = 0.93). In MCI patients, the Aβ1-42/Aβ1-40 ratio was associated with cognitive decline and clinical progression to AD.The diagnostic performance of the EUROIMMUN assays with automation is comparable to other currently used methods. The variability of the method and the value of the Aβ1-42/Aβ1-40 ratio in AD diagnosis need to be validated in large multi-center studies.

Objectives To identify independent predictors of the risk of functional decline in older nursing home (NH) residents. Design A longitudinal observational study. Setting Thirty-one NHs participating in the U.L.I.S.S.E. project, distributed throughout Italy. Participants All older (≥65 years) long-term NH residents without complete disability and with at least one follow-up evaluation during the 12-month study period (n = 1263). Measurements All participants underwent a standardized comprehensive evaluation using the Italian version of the Minimum Data Set for NHs. The activities of daily living (ADLs) Long-Form scale was used to evaluate functional status. Facility characteristics were collected using an ad hoc designed questionnaire. Results Of the NH residents, 40.4% experienced a decline in the ADL during the follow-up. The mixed effect logistic regression model showed that depression (odds ratio [OR] 1.45, confidence interval [CI] 1.16–1.81, P = .005) and the use of antipsychotics (OR 1.30, CI 1.06–1.60, P = .016) were associated with a higher probability of ADL decline, whereas the presence of a geriatrician (OR 0.60, CI 0.41–0.88, P = .015) and a higher than median hour per resident per week of nursing care (OR 0.55, CI 0.37–0.80, P = .006) were associated with a lower risk. Conclusions Our findings suggest that preventing functional decline in NH residents might be possible by optimizing the management of depression and by reducing the current high prescription rate of antipsychotics. Moreover, the presence of a geriatrician, associated with an adequate amount of nursing care, seem to be important facilities characteristics to achieve this goal. These findings should be tested in large-scale pragmatic clinical trials.

This review provides an update on the role, development, and validation of CSF biomarkers in the diagnosis and prognosis of Alzheimer's disease and PD. Some recent developments on novel biomarkers are also discussed. We also give an overview of methodological/technical factors still hampering the global validation and standardization of CSF Alzheimer's disease and PD biomarkers. CSF biomarkers have the potential to improve the diagnostic accuracy at the early stages not only for Alzheimer's disease but also for PD. This step is essential in view of the availability of disease-modifying treatments. Our vision for the future is that analyzing biomarker panels on a minute amount of CSF could provide important information on the whole spectrum of the molecular pathogenic events characterizing these neurodegenerative disorders. CSF core biomarkers have already been included in the diagnostic criteria for Alzheimer's disease, and they are also under consideration as tools to monitor the effects of disease-modifying drugs. With respect to PD, their potential for improving diagnostic accuracy in early diagnosis is under intense research, resembling the same path followed for Alzheimer's disease. © 2016 International Parkinson and Movement Disorder Society.

To assess the accuracy of point-of-care testing for circulatory cathodic antigen in the diagnosis of schistosome infection.We searched MEDLINE, EMBASE, LILACS and other bibliographic databases for studies published until 30 September 2015 that described circulatory cathodic antigen testing compared against one to three Kato-Katz tests per subject - for Schistosoma mansoni - or the filtration of one 10-ml urine sample per subject - for S. haematobium. We extracted the numbers of true positives, false positives, true negatives and false negatives for the antigen testing and performed meta-analyses using a bivariate hierarchical regression model.Twenty-six studies published between 1994 and 2014 met the inclusion criteria. In the detection of S. mansoni, a single antigen test gave a pooled sensitivity of 0.90 (95% confidence interval, CI: 0.84-0.94) and a pooled specificity of 0.56 (95% CI: 0.39-0.71; n = 7) when compared against a single Kato-Katz test. The corresponding values from comparisons with two to three Kato-Katz tests per subject were 0.85 (95% CI: 0.80-0.88) and 0.66 (95% CI: 0.53-0.76; n = 14), respectively. There appeared to be no advantage in using three antigen tests per subject instead of one. When compared against the results of urine filtration, antigen testing for S. haematobium showed poor sensitivity and poor specificity. The performance of antigen testing was better in areas of high endemicity than in settings with low endemicity.Antigen testing may represent an effective tool for monitoring programmes for the control of S. mansoni.Évaluer la précision des tests de détection de l'antigène cathodique circulant pratiqués sur les lieux des soins pour le diagnostic des schistosomiases.Nous avons fait des recherches dans MEDLINE, EMBASE, LILACS et d'autres bases de données bibliographiques pour trouver des études publiées jusqu'au 30 septembre 2015 décrivant les résultats de tests de détection de l'antigène cathodique circulant comparativement à ceux obtenus avec un, deux ou trois tests Kato-Katz réalisé(s) pour chaque sujet (pour le dépistage d'une infection àVingt-six études publiées entre 1994 et 2014 ont respecté les critères d'inclusion. Pour le dépistage des infections àLes tests de détection antigénique peuvent constituer des outils efficaces pour le suivi des programmes de lutte contreEvaluar la exactitud de las pruebas en el punto de atención en busca de antígenos catódicos circulantes en el diagnóstico de infección por esquistosomas.Se realizaron búsquedas en MEDLINE, EMBASE, LILACS y otras bases de datos bibliográficas para encontrar estudios publicados hasta el 30 de septiembre de 2015 que describiesen las pruebas de antígenos catódicos circulantes en comparación con entre una y tres pruebas de Kato–Katz por sujeto (para encontrarEntre 1994 y 2014 se publicaron veintiséis estudios que cumplían los criterios de inclusión. Para detectarLas pruebas de antígenos pueden representar una herramienta eficaz para los programas de supervisión para el control deتقييم دقة الاختبارات التي تتم في أماكن الرعاية السريرية للمستضد المهبطي الدوراني في اكتشاف عدوى البلهارسيا.قمنا بإجراء بحث في قواعد معطيات MEDLINE، و EMBASE، و LILACS وغيرها من القواعد الببليوغرافية الأخرى للعثور على دراسات نشرت حتى 30 سبتمبر/أيلول 2015 والتي تم من خلالها وصف اختبار المستضد المهبطي الدوراني بالمقارنة مع واحد إلى ثلاثة اختبارات بتقنيةKato‑Katz لكل حالة –كانت هناك ست وعشرون دراسة منشورة في الفترة بين عامي 1994 و2014 ملائمة لمعايير الاختيار. في حالة اكتشافقد يمثل اختبار المستضد أداة فعالة لمراقبة البرامج المخصصة لمكافحة旨在评估血吸虫感染诊断中循环阴极抗原即时检测的准确性。.我们搜索了截止 2015 年 9 月 30 日前在美国联机医学文献分析和检索系统 (MEDLINE)、荷兰医学文摘数据库 (EMBASE)、拉丁美洲和加勒比健康科学文献库 (LILACS) 和其他书目数据库中发表的研究， 这些研究对每位研究对象的循环阴极抗原检测与一至三次加藤氏厚涂片检测进行对比描述——以检测在 1994 年到 2014 年间发表的研究中，有二十六项符合纳入标准。抗原检测可用作一种控制Дать оценку точности тестирования на циркулирующий катодный антиген по месту лечения при диагностике шистосомоза.Был осуществлен поиск в базах данных MEDLINE, EMBASE, LILACS и других библиографических базах данных на предмет исследований, опубликованных до 30 сентября 2015 года, в которых результаты тестирования на циркулирующий катодный антиген сравнивались бы с результатами от 1 до 3 анализов проб, взятых у одного пациента, по методу Като-Кац для обнаружения Schistosoma mansoni или с результатами фильтрования одного образца мочи (10 мл), взятого у одного пациента, для обнаружения S. haematobium. Было подсчитано количество истинно положительных, ложно положительных, истинно отрицательных и ложно отрицательных результатов тестирования на антитела, и были проведены метаанализы с конструированием двумерной иерархической регрессии.Двадцать шесть исследований, опубликованных в период между 1994 и 2014 годами, соответствовали критериям включения. При диагностике S. mansoni объединенная чувствительность метода при проведении одного теста на антитела составила 0,90 (95%-й доверительный интервал, ДИ: 0,84–0,94), а объединенная специфичность — 0,56 (95%-й ДИ: 0,39–0,71; n = 7) в сравнении с одним анализом по методу Като-Кац. Соответствующие значения, в сравнении с результатами от 2 до 3 анализов по методу Като-Кац для каждого пациента, были равны 0,85 (95%-й ДИ: 0,80–0,88) и 0,66 (95%-й ДИ: 0,53–0,76; n = 14) соответственно. Было установлено, что проведение трех тестов на антитела вместо одного не является целесообразным. В сравнении с результатами фильтрования мочи чувствительность и специфичность метода при тестировании на антитела для диагностики S. haematobium были неудовлетворительными. Эффективность тестирования на антитела была выше в зонах с высокой эндемичностью, чем в условиях с низкой эндемичностью.Тестирование на антитела может послужить эффективным способом для программ мониторинга по борьбе с S. mansoni.

Background: Cerebrospinal fluid (CSF) is increasingly being used to detect biochemical changes that occur in different neurological conditions. In Alzheimer's disease (AD), three CSF biomarkers (Aβ42, total tau, and phosphorylated tau) are used in clinical practice to support the diagnosis in the prodromal stages of the disease. In Parkinson's disease (PD), the investigation is following the pathway of AD research and some promising markers have been identified, with the main aim to favor an early diagnosis, i.e. in the premotor phase. Some of these CSF markers have also been incorporated in AD and PD clinical trials to demonstrate target engagement of the drug and/or to enrich the patient populations. In this chapter, we will review the main CSF biomarkers for AD and PD and their potential application to clinical trials. Summary: In clinical trials assessing the efficacy of disease-modifying agents for AD, CSF biomarkers are currently used both as a diagnostic criterion for inclusion and for monitoring the biochemical impact of the drug on the upstream neurodegenerative mechanisms. Accordingly, recent trials devoted to PD are following such a procedure, although in this neurodegenerative disorder CSF biomarkers are not ready yet for routine clinical use. Key Messages: AD and PD are neurodegenerative disorders that share a long asymptomatic/prodromal phase in which neurodegenerative phenomena already take place in the brain. Clinical trials assessing the efficacy of disease-modifying agents should include the CSF measurement of related biomarkers as biochemical proof of the underlying pathology as well as of the impact of the drug on these pathogenic mechanisms.

This study aimed at determining the causes of failure of the different proposed strategies to ensure improvement of medication-overuse headache (MOH) patients, since they have not been investigated so far, especially with regard to aspects related to cognitive and behavioural aspects of symptomatic drugs overused by them. One hundred and twenty in-patients, 82 females (68.3 %), median age 49 (42–56) years, affected by MOH were admitted to the study and treated with abrupt discontinuation of the medication overused, a 6-day in-patient detoxification regimen and an immediate start of personalized prophylactic treatment, then followed for 1 year. Leeds Dependence Questionnaire (LDQ), among all the clinical variables, was administered at baseline and at 1-year follow-up visit to assess substance dependence. Of the 120 patients enrolled, 68 (56.7 %) were successfully detoxified (Responder-group), while 52 (43.3 %) were not (Non-Responder-group). At baseline, the mean LDQ total score was slightly higher in the Non-Responder group than in the Responder group (12.08 ± 2.14 vs. 11.94 ± 1.98). Although this difference was not significant at baseline (p > 0.05), the LDQ total score was significantly different (p

Admission hyperglycemia increases the risk of death in patients with acute stroke. However, the most appropriate cut-off of glucose level indicating an increased risk of short-term mortality remains unknown.We aimed at establishing the optimum cut-offs of several variables (including admission blood glucose levels) predicting case-fatality (72hours, 7days) and unfavorable outcome [modified Rankin Scale (mRS) score 5-6 at 7 days] in consecutive first-ever acute ischemic stroke. Receiver operating characteristic (ROC) curves were constructed.Eight hundred eleven consecutive patients were included [median age of 77 (69-83) years; 418 (52%) male; 239 (30%) diabetics; median admission National Institutes of Health Stroke Scale (NIHSS) 7 (4-12), 32 (4%) dead within 72hours; 64 (8%) dead within day 7; 155 (19%) with unfavorable outcome]. Median admission glucose levels were 113 (97-155)mg/dL. Diabetics had significantly higher median glucose levels than non-diabetics [163 (133-214) vs. 107 (92-123) mg/dL, p0.001]. According to ROC analysis, the only significant predictive value of glycemia was ≥143mg/dL for 72-hour fatality (sensitivity 88% and specificity 70%) especially in non-diabetics (sensitivity 88% and sensitivity 62%). This cut-off point was an independent predictor for 72-hour fatality (overall: OR=4.0, CI=1.6-9.9, p=0.003; non-diabetics: OR=4.9, CI=1.7-14.5, p=0.004). The cut-offs of fasting total cholesterol levels and admission leukocytes had poor predictive values for each outcome, while those of admission NIHSS had good discrimination in predicting short-term outcome measures.Admission hyperglycemia (≥143mg/dL) is a strong and an independent predictor for 72-hour fatality, especially in patients with no prior history of diabetes mellitus.

Background: It has been suggested that low cholesterol levels might be associated with an increased risk of hemorrhagic transformation (HT) in patients with acute cerebral ischemia. We systematically reviewed the literature to determine the influence of lipid profiles on the HT risk. Methods: We searched PubMed from 1966 and EMBASE from 1980 for studies that investigated the association between lipid profiles and HT. We performed a meta-analysis (weighted mean difference method) for the comparison between presence and absence of HT (all or symptomatic) for total, low-density-lipoprotein (LDL) and high-density-lipoprotein (HDL) cholesterol, and triglycerides. Results: Eight studies investigating 1,763 patients were eligible, but none was designed specifically to address this question. All studies recruited acute stroke patients selected on the presumed cause of cerebral ischemia or treatment received. The meta-analysis showed that: (i) patients with all HT had lower LDL cholesterol levels (p = 0.008) but no difference in HDL cholesterol levels (p = 0.066), total cholesterol (p = 0.129) and triglycerides (p = 0.900); (ii) patients with symptomatic HT had lower total cholesterol levels (p = 0.035) but did not differ in LDL (p = 0.056) and HDL cholesterol (p = 0.138) and triglyceride (p = 0.851) levels. Conclusion: HT is associated with baseline total and LDL cholesterol levels, but the mechanism of this association needs to be explored to identify preventive strategies.

Although alpha-synuclein is the main constituent of Lewy bodies, cerebrospinal fluid determination on its own does not seem fundamental for the diagnosis of synucleinopathies. We evaluated whether the combination of classical biomarkers, Aβ(1-42) , total tau, phosphorylated tau, and α-synuclein can improve discrimination of Parkinson's disease, dementia with Lewy bodies, Alzheimer's disease, and frontotemporal dementia. Aβ(1-42) , total tau, phosphorylated tau, and α-synuclein were measured in a series of patients with Parkinson's disease (n = 38), dementia with Lewy bodies (n = 32), Alzheimer's disease (n = 48), frontotemporal dementia (n = 31), and age-matched control patients with other neurological diseases (n = 32). Mean α-synuclein levels in cerebrospinal fluid were significantly lower in the pathological groups than in cognitively healthy subjects. An inverse correlation of α-synuclein with total tau (r = -0.196, P < .01) was observed. In the group of patients with Parkinson's disease, Aβ(1-42) , total tau, and phosphorylated tau values were similar to controls, whereas total tau/α-synuclein and phosphorylated tau/α-synuclein ratios showed the lowest values. Cerebrospinal fluid α-synuclein alone did not provide relevant information for Parkinson's disease diagnosis, showing low specificity (area under the curve, 0.662; sensitivity, 94%; specificity, 25%). Instead, a better performance was obtained with the total tau/α-syn ratio (area under the curve, 0.765; sensitivity, 89%; specificity, 61%). Combined determination of α-synuclein and classical biomarkers in cerebrospinal fluid shows differential patterns in neurodegenerative disorders. In particular, total tau/α-synuclein and phosphorylated tau/α-synuclein ratios can contribute to the discrimination of Parkinson's disease. © 2011 Movement Disorder Society.

This paper aims at classifying, on the basis of their disability profile, the population of elderly and quantifying the number of those with a very low level of functioning in a central region of Italy. This is accomplished using a set of variables on the difficulty of accomplishing everyday tasks (Activities of Daily Living, ADL) and functions. This issue is very important for National and Local Health organizations in order to evaluate the need for care, planning services, elaborating policies and allocating resources. Latent class models are applied on data coming from the Italian National Survey on Health Conditions and Appeal to Medicare to extract the latent trait of disability and classify the elder population according to their disability profile. Model selection brings to a classification into four latent classes. Looking at posterior probabilities, classes may be interpreted as follows: elderly without disability, with difficulties in movements, with difficulties in movements and daily tasks, with very low functioning level. Estimates of the amount of population aged 65 or more falling in each class is also provided. Cross-validation shows evidence of the robustness of such classification. Item response theory models are also applied to the items considered to study how functions are lost with increasing levels of disability. In particular, the abilities of climbing stairs and stooping down are those lost first, while those of eating and getting washed are those lost last.

Background and purpose: Magnetization transfer ratio (MTR) technique has identified brain changes in grey and white matter in Parkinsons disease (PD), even in the early phase. However, how these tissue changes differ along the course of the illness is still unclear. This study was aimed at investigating how MTR values change from mild PD (PD1) to patients with advanced PD (PD2). Methods: We measured MTR values by region of interest, in 11 PD1, 11 PD2 and 10 healthy age-matched subjects. Results: Compared with controls, patients with PD1 exhibited a significant MTR reduction in substantia nigra pars compacta, substantia nigra pars reticulata, putamen, periventricular white matter and parietal white matter. In addition to the changes observed in PD1, the PD2 group exhibited a significant MTR reduction in caudate, pons, frontal white matter and lateral thalamus. Conclusion: These results suggest that MTR might reflect morphological changes induced by the disease in distinct brain areas at different stages.

Objective.—A strong association has been demonstrated between migraine, particularly in the chronic form and with medication overuse, and either major depression or various anxiety disorders. However, there has been less systematic research on the links between migraine with medication-overuse headache (MOH) and obsessive-compulsive disorder (OCD). A drug-seeking behavior shares with OCD the compulsive quality of the behavior. We investigated the relationship between OCD and MOH in migraineurs. Methods.—A structured questionnaire was administered to subjects with: episodic migraine (EM) (n = 30), chronic migraine (CM) (n = 24), and MOH with a previous history of EM (n = 33) and 29 control subjects. Psychiatric diagnoses were made by a senior psychiatrist blinded to the diagnosis of migraine. Psychiatric assessment of OCD illness was evaluated by means of The Yale-Brown Obsessive Compulsive Scale (Y-BOCS). Results.—In the subgroup of patients with MOH, psychiatric comorbidity (anxiety and mood disorders) was prevalent compared with CM, EM, and controls (P < .0001). Subclinical OCD was significantly prevalent in MOH patients with respect to other groups (P < .0002). Higher scores in Y-BOCS, as a measure of severity of obsessive-compulsive symptoms, were found in both MOH and CM compared with controls and EM. Conclusions.—The excess of psychiatric comorbidity in patients with MOH can be related either to medication overuse or to chronification of headache. Among anxiety disorders, we observed a high rate of subclinical OCD. However, a direct link between compulsive behavior and medication overuse cannot be established yet. OCD in MOH might be underdiagnosed and undertreated.

Background and purpose: Repeated episodes of hypoxia, hypercapnia and transient blood pressure elevation in obstructive sleep apnea syndrome (OSAS) may damage neutral structures and induce cerebral metabolic impairment. This study aimed to determine the impact of OSAS on cerebral metabolites measured by 1H magnetic resonance spectroscopy (1H -MRS). Methods: Twenty OSAS patients underwent standard overnight polysomnography and 1H-MRS separately. Proton volumes of interest (VOIs) were placed in frontal and midtemporal regions bilaterally. Results: Significantly lower values of the N-acetylaspartate (NAA)/creatine (Cr) ratio were found in frontal regions (P

In recent years a role has been recognized for fibroblast growth factor (FGF)-2 in the pathogenesis of demyelination and the failure of remyelination in experimental models of multiple sclerosis (MS). FGF-2 levels were determined using a sensitive immunoassay in the cerebrospinal fluid (CSF) of 20 patients with clinically isolated syndrome (CIS), 40 patients with relapsing-remitting (R-R) MS, and 30 patients with secondary progressive (SP) MS, correlated with MRI measures. Control CSF samples were obtained from 20 subjects who underwent lumbar puncture for diagnostic purposes and for whom all instrumental and laboratory analyses excluded systemic and nervous system diseases. FGF-2 levels in the CSF of MS and CIS patients were significantly higher than controls (P0.001 and P0.05, respectively). The highest levels were detected in R-R MS patients during relapse and in SP MS patients with an increase of 1 point in EDSS scores in the last 6 months. A significant correlation was found in SP MS patients with lesional load (R=0.43, P0.01) but not with parenchymal fractions as measures of brain atrophy. A slight increase in serum FGF-2 levels was also found in R-R MS patients during relapse with gadolinium enhancing lesions and in SP patients with disability progression. These findings support the implication of FGF-2 in the pathogenesis of MS and concur with recent reports of the involvement of FGF receptor signalling in the disruption of myelin production in differentiated oligodendrocytes and in the loss of adult oligodendrocytes and myelin in vivo due to FGF-2.

Background Lysosomal dysfunction is thought to be a prominent feature in the pathogenetic events leading to Parkinson’s disease (PD). This view is supported by the evidence that mutations in GBA gene, coding the lysosomal hydrolase β-glucocerebrosidase (GCase), are a common genetic risk factor for PD. Recently, GCase activity has been shown to be decreased in substantia nigra and in cerebrospinal fluid of patients diagnosed with PD or dementia with Lewy Bodies (DLB). Here we measured the activity of GCase and other endo-lysosomal enzymes in different brain regions (frontal cortex, caudate, hippocampus, substantia nigra, cerebellum) from PD (n = 26), DLB (n = 16) and age-matched control (n = 13) subjects, screened for GBA mutations. The relative changes in GCase gene expression in substantia nigra were also quantified by real-time PCR. The role of potential confounders (age, sex and post-mortem delay) was also determined. Findings Substantia nigra showed a high activity level for almost all the lysosomal enzymes assessed. GCase activity was significantly decreased in the caudate (−23%) and substantia nigra (−12%) of the PD group; the same trend was observed in DLB. In both groups, a decrease in GCase mRNA was documented in substantia nigra. No other lysosomal hydrolase defects were determined. Conclusion The high level of lysosomal enzymes activity observed in substantia nigra, together with the selective reduction of GCase in PD and DLB patients, further support the link between lysosomal dysfunction and PD pathogenesis, favoring the possible role of GCase as biomarker of synucleinopathy. Mapping the lysosomal enzyme activities across different brain areas can further contribute to the understanding of the role of lysosomal derangement in PD and other synucleinopathies. Electronic supplementary material The online version of this article (doi:10.1186/s13024-015-0010-2) contains supplementary material, which is available to authorized users.

We congratulate Schlattmann et al. [1] for their excellent article, in which they introduced a bivariate mixture model for diagnostic meta-analyses, thereby extending the standard bivariate model [2]. The novelty of their approach relies on the use of a discrete nonparametric distribution for the random effects, which account for the variability in results between studies. Their model is basically a bivariate normal mixture model for logit-transformed observed sensitivities and specificities. Within the identified latent classes, it is assumed that studies are homogeneous with respect to the diagnostic accuracy parameters. The authors claim that their approach ‘‘is the first to explore heterogeneity in terms of its inherent cluster structure and to provide summary estimates of sensitivity and specificity at the same time.’’ In this letter, we would like to point to a recent publication of us [3] in which we proposed a related mixture-based approach. Our approach involves adding a latent class structure to the classical bivariate model. This implies that we use the exact binomial distribution rather a normal approximation and, moreover, that we allow for between studies variability within each latent class by means of normally distributed random effects. As Schlattman et al., we are able to produce summary estimates of sensitivity and specificity while exploring heterogeneity in terms of the underlying cluster structure. We proposed using a combination of EM and NewtoneRaphson algorithms for maximum likelihood estimation, which is readily available in the LatentGOLD (Statistical Innovations, Belmont, MA, USA) software. Moreover, WinBUGS code is now available on request for Bayesian estimation of our latent class bivariate model. An extensive simulation study was performed in which we investigated the validity of the model in terms of parameter bias, aswell as the power associatedwith differentmodel selection criteria. In particular, we investigated the use of Bayesian information criterion (BIC), Akaike information criterion (AIC), and Akaike information criterion 3 (AIC3) in different scenarios. Although in some situations BIC turned out to underestimate the number of mixture components and thereby selecting a model with biased sensitivity and specificity, the other criteria performed very well. We thank the authors for the R package CADAM, and we hope it will be extended in the future with other types of mixture models for diagnostic meta-analyses. In general, we think that diagnostic meta-analyses can be performed within a more comprehensive framework of generalized latent variable modeling, using either a frequentist or a

Objective To examine whether deviation from the standard intention to treat analysis has an influence on treatment effect estimates of randomised trials. Design Meta-epidemiological study. Data sources Medline, via PubMed, searched between 2006 and 2010; 43 systematic reviews of interventions and 310 randomised trials were included. Eligibility criteria for selecting studies From each year searched, random selection of 5% of intervention reviews with a meta-analysis that included at least one trial that deviated from the standard intention to treat approach. Basic characteristics of the systematic reviews and randomised trials were extracted. Information on the reporting of intention to treat analysis, outcome data, risk of bias items, post-randomisation exclusions, and funding were extracted from each trial. Trials were classified as: ITT (reporting the standard intention to treat approach), mITT (reporting a deviation from the standard approach), and no ITT (reporting no approach). Within each meta-analysis, treatment effects were compared between mITT and ITT trials, and between mITT and no ITT trials. The ratio of odds ratios was calculated (value

IntroductionIdiopathic Parkinson’s disease (PD) is a progressive neurodegenerative disorder related to α-synuclein misfolding and aggregation. For this reason, it belongs to the family of ‘synucleinopathies’, which also includes some other neurological diseases. Although imaging and ancillary investigations may be helpful in the diagnostic workup, the diagnosis of PD mostly relies on the clinician’s expertise. Furthermore, there is a need today for markers that can track the disease progression in PD that might improve the evaluation of novel disease-modifying therapies. The cerebrospinal fluid (CSF) has been widely investigated with the purpose of finding useful diagnostic and prognostic biomarkers for PD.Methods and analysisThis systematic review protocol has been developed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses Protocol 2015 statement and was registered on the PROSPERO international prospective register of systematic reviews. An international collaboration will be established. We will search the Cochrane Library, Web of Science, Medline and Embase from inception, using appropriate search strategies. Individual participant data from all included studies will be merged into a single database. We will include any study assessing the diagnostic and prognostic role of CSF biomarkers in PD. To evaluate the risk of bias and applicability of primary diagnostic accuracy studies, we will use Quality Assessment of Diagnostic Accuracy Studies-2 and Quality in Prognostic Studies. We will use standard meta-analytic procedures. We will first explore the utility of each CSF biomarker in turn. For each biomarker, we will assess its diagnostic and prognostic utility by means of receiver operating characteristic analysis and regression models. We will then move towards a multivariate approach considering different panels of biomarkers.Ethics and disseminationOur study will not include confidential data, and no intervention will be involved, so ethical approval is not required. The results of the study will be reported in international peer-reviewed journals.

Introduction Administrative healthcare databases can provide a comprehensive assessment of the burden of diseases in terms of major outcomes, such as mortality, hospital readmissions and use of healthcare resources, thus providing answers to a wide spectrum of research questions. However, a crucial issue is the reliability of information gathered. Aim of this protocol is to validate International Classification of Diseases, 9th Revision—Clinical Modification (ICD-9-CM) codes for major cardiovascular diseases, including acute myocardial infarction (AMI), heart failure (HF), atrial fibrillation (AF) and stroke. Methods and analysis Data from the centralised administrative database of the entire Umbria Region (910 000 residents, located in Central Italy) will be considered. Patients with a first hospital discharge for AMI, HF, AF or stroke, between 2012 and 2014, will be identified in the administrative database using the following groups of ICD-9-CM codes located in primary position: (1) 410.x for AMI; (2) 427.31 for AF; (3) 428 for HF; (4) 433.x1, 434 (excluding 434.x0), 436 for ischaemic stroke, 430 and 431 for haemorrhagic stroke (subarachnoid haemorrhage and intracerebral haemorrhage). A random sample of cases, and of non-cases, will be selected, and the corresponding medical charts retrieved and reviewed for validation by pairs of trained, independent reviewers. For each condition considered, case adjudication of disease will be based on symptoms, laboratory and diagnostic tests, as available in medical charts. Divergences will be resolved by consensus. Sensitivity and specificity with 95% CIs will be calculated. Ethics and dissemination Research protocol has been granted approval by the Regional Ethics Committee. Study results will be disseminated widely through peer-reviewed publications and presentations at national and international conferences.

Measurements of the activities of lysosomal enzymes in cerebrospinal fluid have recently been proposed as putative biomarkers for Parkinson's disease and other synucleinopathies. To define the operating procedures useful for ensuring the reliability of these measurements, we analyzed several pre-analytical factors that may influence the activity of β-glucocerebrosidase, α-mannosidase, β-mannosidase, β-galactosidase, α-fucosidase, β-hexosaminidase, cathepsin D and cathepsin E in cerebrospinal fluid. Lysosomal enzyme activities were measured by well-established fluorimetric assays in a consecutive series of patients (n = 28) with different neurological conditions, including Parkinson's disease. The precision, pre-storage and storage conditions, and freeze/thaw cycles were evaluated. All of the assays showed within- and between-run variabilities below 10%. At -20°C, only cathepsin D was stable up to 40 weeks. At -80°C, the cathepsin D, cathepsin E, and β-mannosidase activities did not change significantly up to 40 weeks, while β-glucocerebrosidase activity was stable up to 32 weeks. The β-galactosidase and α-fucosidase activities significantly increased (+54.9±38.08% after 4 weeks and +88.94±36.19% after 16 weeks, respectively). Up to four freeze/thaw cycles did not significantly affect the activities of cathepsins D and E. The β-glucocerebrosidase activity showed a slight decrease (-14.6%) after two freeze/thaw cycles. The measurement of lysosomal enzyme activities in cerebrospinal fluid is reliable and reproducible if pre-analytical factors are accurately taken into consideration. Therefore, the analytical recommendations that ensue from this study may contribute to the establishment of actual values for the activities of cerebrospinal fluid lysosomal enzymes as putative biomarkers for Parkinson's disease and other neurodegenerative disorders.

Background and purpose Urinary symptoms associated with multiple sclerosis (MS) are common and negatively impact on quality of life, representing a considerable psychosocial and economic burden, often requiring care and hospitalization. Although the importance of identifying and adequately treating urinary symptoms in MS is now well recognized, there is no information, to date, about the real prevalence and impact of bladder symptoms in patients with clinically isolated syndromes (CISs) suggestive of MS. Methods The aim of the present study was to investigate, in a cohort of patients with a diagnosis of CIS suggestive of MS, the prevalence of urinary tract symptoms, their impact on quality of life measures and their association with functional urodynamic dysfunctions. Patients underwent a complete neurological and urological visit, urodynamic investigation and the MSQoL-54 questionnaire. Results Twenty-eight consecutive patients presenting with CISs were enrolled in the study; 53.6% of CIS patients reported urinary symptoms, 46.7% reporting irritative symptoms, 33.3% both irritative and obstructive symptoms and 20% obstructive symptoms alone. Urodynamic abnormalities were observed in 57.1% of the CIS patients. In 17.9% of the CIS patients urodynamic dysfunctions were asymptomatic. The presence of urinary symptoms was associated with lower scores on specific quality of life domains, particularly in women with obstructive symptoms. Conclusions A high prevalence of urinary symptoms and urodynamic dysfunctions in patients with CISs and an association of urinary symptoms with quality of life measures were found. These results highlight the importance of identifying and optimally treating urinary symptoms also at the very early stages of MS.

Background An occlusion or stenosis of intracranial large arteries can be detected in the acute phase of ischaemic stroke in about 42% of patients. The approved therapies for acute ischaemic stroke are thrombolysis with intravenous recombinant tissue plasminogen activator (rt-PA), and mechanical thrombectomy; both aim to recanalise an occluded intracranial artery. The reference standard for the diagnosis of intracranial stenosis and occlusion is intra-arterial angiography (IA) and, recently, computed tomography angiography (CTA) and magnetic resonance angiography (MRA), or contrast-enhanced MRA. Transcranial Doppler (TCD) and transcranial colour Doppler (TCCD) are useful, rapid, noninvasive tools for the assessment of intracranial large arteries pathology. Due to the current lack of consensus regarding the use of TCD and TCCD in clinical practice, we systematically reviewed the literature for studies assessing the diagnostic accuracy of these techniques compared with intra-arterial IA, CTA, and MRA for the detection of intracranial stenosis and occlusion in people presenting with symptoms of ischaemic stroke. Objectives To assess the diagnostic accuracy of TCD and TCCD for detecting stenosis and occlusion of intracranial large arteries in people with acute ischaemic stroke. Search methods We limited our searches from January 1982 onwards as the transcranial Doppler technique was only introduced into clinical practice in the 1980s. We searched MEDLINE (Ovid) (from 1982 to 2018); Embase (Ovid) (from 1982 to 2018); Database of Abstracts of Reviews of Effects (DARE); and Health Technology Assessment Database (HTA) (from 1982 to 2018). Moreover, we perused the reference lists of all retrieved articles and of previously published relevant review articles, handsearched relevant conference proceedings, searched relevant websites, and contacted experts in the field. Selection criteria We included all studies comparing TCD or TCCD (index tests) with IA, CTA, MRA, or contrast-enhanced MRA (reference standards) in people with acute ischaemic stroke, where all participants underwent both the index test and the reference standard within 24 hours of symptom onset. We included prospective cohort studies and randomised studies of test comparisons. We also considered retrospective studies eligible for inclusion where the original population sample was recruited prospectively but the results were analysed retrospectively. Data collection and analysis At least two review authors independently screened the titles and abstracts identified by the search strategies, applied the inclusion criteria, extracted data, assessed methodological quality (using QUADAS-2), and investigated heterogeneity. We contacted study authors for missing data. Main results A comprehensive search of major relevant electronic databases (MEDLINE and Embase) from 1982 to 13 March 2018 yielded 13,534 articles, of which nine were deemed eligible for inclusion. The studies included a total of 493 participants. The mean age of included participants was 64.2 years (range 55.8 to 69.9 years). The proportion of men and women was similar across studies. Six studies recruited participants in Europe, one in south America, one in China, and one in Egypt. Risk of bias was high for participant selection but low for flow, timing, index and reference standard. The summary sensitivity and specificity estimates for TCD and TCCD were 95% (95% CI = 0.83 to 0.99) and 95% (95% CI = 0.90 to 0.98), respectively. Considering a prevalence of stenosis or occlusion of 42% (as reported in the literature), for every 1000 people who receive a TCD or TCCD test, stenosis or occlusion will be missed in 21 people (95% CI = 4 to 71) and 29 (95% CI = 12 to 58) will be wrongly diagnosed as harbouring an intracranial occlusion. However, there was substantial heterogeneity between studies, which was no longer evident when only occlusion of the MCA was considered, or when the analysis was limited to participants investigated within six hours. The performance of either TCD or TCCD in ruling in and ruling out a MCA occlusion was good. Limitations of this review were the small number of identified studies and the lack of data on the use of ultrasound contrast medium. Authors' conclusions This review provides evidence that TCD or TCCD, administered by professionals with adequate experience and skills, can provide useful diagnostic information for detecting stenosis or occlusion of intracranial vessels in people with acute ischaemic stroke, or guide the request for more invasive vascular neuroimaging, especially where CT or MR-based vascular imaging are not immediately available. More studies are needed to confirm or refute the results of this review in a larger sample of stroke patients, to verify the role of contrast medium and to evaluate the clinical advantage of the use of ultrasound.

Background: An increasing number of diagnostic tests and biomarkers have been validated during the last decades, and this will still be a prominent field of research in the future because of the need for personalized medicine. Strict evaluation is needed whenever we aim at validating any potential diagnostic tool, and the first requirement a new testing procedure must fulfill is diagnostic accuracy. Summary: Diagnostic accuracy measures tell us about the ability of a test to discriminate between and/or predict disease and health. This discriminative and predictive potential can be quantified by measures of diagnostic accuracy such as sensitivity and specificity, predictive values, likelihood ratios, area under the receiver operating characteristic curve, overall accuracy and diagnostic odds ratio. Some measures are useful for discriminative purposes, while others serve as a predictive tool. Measures of diagnostic accuracy vary in the way they depend on the prevalence, spectrum and definition of the disease. In general, measures of diagnostic accuracy are extremely sensitive to the design of the study. Studies not meeting strict methodological standards usually over- or underestimate the indicators of test performance and limit the applicability of the results of the study. Key Messages: The testing procedure should be verified on a reasonable population, including people with mild and severe disease, thus providing a comparable spectrum. Sensitivities and specificities are not predictive measures. Predictive values depend on disease prevalence, and their conclusions can be transposed to other settings only for studies which are based on a suitable population (e.g. screening studies). Likelihood ratios should be an optimal choice for reporting diagnostic accuracy. Diagnostic accuracy measures must be reported with their confidence intervals. We always have to report paired measures (sensitivity and specificity, predictive values or likelihood ratios) for clinically meaningful thresholds. How much discriminative or predictive power we need depends on the clinical diagnostic pathway and on misclassification (false positives/negatives) costs.

Introduction The diagnostic criteria currently used for Parkinson9s disease (PD) are mainly based on clinical motor symptoms. For these reasons many biomarkers are under investigation to support the diagnosis at the early stage. The neuropathological hallmark of PD is represented by Lewy bodies (LBs), which are intracytoplasmic inclusions in substantia nigra neurons. The major component of LBs, α-synuclein (α-syn), has been implicated in the pathogenesis of PD and in other ‘synucleinopathies’ such as multisystem atrophy (MSA) and dementia with LBs (DLBs). Several studies have investigated this presynaptic protein as a potential biomarker of PD. The aim of our meta-analysis is to determine the ability of cerebrospinal fluid (CSF) concentrations of total α-syn, oligomeric α-syn and phosphorylated α-syn to discriminate patients with PD from healthy participants, non-degenerative neurological controls and patients suffering from parkinsonism and or synucleinopathies. Methods and analysis This systematic review protocol has been developed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses Protocol (PRISMA-P) 2015 statement and was registered on PROSPERO (CRD42016013217). We will search Cochrane Library, Web of Science, MEDLINE (via PubMed) and EMBASE from inception, using appropriate search strategies. Two independent reviewers will screen titles, abstracts and full-text articles, and will complete data abstraction. We will include studies that involved patients with PD, DLB, MSA, progressive supranuclear palsy, corticobasal disease and vascular PD, and in which at least one between total α-syn, oligomeric α-syn and phosphorylated α-syn was measured in CSF. To evaluate the risk of bias and applicability of primary diagnostic accuracy studies, we will use QUADAS-2. Ethics and dissemination Our study will not include confidential data, and no intervention will be involved, so ethical approval is not required. The results of the study will be reported in international peer-reviewed journals.