Search

The phosphorylated neurofilament heavy chain (pNfH) is a promising biomarker in amyotrophic lateral sclerosis (ALS). We examined plasma pNfH concentrations in order to corroborate its role as a diagnostic and prognostic biomarker in ALS. Incident ALS cases enrolled in a population-based registry were retrospectively selected and matched by sex and age with a cohort of healthy volunteers. Plasma pNfH levels were measured by an ELISA kit and correlated with clinical parameters. Discrimination ability of pNfH was tested using receiving operating characteristic (ROC) curves. Kaplan-Meier (KM) analysis and Cox proportional hazard models were used for survival analysis. Plasma pNfH was significantly higher in patients compared to controls. An optimal cut-off of 39.74 pg/ml discriminated cases from controls with an elevated sensitivity and specificity. Bulbar-onset cases had higher plasma pNfH compared to spinal onset (p = 0.0033). Furthermore, plasma pNfH positively correlated with disease progression rate (r = 0.19, p = 0.031). Baseline plasma pNfH did not influence survival in our cohort. Our findings confirmed the potential utility of plasma pNfH as a diagnostic biomarker in ALS. However, further studies with longitudinal data are needed to corroborate its prognostic value.

BACKGROUND: The COVID-19 pandemic is changing clinical practice in neurology, after the governments decided the introduction of social distancing and interruption of medical non-emergency services in many countries. Teleneurology is an effective tool for the remote evaluation of patients but its adoption for frontotemporal lobar dementia (FTD) is in a preliminary stage. OBJECTIVE: We evaluated multidisciplinary assessment of patients with FTD using telehealth during the COVID-19 pandemic. METHODS: All patients received a diagnosis of FTD during 2018-2019 according to international criteria. A structured questionnaire and Clinical Dementia Rating Scale (CDR)-FTD were used by the neurologist with patients and/or caregivers. Index symptoms of COVID-19 infection were searched. RESULTS: Twenty-eight clinical interviews were completed with caregivers and four with both patients/caregivers. Most patients and caregivers were satisfied with the neurological interview and expressed their willingness to continue to be included in remote evaluation programs (90%). Fifty percent of patients experienced significant worsening of clinical picture and quality of life since the start of social distancing. The CDR-FTD scale revealed a significant worsening of behavior (p = 0.01) and language functions (p = 0.009), compared to the last in-person evaluation at the center. One patient presented index symptoms of COVID-19 infection and was confirmed to be positive for COVID-19 with pharyngeal swab. CONCLUSION: The study was conducted in Italy, one of the countries hit particularly hard by the COVID-19 pandemic, with interruption of all non-emergency medical services. Our study indicates that telemedicine is a valid tool to triage patients with FTD to increase practice outreach and efficiency.

Background: Teleneurology is an effective tool for the rapid evaluation of patients in remote locations with a well-established use in stroke and epilepsy. To date its adoption for Amyotrophic Lateral Sclerosis (ALS) care is still in a preliminary stage. We evaluated the feasibility of multidisciplinary assessment of patients with ALS, using telememedicine during the emergency determined by the COVID-19 pandemic. Methods: All patients included in this survey had received a diagnosis of ALS according to international criteria after a complete clinical and paraclinical assessment during 2019. A structured questionnaire was used by the neurologist with the patient or the caregiver. A video interaction was offered but refused by all patients because they did not feel comfortable or did not have smartphone. Results: Out of 31 clinical interviews 8 were completed directly with the patients and 23 with patients' caregivers. In a successive survey, most of patients were satisfied with the neurological interview (85%), the possibility to interact directly with the clinician being at home (85%) and reduction of economic and time costs because they avoided unnecessary travel to the clinic. Most of subjects expressed their willingness to continue to be included in remote evaluation programs (90%). Notably, none of the patients presented index symptoms of Covid-19 infection. Conclusion: Our study indicates that telemedicine is a valid tool to triage patients with ALS to increase practice outreach and efficiency. Delivery of care via telemedicine was effective and successful in people with ALS in the dramatic and sudden crisis determined by Covid-19 outbreak.

The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10−5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms.

Percutaneous endoscopic gastrostomy (PEG) is the standard procedure for feeding severely dysphagic patients with amyotrophic lateral sclerosis (ALS). It is associated with prolonged survival and improvement in quality of life. Nasal inspiratory pressure during a sniff (SNIP) is a respiratory test used extensively in ALS for the assessment of inspiratory muscle strength. In this study, we aimed to investigate the role of SNIP at baseline to predict PEG placement in ALS. Data from a clinical incident cohort of 179 ALS cases attending the multidisciplinary ALS unit of the University of Bari between April 2006 and December 2012 were retrospectively analysed. At baseline, patients underwent detailed neurological, nutritional and respiratory assessments, including measurements of SNIP and forced vital capacity (FVC). Patients were therefore followed up approximately every three to six months until they were able to attend the centre. The censoring date for the survival analysis was 15 April 2014, with PEG placement as the main outcome. Cox proportional hazard regression models were used to examine the association between SNIP and PEG placement, adjusted for possible confounders. During the follow-up period, 75 participants (42%) received PEG implant. PEG placement was more frequent (57% vs. 31%, p = 0.001) and earlier (after 11.6 ± 14.0 months from the first visit, vs. 23.3 ± 15.5 months, p &lt, 0.0001) in the group of patients with baseline SNIP ≤ 40 cm H2O. Baseline SNIP was a predictor of PEG placement even after correction for multiple potential confounders (HR 0.98, 95% CI: 0.96–0.99, p = 0.02). To conclude, the present study showed that SNIP at baseline is an early indicator of disease progression and therefore of the need for enteral nutrition in ALS.

In amyotrophic lateral sclerosis (ALS), memory deficits may be primary or secondary to executive dysfunction. We assessed episodic memory and executive function of nondemented ALS patients, comparing episodic memory profiles and learning rates of ALS patients with those of mild cognitive impairment (MCI) subjects and cognitively healthy controls (HC). In a multidisciplinary tertiary centre for motor neuron disease, 72 nondemented ALS patients, 57 amnestic MCI (aMCI), 89 single non amnestic MCI with compromised executive functions (dysexecutive MCI), and 190 HC were enrolled. They were screened using the Frontal Assessment Battery and Mini Mental State Examination. Episodic memory performances and learning rates were tested using the Rey Auditory Verbal Learning Test (RAVLT). Episodic memory dysfunction (immediate recall) was found in 14 ALS patients (19.4%). The ALS group had lower performance than HC on immediate recall, without differences in learning rate, and better performance than aMCI subjects on all RAVLT measures. Compared to dysexecutive MCI subjects, ALS patients had only better verbal learning abilities. ALS patients with executive dysfunction had a lower score on immediate and delayed recalls, verbal learning, and primacy effect than ALS patients without executive dysfunction. The immediate recall among couples of diagnostic groups differed in a statistically significant way except for the ALS/dysexecutive MCI groups. In ALS patients, episodic memory performances and learning rates appeared to be better than in aMCI subjects and similar to those with dysexecutive MCI, suggesting also a secondary functional damage due to executive impairment.

Aim of the study Beta-Amyloid 1–42 peptide (βA42) is a cerebro-spinal fluid (CSF) biomarker, key element of the NIA Alzheimer's disease diagnostic criteria. The enzyme-linked immunosorbent assay (ELISA) has been the mainstay method for βA42 measurement on cerebrospinal fluid (CSF). Recently, a new βA42 measurement method in chemiluminescence enzyme immunoassay (CLEIA) is available on Lumipulse G 600 II automatic platform. The aim of the work was to evaluate the concordance of the ELISA and the new method (CLEIA) in the CSF βA42 levels measurement. Materials and methods CSF βA42 levels were assayed in 49 samples using the ELISA method (Innotest β- amyloid 1–42, Fujirebio Europe N.V., Gent, Belgium) and CLEIA method on Lumipulse G600II fully automatic platform (Lumipulse G β- amyloid 1–42, Fujirebio Europe N.V., Gent, Belgium). We compared values of the two methods using acceptability interval based on Inherent Combined Imprecision (ICI), the Passing-Bablok regression analysis, the Pearson correlation coefficient (r) and the Bland-Altman plot. Results The analysis of the ICI showed that the two methods differ substantially. The regression equation (y = −103.04 + 1.52×) highlighted the presence of proportional systematic difference, without significant deviation from linearity (p = .42). The Pearson correlation coefficient was 0.826. The Bland-Altman plot analysis showed a significant systematic difference in the two methods: ELISA measurements were in average –27.06% (95% CI –31.89 to −22.23%) lower compared to CLEIA ones. Conclusions Our study highlighted a difference between the two methods. Therefore, the cut-off for the normal levels of βA42 should be reviewed in the laboratory report.

Frontotemporal dementia (FTD) is a heterogeneous clinical entity that includes several disorders characterized by different cellular mechanisms. Distinctive clinical features in FTD include behavioral, affective, and cognitive symptoms. Unfortunately, little progress has been made over the past 20 years in terms of the development of effective disease-modifying drugs with the currently available symptomatic treatments having limited clinical utility.This article reviews the principal pharmacological intervention studies for FTD. These are predominantly randomized clinical trials and include symptomatic treatments and potential disease-modifying drugs.There is insufficient evidence on effective treatments for FTD and studies with better methodological backgrounds are needed. Most studies reporting therapeutic benefits were conducted with selective serotonin reuptake inhibitors, while anti-dementia drugs have been ineffective in FTD. Since the underlying pathology of FTD mostly consists of abnormal tau protein or TDP-43 aggregates, treatments are being developed to interfere with their aggregation process or with the clearance of these proteins. Furthermore, disease-modifying treatments remain years away as demonstrated by the recent negative Phase III findings of a tau aggregation inhibitor (LMTM) for treating the behavioral variant of FTD. The results from current ongoing Phase I/II trials will hopefully give light to future treatment options.

ObjectiveThe goal of the present work, based on a collaborative research registry in Italy (the Salento-Brescia Registry), was to assess the incidence of frontotemporal lobar degeneration (FTLD) and to define the frequencies of different FTLD phenotypes in the general population.MethodsThe study was conducted from January 1, 2017, to December 31, 2017, in 2 Italian provinces: Lecce (in Puglia) in the south (area 2,799.07 km2, inhabitants 802,082) and Brescia (in Lombardy) in the north (area 4,785.62 km2, inhabitants 1,262,678). During the study period, all new cases of FTLD (incident FTLD) were counted, and all patients' records were reviewed. The incidence was standardized to the Italian general population in 2017.ResultsIn the 2 provinces, 63 patients with FTLD were diagnosed. The incidence rate for FTLD was 3.05 (95% confidence interval [CI] 2.34–3.90) per 100,000 person-years (py), while the age-sex standardized incidence rate was 3.09 (95% CI 2.95–3.23) per 100,000 py. In the Italian population, the lifetime risk was 1:400. There was a progressive increase in FTLD incidence across age groups, reaching its peak in the 75- to 79-year-old group, with an incidence rate of 15.97 (95% CI 8.94–26.33) per 100,000 py. The behavioral variant of frontotemporal dementia was the most common phenotype (37%). No difference in crude incidence rate between the 2 provinces was observed.ConclusionFTLD is a more common form of dementia than previously recognized, with a risk spanning in a wide age range and with maximum incidence in the mid-70s. Improved knowledge of FTLD epidemiology will help to provide appropriate public health service policies.

We have comprehensively documented a case of semantic variant of primary progressive aphasia (sv-PPA) presenting with early-onset pathological gambling (PG). While a growing number of studies have shown the presence of behavioral alterations in patients with sv-PPA, PG has been observed only in the behavioral variant of frontotemporal dementia (bv-FTD). To date, no case of PG with the co-occurrence of prominent semantic deficits at the onset of the disease has been reported in the literature. Impulse disorders at onset may wrongly lead to a misdiagnosis (ie, psychiatric disorders). Therefore, a wider characterization of cognitive/aphasia symptoms in patients presenting impulse disorders and predominant language dysfunctions is recommended.

Recent research on behavioral variant frontotemporal dementia (bvFTD) has shown that personality changes and executive dysfunctions are accompanied by a disease-specific anatomical pattern of cortical and subcortical atrophy. We investigated the structural topological network changes in patients with bvFTD in comparison to healthy controls. In particular, 25 bvFTD patients and 20 healthy controls underwent structural 3T MRI. Next, bilaterally averaged values of 34 cortical surface areas, 34 cortical thickness values, and six subcortical volumes were used to capture single-subject anatomical connectivity and investigate network organization using a graph theory approach. Relative to controls, bvFTD patients showed altered small-world properties and decreased global efficiency, suggesting a reduced ability to combine specialized information from distributed brain regions. At a local level, patients with bvFTD displayed lower values of local efficiency in the cortical thickness of the caudal and rostral middle frontal gyrus, rostral anterior cingulate, and precuneus, cuneus, and transverse temporal gyrus. A significant correlation was also found between the efficiency of caudal anterior cingulate thickness and Mini-Mental State Examination (MMSE) scores in bvFTD patients. Taken together, these findings confirm the selective disruption in structural brain networks of bvFTD patients, providing new insights on the association between cognitive decline and graph properties.

Background: The etiology of frontotemporal dementia (FTD) is poorly understood. To identify genes with predicted expression levels associated with FTD, we integrated summary statistics with external reference gene expression data using a transcriptome-wide association study approach. Methods: FUSION software was used to leverage FTD summary statistics (all FTD: n = 2154 cases, n = 4308 controls; behavioral variant FTD: n = 1337 cases, n = 2754 controls; semantic dementia: n = 308 cases, n = 616 controls; progressive nonfluent aphasia: n = 269 cases, n = 538 controls; FTD with motor neuron disease: n = 200 cases, n = 400 controls) from the International FTD-Genomics Consortium with 53 expression quantitative loci tissue type panels (n = 12,205; 5 consortia). Significance was assessed using a 5% false discovery rate threshold. Results: We identified 73 significant gene–tissue associations for FTD, representing 44 unique genes in 34 tissue types. Most significant findings were derived from dorsolateral prefrontal cortex splicing data (n = 19 genes, 26%). The 17q21.31 inversion locus contained 23 significant associations, representing 6 unique genes. Other top hits included SEC22B (a gene involved in vesicle trafficking), TRGV5, and ZNF302. A single gene finding (RAB38) was observed for behavioral variant FTD. For other clinical subtypes, no significant associations were observed. Conclusions: We identified novel candidate genes (e.g., SEC22B) and previously reported risk regions (e.g., 17q21.31) for FTD. Most significant associations were observed in dorsolateral prefrontal cortex splicing data despite the modest sample size of this reference panel. This suggests that our findings are specific to FTD and are likely to be biologically relevant highlights of genes at different FTD risk loci that are contributing to the disease pathology.

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins. ispartof: NEUROBIOLOGY OF AGING vol:92 ispartof: location:United States status: published

Funder: QingLan Research Project of Jiangsu for Outstanding Young Teachers, Funder: Project funded by Postdoctoral Science Foundation of Xuzhou Medical University, Funder: Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) for Xuzhou Medical University, We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93–1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53–1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population.

The prevalence of late-life depression (LLD) depends on the study sample, measurements, and diagnostic approaches. We estimated the 30 item-Geriatric Depression Scale (GDS-30) accuracy against the gold standard LLD diagnosis made with the Semi-structured Clinical Diagnostic Interview for DSM-IV-TR Axis I Disorders, focusing on the prevalence of a late-life major depressive disorder (MDD), in a population-based sample of 843 subjects aged65 years, subdivided into three groups: normal cognition, subjective memory complaints, and mild cognitive impairment. At the optimal cut-off score (≥4), the GDS-30 showed 65.1% sensitivity and 68.4% specificity for LLD (63% and 66% for late-life MDD, respectively). Using the standard cut-off score (≥10), the GDS-30 specificity reached 91.2%, while sensitivity dropped to 37.7%, indicating a lower screening accuracy [area under the curve(AUC):0.728, 95% confidence interval(CI):0.67-0-78]. The GDS-30 performance was associated with educational level, but not with age, gender, cognition, apathy, and somatic/psychiatric multimorbidity. For subjective memory complaints subjects, at the optimal cut-off score (≥7), the GDS-30 showed better discrimination performances (AUC=0.792,95%CI:0.60-0.98), but again the educational level affected the diagnostic performance. In subjective memory complaints subjects, symptom-based scales like the GDS-30 may feature a better performance for diagnosing depression in older age, but the GDS-30 seems to require adjustment to the patient's educational level.

We assessed nigral dorsolateral hyperintensity (swallow tail sign) at susceptibility-weighted imaging using 3T-MRI in 15 dementia with Lewy bodies (DLB), 11 Alzheimer's disease (AD), and 8 frontotemporal dementia (FTD) patients and 10 subjects with subjective memory complaint (SMC). More DLB patients lacked nigral hyperintesity (p < 0.05). Sensitivity, specificity, and accuracy of DLB diagnosis were, respectively: 80%, 64%, and 73% versus AD; 80%, 75%, and 78% versus FTD; and 80%, 90%, and 84% versus SMC. Considering bilateral loss, sensitivity decreased (53%) but specificity increased (82-100%). Swallow tail sign loss, especially if bilateral, can be useful for DLB diagnosis.

We explored the associations of age-related central auditory processing disorder (CAPD) with mild cognitive impairment (MCI) and dementia in an older population-based cohort in Apulia, Southern Italy (GreatAGE Study).Cross-sectional data from a population-based study.Castellana Grotte, Bari, Italy.Between 2013 and 2018, MCI, dementia, age-related CAPD (no disabling hearing loss and50% score on the SSI-ICM test [Synthetic Sentence Identification-Ipsilateral Competing Message]), neurologic and neuropsychological examinations, and serum metabolic biomarkers assays were investigated on 1647 healthy volunteers aged65 years.The prevalences of age-related CAPD, MCI, and dementia were 14.15%, 15.79%, and 3.58%, respectively. Among the subjects with MCI and dementia, 19.61% and 42.37% had age-related CAPD. In the regressive models, age-related CAPD was associated with MCI (odds ratio, 1.50; 95% CI, 1.01-2.21) and dementia (odds ratio, 2.23; 95% CI, 1.12-4.42). Global cognition scores were positively associated with increasing SSI-ICM scores in linear models. All models were adjusted for demographics and metabolic serum biomarkers.The tight association of age-related CAPD with MCI and dementia suggests the involvement of central auditory pathways in neurodegeneration, but it is not clear which is the real direction of this association. However, CAPD is a possible diagnostic marker of cognitive dysfunction in older patients.

Background In clinical practice, the use of plasma β-Amyloid1–42 (Aβ1–42) as biomarker for Alzheimer's disease is largely limited by the absence of reference values. The aim of this study was to evaluate Aβ1–42 plasma concentrations in cognitively normal subjects and to propose reference values. Methods Plasma samples were obtained from 245 subjects, with a wide age-range (19–89 years), enrolled at the Unit of Laboratory Medicine of the “Azienda Ospedaliera Cardinale G. Panico” (younger subjects) and from a population-based study on aging (GreatAGE study) (older subjects). Three different age-groups were established: young (≤ 34), adult (35 ≤ age ≤ 64) and old (>64). The Innogenetics Elisa kit for plasma Aβ1–42 was used for the analysis. Results The mean (SD) concentration of plasma Aβ1–42 was 17.65 (5.71) pg/mL. A positive trend was found in Aβ1–42 levels across the three age groups (p Conclusion The present study proposes reference values for plasma Aβ1–42. Nevertheless, further studies are needed to confirm these results and corroborate the use of these reference values in clinical practice.

OBJECTIVE To evaluate whether the presence of pseudobulbar affect (PBA) in an early stage of the disease influences survival in a population-based incident cohort of amyotrophic lateral sclerosis (ALS). METHODS Incident ALS cases, diagnosed according to El Escorial criteria, were enrolled from a prospective population-based registry in Puglia, Southern Italy. The Center for Neurologic Study-Lability Scale (CNS-LS), a self-administered questionnaire, was used to evaluate PBA. Total scores range from 7 to 35. A score ≥13 was used to identify PBA. Cox proportional hazard models were used for survival analysis. The modified C-statistic for censored survival data was used for models' discrimination. RECursive Partitioning and AMalgamation (RECPAM) analysis was used to identify subgroups of patients with different patterns of risk, depending on baseline characteristics. RESULTS We enrolled 94 sporadic ALS, median age of 64 years (range: 26-80). At the censoring date, 65 of 94 (69.2%), 39 of 60 (65.0%), and 26 of 34 (76.5%) patients reached the outcome (tracheotomy/death), in the whole, non-PBA and in the PBA groups, respectively. Kaplan-Meier survival curves for the two subgroups were not significantly different (log-rank test: 1.3, P = .25). The discrimination ability of a multivariable model with demographic and clinical variables of interest was not improved by adding PBA. In the RECPAM analysis, ALSFRSr and the total score of CNS-LS scale (

Background: Speech and language impairments are the key clinical feature in several neurodegenerative disorders and primary progressive aphasia (PPA) is the syndrome where they are the prominent features. Their accurate and early identification may increase the diagnosis in the clinical setting. This approach may allow a better discrimination between the different neurodegenerative disorders and the PPA variants, i.e., nonfluent, semantic, logopenic.Aims: The aim of this work is twofold: (1) to provide an overview of the available neuropsychological tests for the diagnosis of PPA and/or for the differentiation among the PPA variants and (2) to evaluate the methodological quality and the psychometric characteristics of these tests.Methods & Procedures: This review was conducted following PRISMA guidelines. Search terms were chosen based on the research questions and used in a search in two databases. Then, inclusion criteria were formulated and papers meeting the criteria were reviewed. The methodo...

Among metabolic syndrome components, the effects of higher plasma glucose levels on cognitive decline (CD) have been considered in few studies. We evaluated the associations among midlife glycemia, total cholesterol, high-density lipoprotein cholesterol, triglycerides, midlife insulin resistance [homeostasis model assessment for insulin resistance (HOMA-index)], and CD in the older subjects of the population-based MICOL Study (Castellana Grotte, Italy) at baseline (M1) and at follow-ups seven (M2) and twenty years later (M3). At M1, a dementia risk score and a composite cardiovascular risk score for dementia were calculated. For 797 subjects out of 833, we obtained a Mini-Mental State Examination (MMSE) score at M3, subdividing these subjects in three cognitive functioning subgroups: normal cognition, mild CD, and moderate-severe CD. Mean fasting glycemia at baseline was significantly higher in moderate-severe CD subgroup (114.6±71.4 mg/dl) than in the normal cognition subgroup (101.2±20.6). Adjusting for gender, age, and other metabolic components, higher fasting glycemia values both at M1 [odds ratio (OR) = 1.31; 95% confidence interval (CI): 1.08-1.59] and M2 (OR = 1.26; 95% CI: 1.01-1.57) were associated with an increased risk of moderate-severe CD. Mean HOMA index value was significantly higher in the moderate-severe CD subgroup (5.7±9.4) compared to the normal cognition subgroup (2.9±1.4) at M1. The dementia risk probability (MMSE < 24) increased moving through higher categories of the dementia risk score and decreased as long as the cardiovascular score increased. The present findings highlighted the indication to control blood glucose levels, regardless of a diagnosis of diabetes mellitus, as early as midlife for prevention of late-life dementia.

The term frontal lobe syndrome refers to a clinical spectrum of symptoms leading to difficulties in executive, behavioral, and social cognition functions (i.e., empathy and theory of mind), usually associated with functional or structural changes in the prefrontal cortex. In this chapter, we provide an overview of the frontosubcortical circuits, the related clinical syndromes, and the main neurodegenerative diseases leading to cortical dementia with prominent frontal deficits. There is a growing literature on the behavioral and neural correlates of specific deficits related to each of the main components of this clinical syndrome. However, there are a number of issues, and alternative interpretations of frontal lobe syndrome, that have been proposed by different studies, since this term has been used in many ways over the years. A frontal lobe syndrome is reported in numerous neurodegenerative diseases, such as frontotemporal dementia, Alzheimer disease, and Parkinson’s disease.

Bipolar disorder (BD) could represent a prodromal state of frontotemporal dementia (FTD). Two patients affected by lifelong BD with a progressive decline of cognitive functions, behavioral, and neurological signs, reached the early diagnosis of FTD before the age of 60. They were diagnosed as affected by primary progressive aphasia and FTD with parkinsonism, respectively. A diagnosis of FTD should therefore be taken into account, in case of unexpected cognitive and behavioral decline in patients with a long history of BD. Follow-up studies with genetic, neuropsychological, and neuroimaging markers of these BD/FTD patients could further explore some of the underlying association, opening new viable therapeutic options.

Background and purpose A strong association between time to generalization (TTG), considered as the time of spreading of the clinical signs from spinal or bulbar localization to both, and survival was recently identified in patients with amyotrophic lateral sclerosis (ALS). Thus, TTG may be used as an early to intermediate end-point in survival studies. The aim of the present study was to test TTG as a predictor of survival in ALS. Methods This was an observational retrospective study of ALS patients from a tertiary referral centre over a 5-year follow-up period. Results In 212 ALS patients, TTG was associated with time to death/tracheostomy [R 0.62, 95% confidence interval (CI) 0.53–0.70; P < 0.001]. In a time-to-event analysis, longer TTG resulted in lower risk to reach a composite outcome (death or tracheostomy) both in univariate [hazard ratio (HR) 0.98, 95% CI 0.97–0.99] and multivariate Cox analyses (HR 0.98, 95% CI 0.96–0.99). TTG predicted death/tracheostomy at 4 years (C-statistic 0.58; 95% CI 0.53–0.63) and at 5 years (C-statistic 0.58; 95% CI 0.53–0.62). Conclusions Based on the present results from a large clinical cohort, TTG may be used as a new early to intermediate end-point to describe the ALS natural history. TTG may be potentially useful as a new primary outcome measure for clinical trials.

ATENCIÓ: la correcció està també al DDD, cal relacionar??? https://ddd.uab.cat/record/226203 Altres ajuts: The following studies and consortia have contributed to this manuscript. Amsterdam dementia Cohort (ADC): Research of the Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. Genotyping of the Dutch case-control samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW projectnumber 733051061). 100-Plus study: We are grateful for the collaborative efforts of all participating centenarians and their family members and/or relations. This work was supported by Stichting Alzheimer Nederland (WE09.2014-03), Stichting Diorapthe, horstingstuit foundation, Memorabel (ZonMW projectnumber 733050814) and Stichting VUmc Fonds. Genotyping of the 100-Plus Study was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW projectnumber 733051061). German Study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe): This study/publication is part of the German Research Network on Dementia (KND), the German Research Network on Degenerative Dementia (KNDD; German Study on Ageing, Cognition and Dementia in Primary Care Patients; AgeCoDe), and the Health Service Research Initiative (Study on Needs, health service use, costs and health-related quality of life in a large sample of oldest-old primary care patients (85+; AgeQualiDe)) and was funded by the German Federal Ministry of Education and Research (grants KND: 01GI0102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 01GI0434; grants KNDD: 01GI0710, 01GI0711, 01GI0712, 01GI0713, 01GI0714, 01GI0715, 01GI0716; grants Health Service Research Initiative: 01GY1322A, 01GY1322B, 01GY1322C, 01GY1322D, 01GY1322E, 01GY1322F, 01GY1322G). Alfredo Ramirez was partly supported by the ADAPTED consortium: Alzheimer's disease Apolipoprotein Pathology for Treatment Elucidation and Development, which has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115975. Brain compendium: This work was funded by the UK Medical Research Council (13044). P.F.C. is a Wellcome Trust principal Fellow (212219/Z/18/Z) and a UK NIHR Senior Investigator, who receives support from the Medical Research Council Mitochondrial Biology Unit (MC_UU_00015/9), and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.Clinical AD, Sweden: We would like to thank UCL Genomics for performing the genotyping analyses. Danish data: The studies behind the Danish long-lived cases received funding from The National Program for Research Infrastructure 2007 (grant no. 09-063256), the Danish Agency for Science Technology and Innovation, the Velux Foundation, the US National Institute of Health (P01 AG08761), the Danish Agency for Science, Technology and Innovation/The Danish Council for Independent Research (grant no. 11-107308), the European Union's Seventh Framework Programme (FP7/2007-2011) under grant agreement no. 259679, the INTERREG 4 A programme Syddanmark-Schleswig-K.E.R.N. (by EU funds from the European Regional Development Fund), the CERA Foundation (Lyon), the AXA Research Fund, Paris, and The Health Foundation (Helsefonden), Copenhagen, Denmark. The GOYA study was conducted as part of the activities of the Danish Obesity Research Centre (DanORC, www.danorc.dk) and The MRC centre for Causal Analyses in Translational Epidemiology (MRC CAiTE). The genotyping for GOYA was funded by the Wellcome Trust (WT 084762). GOYA is a nested study within The Danish National Birth Cohort which was established with major funding from the Danish National Research Foundation. Additional support for this cohort has been obtained from the Pharmacy Foundation, the Egmont Foundation, The March of Dimes Birth Defects Foundation, the Augustinus Foundation, and the Health Foundation. Fundació ACE (FACE): We would like to thank patients and controls who participated in this project. We are indebted to Trinitat Port-Carbó and her family for their support of Fundació ACE research programs. Fundació ACE collaborates with the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, Spain) and is one of the participating centers of the Dementia Genetics Spanish Consortium (DEGESCO). Agustín Ruiz has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking ADAPTED Grant No. 115975 and by grants PI13/02434 and PI16/01861. Acción Estratégica en Salud, integrated in the Spanish National R + D + I Plan and financed by ISCIII (Instituto de Salud Carlos III)-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER- "Una manera de Hacer Europa"), by Fundación bancaria "La Caixa" and Grifols SA (GR@ACE project). Genetics of Healthy Ageing Study (GEHA - NL): The work described in this paper was funded mainly by the EU GEHA Project contract no. LSHM-CT-2004-503-270. Gothenburg Birth Cohort (GBC) Studies: We would like to thank UCL Genomics for performing the genotyping analyses. The studies were supported by The Stena Foundation, The Swedish Research Council (2015-02830, 2013-8717), The Swedish Research Council for Health, Working Life and Wellfare (2013-1202, 2005-0762, 2008-1210, 2013-2300, 2013-2496, 2013-0475), The Brain Foundation, Sahlgrenska University Hospital (ALF), The Alzheimer's Association (IIRG-03-6168), The Alzheimer's Association Zenith Award (ZEN-01-3151), Eivind och Elsa K:son Sylvans Stiftelse, The Swedish Alzheimer Foundation. International FTD-Genomics Consortium (IFGC): International FTD-Genomics Consortium (IFGC): The authors thank the IFGC for providing relevant data to support the analyses presented in this manuscript. Further acknowledgments for IFGC (https://ifgcsite.wordpress.com/), e.g. full members list and affiliations, are found in the online supplementary files. IPDGC (​The International Parkinson Disease Genomics Consortium): We also would like to thank all members of the International Parkinson Disease Genomics Consortium (IPDGC). See for a complete overview of members, acknowledgements and funding http://pdgenetics.org/partners. Kompetenznetz Multiple Sklerose (KKNMS): This work was supported by the German Ministry for Education and Research (BMBF) as part of the "German Competence Network Multiple Sclerosis" (KKNMS) (grant nos. 01GI0916 and 01GI0917) and the Munich Cluster for Systems Neurology (SyNergy). TA was supported by the BMBF through the Integrated Network IntegraMent, under the auspices of the e:Med Programme (01ZX1614J). BH was supported by the EU Horizon 2020 project MultipleMS.Longitudinal Aging Study Amsterdam (LASA) is largely supported by a grant from the Netherlands Ministry of Health, Welfare and Sports, Directorate of Long-Term Care. The authors are grateful to all LASA participants, the fieldwork team and all researchers for their ongoing commitment to the study. Leiden Longevity Study: This study was supported by a grant from the Innovation-Oriented Research Program on Genomics (SenterNovem IGE05007), the Centre for Medical Systems Biology, and the Netherlands Consortium for Healthy Ageing (Grant 050-060-810), all in the framework of the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NWO) and by Unilever Colworth.Maria Carolina Dalmasso: Georg Forster Research Award (Alexander von Humboldt Foundation). Mayo Clinic AD, DLB, PD, PSP: We thank the patients and their families for their participation, without whom these studies would not have been possible. Funding for this work was supported by National Institute on Aging [RF AG051504 to NET.; U01 AG046139 to NET]; and National Institute of Neurological Disorders and Stroke [R01 NS080820 to NET; P50 NS072187]. The Mayo Clinic is a Lewy Body Dementia Association (LBDA) Research Center of Excellence, American Parkinson Disease Association (APDA) Information and Referral Center and Center for Advanced Research, NINDS Tau Center without Walls (U54-NS100693) and is supported by Mayo Clinic AD and related dementias genetics program, The Little Family Foundation, the Mangurian Foundation for Lewy body research and NINDS R01 NS078086 (to OAR). The PD program at the Mayo Clinic Florida is also supported by the Mayo Clinic Center for Regenerative Medicine, Mayo Clinic Center for Individualized Medicine, Mayo Clinic Neuroscience Focused Research Team (Cecilia and Dan Carmichael Family Foundation, and the James C. and Sarah K. Kennedy Fund for Neurodegenerative Disease Research at Mayo Clinic in Florida), the gift from Carl Edward Bolch, Jr., and Susan Bass Bolch, and The Sol Goldman Charitable Trust. Samples included in this study are from the brain bank at Mayo Clinic in Jacksonville which is supported by CurePSP The online version of this article (10.1007/s00401-019-02026-8) contains supplementary material, which is available to authorized users.

Mutations in the microtubule-associated protein tau (MAPT) gene cause autosomal dominant frontotemporal lobar degeneration with tau inclusions (FTLD-tau). MAPT p.R406W carriers present clinically with progressive memory loss and neuropathologically with neuronal and glial tauopathy. However, the pathogenic events triggered by the expression of the mutant tau protein remain poorly understood. To identify the genes and pathways that are dysregulated in FTLD-tau, we performed transcriptomic analyses in induced pluripotent stem cell (iPSC)–derived neurons carrying MAPT p.R406W and CRISPR/Cas9-corrected isogenic controls. We found that the expression of the MAPT p.R406W mutation was sufficient to create a significantly different transcriptomic profile compared with that of the isogeneic controls and to cause the differential expression of 328 genes. Sixty-one of these genes were also differentially expressed in the same direction between MAPT p.R406W carriers and pathology-free human control brains. We found that genes differentially expressed in the stem cell models and human brains were enriched for pathways involving gamma-aminobutyric acid (GABA) receptors and pre-synaptic function. The expression of GABA receptor genes, including GABRB2 and GABRG2, were consistently reduced in iPSC-derived neurons and brains from MAPT p.R406W carriers. Interestingly, we found that GABA receptor genes, including GABRB2 and GABRG2, are significantly lower in symptomatic mouse models of tauopathy, as well as in brains with progressive supranuclear palsy. Genome wide association analyses reveal that common variants within GABRB2 are associated with increased risk for frontotemporal dementia (P −3). Thus, our systems biology approach, which leverages molecular data from stem cells, animal models, and human brain tissue can reveal novel disease mechanisms. Here, we demonstrate that MAPT p.R406W is sufficient to induce changes in GABA-mediated signaling and synaptic function, which may contribute to the pathogenesis of FTLD-tau and other primary tauopathies.

Beta-Amyloid 1-42 peptide (βA42) is a cerebro-spinal fluid (CSF) biomarker, key element of the NIA Alzheimer's disease diagnostic criteria. The enzyme-linked immunosorbent assay (ELISA) has been the mainstay method for βA42 measurement on cerebrospinal fluid (CSF). Recently, a new βA42 measurement method in chemiluminescence enzyme immunoassay (CLEIA) is available on Lumipulse G 600 II automatic platform. The aim of the work was to evaluate the concordance of the ELISA and the new method (CLEIA) in the CSF βA42 levels measurement.CSF βA42 levels were assayed in 49 samples using the ELISA method (Innotest β- amyloid 1-42, Fujirebio Europe N.V., Gent, Belgium) and CLEIA method on Lumipulse G600II fully automatic platform (Lumipulse G β- amyloid 1-42, Fujirebio Europe N.V., Gent, Belgium). We compared values of the two methods using acceptability interval based on Inherent Combined Imprecision (ICI), the Passing-Bablok regression analysis, the Pearson correlation coefficient (r) and the Bland-Altman plot.The analysis of the ICI showed that the two methods differ substantially. The regression equation (y = -103.04 + 1.52×) highlighted the presence of proportional systematic difference, without significant deviation from linearity (p = .42). The Pearson correlation coefficient was 0.826. The Bland-Altman plot analysis showed a significant systematic difference in the two methods: ELISA measurements were in average -27.06% (95% CI -31.89 to -22.23%) lower compared to CLEIA ones.Our study highlighted a difference between the two methods. Therefore, the cut-off for the normal levels of βA42 should be reviewed in the laboratory report.

Background Most studies focused on only one measure of social dysfunction in older age, without proper validation and distinction across different dimensions including subjectivity, structural, and functional aspects. Objective We sought to validate the Social Dysfunction Rating Scale (SDRS) and its factorial structure, also determining the association of SDRS with cognitive functions, global psychopathology, and social deprivation. Methods The SDRS was administered to 484 Italian community-dwelling elderly, recruited in the GreatAGE study, a population-based study on aging conducted in Castellana Grotte, Bari, Southern Italy. We determined objective and subjective psychometric properties of SDRS against the gold standard evaluation of social dysfunction according to the Semi-structured Clinical Diagnostic Interview for DSM-IV-TR Axis I Disorders (SCID-I) criterion. Results The SDRS showed a moderate accuracy with an optimal cut-off of 26 maximized with higher sensitivity (0.74,95% CI:0.63-0.84) than specificity (0.57,95% CI:0.50-0.64). A five-factor structure was carried out and five dimensions of SDRS were identified (loneliness; social isolation; feeling of contribution/uselessness; lack of leisure activities; anxiety for the health). Education and global cognitive functions were inversely correlated to SDRS, while a direct association with global psychopathology, depression, and apathy was found. The prevalence of higher SDRS scores was major in subjects with current psychiatric disorders versus other subjects.∥Conclusion: The SDRS could be a valid instrument to capture both size and quality of social dysfunction, both in subjects with psychiatric disorders and in normal subjects. Several categories of social dysfunction differed only in the degree of health deprivation, not in social or material deprivation.

In clinical practice, the use of plasma β-Amyloid1-42 (AβPlasma samples were obtained from 245 subjects, with a wide age-range (19-89 years), enrolled at the Unit of Laboratory Medicine of the "Azienda Ospedaliera Cardinale G. Panico" (younger subjects) and from a population-based study on aging (GreatAGE study) (older subjects). Three different age-groups were established: young (≤ 34), adult (35 ≤ age ≤ 64) and old (64). The Innogenetics Elisa kit for plasma AβThe mean (SD) concentration of plasma AβThe present study proposes reference values for plasma Aβ

The recent failure of several clinical trials on anti-β-amyloid (Aβ) drugs in Alzheimer's disease (AD) suggested earlier intervention in the disease course. Secondary prevention trials have been started in autosomal-dominant AD (ADAD) individuals without cognitive dysfunction and in cognitively healthy subjects at risk of developing sporadic AD (SAD).Herein, the authors discuss prevention trials in ADAD and SAD, with a focus on the anti-Aβ monoclonal antibodies solanezumab and gantenerumab presently in Phase III clinical development. These therapies are also being tested in the Dominantly Inherited Alzheimer's Network Trials Unit (DIAN-TU).Anti-Aβ monoclonal antibodies are being tested in subjects at the preclinical stage of ADAD and even in symptom-free subjects at risk of developing SAD. The subsequent DIAN-TU Adaptive Prevention Trial is a 4-year study that will assess whether such biomarker effects may stop the progress of the AD process, preventing cognitive symptoms. The hope is to interfere in the disease course when it is not too late. A clinical success of these prevention trials would represent the proof of the Aβ hypothesis of AD.

We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05–21.6; P=1 × 10−4) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10−7). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08–1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies., Relatives of patients with amyotrophic lateral sclerosis have an unexpectedly high incidence of schizophrenia. Here, the authors show a genetic link between the two conditions, suggesting shared neurobiological mechanisms.

Age-related hearing loss (ARHL) and dementia are two highly prevalent conditions in the adult population. Recent studies have suggested that hearing loss is independently associated with poorer cognitive functioning. The aim of this study was to evaluate the prevalence of ARHL and cognitive impairment in a large sample of subjects older than 65 years and to correlate hearing function with cognitive function. A total of 488 subjects older than 65 years (mean age 72.8 years) participating in the Great Age Study underwent a complete audiological, neurological and neuropsychological evaluation as part of a multidisciplinary assessment. The prevalence of a hearing loss greater than 25 dB HL was 64.1%, of Central Auditory Processing Disorder (CAPD) was 14.3 and 25.3% of the subjects reported a hearing handicap as reported on the Hearing Handicap Inventory for the Elderly Screening Version questionnaire. Multiple logistic regression analysis corrected for gender, age and education duration showed that mild cognitive impairment (MCI) was significantly associated with hearing impairment (CAPD and hearing threshold; odds ratio 1.6, p = 0.05) and that Alzheimer's disease (AD) was significantly associated with CAPD (odds ratio 4.2, p = 0.05). Given that up to 80% of patients affected by MCI convert to AD, adding auditory tests to a screening cognitive battery might have value in the early diagnosis of cognitive decline.

Introduction We investigated the clinical differences between familial and sporadic frontotemporal dementia (FTD), screening for mutations in known FTD genes. Methods We diagnosed 22 affected individuals belonging to eight families and 43 sporadic cases with FTD in Apulia, Southern Italy, in 2 years. Mutations in common causative FTD genes ( GRN , MAPT , VCP , and TARDBP ) and C9ORF72 expansions were screened. Results Behavioral variant of FTD was the most common clinical subtype (50% and 69% in familial and sporadic cases, respectively). Social conduct impairment/disinhibition, loss of insight, and inflexibility were the most frequent clinical features observed at onset. One new mutation was identified in GRN in family A. Discussion Disease onset in sporadic FTD was more frequently characterized by a clustering of behavioral symptoms with apathy and loss of personal hygiene. Mutations in common causative FTD genes are not a major cause of familial and sporadic FTD in the Southern Italian population.

Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved., To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.

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

The objective of the study was to present a detailed clinical, genetic, and epigenetic characterization of 2 amyotrophic lateral sclerosis (ALS) concordant dizygotic twins. The described cases underwent clinical and paraclinical examinations according to the motor neuron disease protocol of our referral center. Mutation analysis of the major causative genes related to ALS was performed. The methylation profile of the CpG island located in the promoter region of C9orf72 and in the repeat region itself was investigated by bisulfite sequencing of C9orf72 expansion carriers. The described cases presented an overlapping phenotype. Genetic analysis revealed the presence of an abnormal (>50 repeats) G(4)C(2)-repeat expansion in C9orf72. Both the direct bisulfite sequencinge-sensitive and the methylation-sensitive HhaI assays did not reveal any DNA methylation at the CpG island 5 ' of the G(4)C(2) repeat in C9orf72. The (G(4)C(2)) n methylation assay indicated that also the expansion itself was not methylated in both twins, suggesting a probably intermediate allele expansion. This is the first report of ALS-concordant dizygotic twins carrying a C9orf72 expansion probably of intermediate length, and with a detailed clinical and genetic characterization. Twin studies add significant information about the mechanisms of C9orf72 expansion pleiotropism, probably driven by genetic, epigenetic, and environmental factors. (C) 2018 Elsevier Inc. All rights reserved.

Background:We detected the general level of knowledge about the early diagnosis of Alzheimer's disease (AD) and subsequent care in general practitioners (GPs) from Southern Italy. We explored also the GP perception about their knowledge and training on diagnosis and management of AD.Methods:On a sample of 131 GPs, we administered two questionnaires: the GP-Knowledge, evaluating GPs’ expertise about AD epidemiology, differential diagnosis, and available treatments, and the GP-QUestionnaire on Awareness of Dementia (GP-QUAD), assessing the GPs’ attitudes, awareness, and practice regarding early diagnosis of dementia.Results:Specific screening tests or protocols to diagnose and manage dementia were not used by 53% of our GPs. The training on the recognition of early AD signs and symptoms was considered inadequate by 55% of the participants. Females were more likely to consider their training insufficient (58%) compared to males (53%). Female GPs were less likely to prescribe antipsychotic drugs to control neuropsychiatric symptoms (NPS) and suggest specialist advice in late stage of cognitive impairment. Multiple Correspondence Analysis (MCA) performed only on GP-QUAD suggested two dimensions explaining 26.1% (“GP attitude”) and 20.1% (“GP knowledge”) of the inertia for a total of 46.2%,Conclusion:In our survey on GP clinical practice, several problems in properly recognizing early AD symptoms and subsequently screening patients to be referred to secondary/tertiary care centers for diagnosis confirmation have emerged. In the future, specific training programs and educational projects for GPs should be implemented also in Italy to improve detection rates and management of dementia in primary care.

Neuropathogical hallmarks of Alzheimer’s disease (AD) are intracellular neurofibrillary tangles (NFTs) composed of paired helical filaments (PHFs) and straight filaments partly constituted of hyper...

Background: The investigator is faced with several challenges when planning a randomized clinical trial (RCT). In the early phase, issues are particularly challen

Heterozygous loss of function mutations in granulin represent a significant cause of frontotemporal lobar degen- eration with ubiquitin and TDP-43 inclusions (FTLD-TDP). We report a novel GRN splice site mutation (c.709-2 A>T), segregating with frontotemporal dementia spectrum in a large family from southern Italy. The GRN c.709-2 A>T is predicted to result in the skipping of exon 8, leading to non-sense mediated mRNA decay. Moreover, the PGRN plasma levels in the GRN c.709-2 A>T carriers were significantly lower (24 ng/ml) compared to controls (142.7 ng/ml) or family members non-carriers (82.0 ng/ml) (p-value = 0.005, Kruskal Wallis), suggesting progranulin haploinsufficiency. We do not report any potential pathogenic GRN mutation in a follow-up cohort composed of 6 FTD families and 43 sporadic FTD cases, from the same geographic area. Our study suggests that GRN (c.709-2 A>T) is a novel and likely very rare cause of FTD in this Italian cohort. Finally, in line with previous studies, we show that GRN haploinsufficiency leads to a heterogeneous clinical picture, and plasma progranulin levels may be a reliable tool to identify GRN loss of function mutations. However, given that a) genetic and environmental factors, gender, and age may regulate PGRN plasma levels and b) plasma progranulin levels may not reflect PGRN levels in the central nervous system, we suggest that the measurement of progranulin in the plasma should always be coupled with genetic screening of GRN for mutations.

International audience; The investigator is faced with several challenges when planning a randomized clinical trial (RCT). In the early phase, issues are particularly challenging for RCTs in neurodegenerative disorders (NDD). At the time of inclusion in the study, an early and accurate diagnosis is mandatory. Variability of diagnostic criteria, mostly based on clinical grounds, lag time between onset and enrolment, and phenotypic heterogeneity are the main drivers of diagnostic complexity. High-quality data in terms of diagnostic reliability, phenotypic description, follow-up, and evaluation of outcomes are key determinants and are highly conditioned by the expertise of the investigators and center recruitment rate. Representativeness of NDD patients is mandatory to postulate the generalizability of the results of RCTs. There is, however, a systematic selection bias in terms of age (more likely to be younger), sex (more likely to be male), ethnicity (more likely to be of European/Caucasian origin), and other prognostic factors (more likely to be favorable). In the publication phase, researchers need to report properly all of the main features of the RCT. Consolidated Standards of Reporting Trials (CONSORT) facilitates the report and interpretation of RCTs, but adherence to these guidelines needs to be improved. Several issues discussed in this review may alter the internal and external validity of an RCT. To date, the impact on phenotype at study entry has often been overlooked. A differential effect of the selection of subjects and of specific clinical and nonclinical features needs to be systematically explored in the RCT planning phase.