Search

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.

Mutations in the PSEN1 gene are the most common cause of autosomal dominant Alzheimer’s disease, and are characterized by a high phenotype variability. This study describes a five-generation family, with a prevalent late-onset of the disease and a high frequency of depression, in which a new missense mutation (c.789T > G, p.Cys263Trp) in exon 8 of the PSEN1 gene was found. Only the proband presented an early onset at the age of 45 with attention deficit, followed by spatial disorientation, psychiatric symptoms and parkinsonian signs. The other two cases had a late onset of the disease and a typical presentation with memory loss. Both were characterized by a high level of anxiety and depression. The disease course was different with signs of Lewy body dementia for the proband’s mother, and pyramidal involvement and a shorter disease duration for the proband’s maternal aunt. The other eight cases with late-onset dementia and three cases with a long history of depression have been reported in the family pedigree, underlying the high phenotype variability of PSEN1 mutations.

Rationale & Objective In the general population, cognitive impairment is associated with increased mortality, and higher levels of education are associated with lower risks for cognitive impairment and mortality. These associations are not well studied in patients receiving long-term hemodialysis and were the focus of the current investigation. Study Design Prospective cohort study. Setting & Participants Adult hemodialysis patients treated in 20 Italian dialysis clinics. Exposures Patients’ cognitive function across 5 domains (memory, attention, executive function, language, and perceptual-motor function), measured using a neuropsychological assessment comprising 10 tests; and patients’ self-reported years of education. Outcome All-cause mortality. Analytical Approach Nested multivariable Cox regression models were used to examine associations of cognition (any domain impaired, number of domains impaired, and global function score from principal components analysis of unadjusted test scores) and education with mortality and whether there were interactions between them. Results 676 (70.6%) patients participated, with a median age of 70.9 years and including 38.8% women. Cognitive impairment was present in 79.4% (527/664; 95% CI, 76.3%-82.5%). During a median follow-up of 3.3 years (1,874 person-years), 206 deaths occurred. Compared to no cognitive impairment, adjusted HRs for mortality were 1.77 (95% CI, 1.07-2.93) for any impairment, 1.48 (95% CI, 0.82-2.68) for 1 domain impaired, 1.88 (95% CI, 1.01-3.53) for 2 domains, and 2.01 (95% CI, 1.14-3.55) for 3 to 5 domains. The adjusted HR was 0.68 (95% CI, 0.51-0.92) per standard deviation increase in global cognitive function score. Compared with primary or lower education, adjusted HRs were 0.79 (95% CI, 0.53-1.20) for lower secondary and 1.13 (95% CI, 0.80-1.59) for upper secondary or higher. The cognition-by-education interaction was not significant (P = 0.7). Limitations Potential selection bias from nonparticipation and missing data; no data for cognitive decline; associations with education were not adjusted for other socioeconomic factors. Conclusions Cognitive impairment is associated with premature mortality in hemodialysis patients. Education does not appear to be associated with mortality.

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.

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.

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.

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.

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 (

Comprehensive geriatric assessment (CGA) is a multidimensional and multidisciplinary diagnostic process focused on determining the clinical profile, pathological risk, residual skills, short- and long-term prognosis, and personalized therapeutic and care plan of the functionally compromised and frail older subjects. Previous evidence suggested that the effectiveness of CGA programs may be influenced by settings where the CGA is performed [i.e., hospital, posthospital discharge/long-term care facilities (LTCFs), or community/home] as well as the specific clinical conditions of older frail individuals. In this scenario, CGA and quality of care in LTCFs have been a challenge for decades. In the present article, we systematically reviewed evidence from the last three decades of clinical research devoted to systematic implementation of CGA programs in LTCFs, that is, nursing homes, care homes, residential homes, and rehabilitation facilities. In the United States, all LTC residents must undergo a CGA on a regular basis on admission to a facility, prompting the development of the Resident Assessment Instrument (RAI) Minimum Data Set, a specific CGA-based assessment tool in this population. In the LTCF setting, the present reviewed evidence suggested that most complex older subjects may benefit from a CGA in terms of improved quality of care and reduced hospitalization events and that CGA must be standardized across healthcare settings to promote greater health system integration and coordination. In the LTCF setting, particularly in nursing homes, other new and promising CGA programs have also been proposed to develop rapid screening CGA-based tools to enhance in the future the ability of primary care physicians to recognize and treat geriatric syndromes in this setting. However, at present, the interRAI suite of instruments represented an integrated health information system that has the potential to provide person-centered information transcending healthcare settings.

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.

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.

Citizens in an ageing World population are at higher risk of cognitive impairment and dementia with considerable negative consequences for their autonomy and quality of life, that of those who care for them, and the sustainability of health and care systems. Thus, the need for strategies to avoid or delay the process of cognitive decline. Innovative ICT solutions should play a role in tertiary prevention of cognitive decline supporting active and healthy ageing and countering the cognitive decline in the elderly subjects. In this study, we tested whether a computerized cognitive training (CCT) with an application of serious games (computerized neuropsychological battery) may produce an improve of cognitive functions and beneficial enhancement of the resting state eyes-closed electroencephalographic (rsEEG) rhythms deranging typically in Alzheimer’s disease (AD) patients. Ten AD patients were enrolled and completed the 15 daily CCT sessions. Standard neuropsychological testing and rsEEG recordings were performed before and after the CCT program. eLORETA estimated the rsEEG cortical sources. Statistical results (p 0.05) was observed in the rsEEG markers after the CCT program. These preliminary results suggest that the CCT program with this application of serious games may represent a useful and practical approach to slow down the cognitive decline in AD patients even if it has no effect on the cortical neural synchronization mechanisms of rsEEG, possibly because of the impaired integrity of the cholinergic system in these patients.

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

Presbycusis or age related hearing loss (ARHL) is the most common sensory deficit in the elderly. It is a multifactorial condition that involves a multitude of intrinsic and extrinsic factors acting on the inner ear over a lifetime, which cumulatively lead to impairments in cochlear transduction of acoustic signals. ARHL is characterized by a loss of hearing sensitivity and a decreased ability to understand speech in the presence of background noise. Epidemiological studies have shown that in the USA hearing loss prevalence approximately doubles every decade of life from the second through to the seventh decade. In Europe, approximately 30% of males and 20% of females have a hearing loss of 30dB HL or more at age 70 years, and 55% of males and 45% of females at age 80 years. Central auditory processing disorders (CAPD) refer to an impairment in the central auditory pathways that leads to impaired speech understanding. The prevalence of CAPD in subjects older than 65 years has been reported to be b...

A prolonged preclinical phase of more than two decades before the onset of dementia suggested that initial brain changes of Alzheimer's disease (AD) and the symptoms of advanced AD may represent a unique continuum. Given the very limited therapeutic value of drugs currently used in the treatment of AD and dementia, preventing or postponing the onset of AD and delaying or slowing its progression are becoming mandatory. Among possible reversible risk factors of dementia and AD, vascular, metabolic, and lifestyle-related factors were associated with the development of dementia and late-life cognitive disorders, opening new avenues for the prevention of these diseases. Among diet-associated factors, coffee is regularly consumed by millions of people around the world and owing to its caffeine content, it is the best known psychoactive stimulant resulting in heightened alertness and arousal and improvement of cognitive performance. Besides its short-term effect, some case-control and cross-sectional and longitudinal population-based studies evaluated the long-term effects on brain function and provided some evidence that coffee, tea, and caffeine consumption or higher plasma caffeine levels may be protective against cognitive impairment/decline and dementia. In particular, several cross-sectional and longitudinal population-based studies suggested a protective effect of coffee, tea, and caffeine use against late-life cognitive impairment/decline, although the association was not found in all cognitive domains investigated and there was a lack of a distinct dose-response association, with a stronger effect among women than men. The findings on the association of coffee, tea, and caffeine consumption or plasma caffeine levels with incident mild cognitive impairment and its progression to dementia were too limited to draw any conclusion. Furthermore, for dementia and AD prevention, some studies with baseline examination in midlife pointed to a lack of association, although other case-control and longitudinal population-based studies with briefer follow-up periods supported favourable effects of coffee, tea, and caffeine consumption against AD. Larger studies with longer follow-up periods should be encouraged, addressing other potential bias and confounding sources, so hopefully opening new ways for diet-related prevention of dementia and AD.

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.

Objective Convergent evidence indicates that apathy affects cognitive behavior in different neurological and psychiatric conditions. Studies of clinical populations have also suggested the primary involvement of the prefrontal cortex and the basal ganglia in apathy. These brain regions are interconnected at both the structural and functional levels and are deeply involved in cognitive processes, such as working memory and attention. However, it is unclear how apathy modulates brain processing during cognition and whether such a modulation occurs in healthy young subjects. To address this issue, we investigated the link between apathy and prefrontal and basal ganglia function in healthy young individuals. We hypothesized that apathy may be related to sub-optimal activity and connectivity in these brain regions. Methods Three hundred eleven healthy subjects completed an apathy assessment using the Starkstein’s Apathy Scale and underwent fMRI during working memory and attentional performance tasks. Using an ROI approach, we investigated the association of apathy with activity and connectivity in the DLPFC and the basal ganglia. Results Apathy scores correlated positively with prefrontal activity and negatively with prefrontal-basal ganglia connectivity during both working memory and attention tasks. Furthermore, prefrontal activity was inversely related to attentional behavior. Conclusions These results suggest that in healthy young subjects, apathy is a trait associated with inefficient cognitive-related prefrontal activity, i.e., it increases the need for prefrontal resources to process cognitive stimuli. Furthermore, apathy may alter the functional relationship between the prefrontal cortex and the basal ganglia during cognition.

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.

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.

Previous evidence showed a 75.5% best accuracy in the classification of 120 Alzheimer's disease (AD) patients with dementia and 100 matched normal elderly (Nold) subjects based on cortical source current density and linear lagged connectivity estimated by eLORETA freeware from resting state eyes-closed electroencephalographic (rsEEG) rhythms (Babiloni et al., 2016a). Specifically, that accuracy was reached using the ratio between occipital delta and alpha1 current density for a linear univariate classifier (receiver operating characteristic curves). Here we tested an innovative approach based on an artificial neural network (ANN) classifier from the same database of rsEEG markers. Frequency bands of interest were delta (2–4 Hz), theta (4–8 Hz Hz), alpha1 (8–10.5 Hz), and alpha2 (10.5–13 Hz). ANN classification showed an accuracy of 77% using the most 4 discriminative rsEEG markers of source current density (parietal theta/alpha 1, temporal theta/alpha 1, occipital theta/alpha 1, and occipital delta/alpha 1). It also showed an accuracy of 72% using the most 4 discriminative rsEEG markers of source lagged linear connectivity (inter-hemispherical occipital delta/alpha 2, intra-hemispherical right parietal-limbic alpha 1, intra-hemispherical left occipital-temporal theta/alpha 1, intra-hemispherical right occipital-temporal theta/alpha 1). With these 8 markers combined, an accuracy of at least 76% was reached. Interestingly, this accuracy based on 8 (linear) rsEEG markers as inputs to ANN was similar to that obtained with a single rsEEG marker (Babiloni et al., 2016a), thus unveiling their information redundancy for classification purposes. In future AD studies, inputs to ANNs should include other classes of independent linear (i.e., directed transfer function) and non-linear (i.e., entropy) rsEEG markers to improve the classification.

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.

The failure of several Phase II/III clinical trials in Alzheimer’s disease (AD) with drugs targetingβ-amyloid accumulation in the brain fuelled an increasing interest in alternative treatments against tau pathology, including approaches targeting tau phosphatases/kinases, active and passive immunization, and anti-tau aggregation. The most advanced tau aggregation inhibitor (TAI) is methylthioninium (MT), a drug existing in equilibrium between a reduced (leuco-methylthioninium) and oxidized form (MT+). MT chloride (methylene blue) was investigated in a 24-week Phase II clinical trial in 321 patients with mild to moderate AD that failed to show significant positive effects in mild AD patients, although long-term observations (50 weeks) and biomarker studies suggested possible benefit. The dose of 138 mg/day showed potential benefits on cognitive performance of moderately affected AD patients and cerebral blood flow in mildly affected patients. Further clinical evidence will come from the large ongoing Phase III trials for the treatment of AD and the behavioral variant of frontotemporal dementia on a new form of this TAI, more bioavailable and less toxic at higher doses, called TRx0237. More recently, inhibitors of tau acetylation are being actively pursued based on impressive results in animal studies obtained by salsalate, a clinically used derivative of salicylic acid.

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.

Advancing age is the focus of recent studies on familial and sporadic Alzheimer's disease (AD), suggesting a prolonged pre-clinical phase several decades before the onset of dementia symptoms. Influencing some age-related conditions, such as frailty, may have an impact on the prevention of late-life cognitive disorders. Frailty reflects a nonspecific state of vulnerability and a multi-system physiological change with increased risk for adverse health outcomes in older age. In this systematic review, frailty indexes based on a deficit accumulation model were associated with late life cognitive impairment and decline, incident dementia, and AD. Physical frailty constructs were associated with late-life cognitive impairment and decline, incident AD and mild cognitive impairment, vascular dementia, non-AD dementias, and AD pathology in older persons with and without dementia, thus also proposing cognitive frailty as a new clinical condition with co-existing physical frailty and cognitive impairment in non-demented older subjects. Considering both physical frailty and cognitive impairment as a single complex phenotype may be central in the prevention of dementia and its subtypes with secondary preventive trials on cognitive frail older subjects. The mechanisms underlying the cognitive-frailty link are multi-factorial, and vascular, inflammatory, nutritional, and metabolic influences may be of major relevance. There is a critical need for randomized controlled trials of intervention investigating the role of nutrition and/or physical exercise on cognitive frail subjects with the progression to dementia as primary outcome. These preventive trials and larger longitudinal population-based studies targeting cognitive outcomes could be useful in further understanding the cognitive-frailty interplay in older age.

IntroductionThe validity of the 30-item Geriatric Depression Scale (GDS-30) in detecting late-life depression (LLD) requires a certain level of cognitive functioning. Further research is needed in population-based setting on other socio-demographic and cognitive variables that could potentially influence the accuracy of clinician rated depression.ObjectiveTo compare the diagnostic accuracy of two instruments used to assess depressive disorders [(GDS-30) and the Semi-structured Clinical Diagnostic Interview for DSM-IV-TR Axis I Disorders (SCID)] among three groups with different levels of cognitive functioning (normal, Mild Cognitive Impairment – MCI, Subjective Memory Complain – SMC) in a random sampling of the general population 65+ years.MethodsThe sample, collected in a population-based study (GreatAGE Study) among the older residents of Castellana Grotte, South-East Italy, included 844 subjects (54.50% males). A standardized neuropsychological battery was used to assess MCI, SMC and depressive symptoms (GDS-30). Depressive syndromes were diagnosed through the SCID IV-TR. Socio-demographic and cognitive variables were taken into account in influencing SCID performance.ResultsAccording to the SCID, the rate of depressive disorders was 12.56%. At the optimal cut-off score (≥ 4), GDS-30 had 65.1% sensitivity and 68.4% specificity in diagnosing depressive symptoms. Using a more conservative cut-off (≥ 10), the GDS-30 specificity reached 91.1% while sensitivity dropped to 37,7%. The three cognitive subgroups did not differ in the rate of depression diagnosis. Educational level is the only variable associated to the SCID diagnostic performance (P = 0.015).ConclusionsAt the optimal cut-off, GDS-30 identified lower levels of screening accuracy for subjects with normal cognition rather than for SMC (AUC 0.792 vs. 0.692); educational attainment possibly may modulate diagnostic clinician performance.Disclosure of interestThe authors have not supplied their declaration of competing interest.

IntroductionSeveral studies have reported controversial links between swallowing disturbances (SD) and psychiatric disorders in older age. The available data on the epidemiology of SD in the general population are scarce and often conflicting, because of numerous methodological factors source of possible counfounders.ObjectivesWe aimed to screen the presence of psychiatric and cognitive disorders associated with SD in a random sampling of the general population ≥ 65.MethodsA sample of 1127 elderly individuals collected in a population-based study (GreatAGE) in Castellana Grotte (53,50% males, mean age 74.1 ± 6.3 years), South-East Italy, were mailed a validated self-report questionnaire to assess SD (Eating Assessment Tool-EAT10). Psychiatric disorders and symptoms [assessed with Semi-structured Clinical Diagnostic Interview for DSM-IV-TR Axis I Disorders, Geriatric Depression Scale-30 (GDS-30) and Symptom Checklist Revised-90 (SCL-90R)], cognitive functions were assessed with a comprehensive neuropsychological battery, neurological exam, and demographics were compared in participants with and without SD using t-tests and Mann–Whitney U-test.ResultsThe prevalence rates of SD amounted at 5.97%. Psychiatric diagnosis (24.22% of the sample) was statistically significant associated with SD (EAT ≥ 3, P = 0.038), and a trend was found for major depressive disorder and generalized anxiety disorder. Among SCL-90R domains, only anxiety showed a significant association with EAT ≥ 3 (P = 0.006). GDS-30 score was found to be higher in subjects with SD (P = 0.008). Cognitive functions did not differ between the two groups except for an increasing trend for Clinical Dementia Rating Scale in EAT ≥ 3 (P = 0.058).ConclusionsThese preliminary results showed an association between SD in older age and late-life major depression and anxiety disorders.Disclosure of interestThe authors have not supplied their declaration of competing interest.

IntroductionDepression is a common disorder in late-life. Structured clinical interviews may be less efficient compared to self-administered questionnaires, but provide more accurate findings in terms of diagnosis. No population-based studies with both these depression assessment instruments have been ever performed.ObjectivesTo estimate the GDS-30 accuracy for depression assessment against the gold standard [Semi-structured Clinical Diagnostic Interview for DSM-IV-TR Axis I Disorders (SCID)] in subjects 65+ years in a random sampling of the general population.MethodsThe sample was collected in a population-based study (GreatAGE) conducted among elderly residents in Castellana, Southeast Italy. It includes 597 participants (57.62% males, mean age 73 years). Depression was assessed through the GDS-30 and the SCID, both double-blinded administered respectively by a trained neuropsychologist and psychiatrist. The GDS-30 screening performances were analyzed using ROC curves.ResultsAccording to the gold standard SCID, the rate of depressive disorder was 10.22% (15.81% of women; 6.1% of men) while with GDS-30 instrument 12.06% of the residents met the depression cutoff. Only 36.1% of GDS cases were true positive. At the optimal cutoff score (> 5), GDS had 62% sensitivity and 81% specificity. Using a more conservative cutoff (> 9), the GDS-30 specificity reached 91% while sensitivity dropped to 43%.ConclusionsThese preliminary results from the first population-based study that compares GDS-30 and SCID showed that the GDS-30 identified adequate levels of screening accuracy (AUC 0.76) compatible with scores established in community settings.FundingPRIN2009E4RM4Z.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Phenomenological differences between older patients with late- and early-onset depression may reflect differences in aetiology and neuropathological processes involved in these two types of depression. Early- onset depression has been mainly correlated to a family history of depression while late-onset depression has been principally correlated to vascular dysfunction. The same cortical and sub-cortical areas are involved in both types of depression. However, lesions in these brain areas and cognitive impairment are most pronounced in late-onset depression. Based on these observations we propose a common neuroanatomical substrate but different pathophysiological processes implicated in these two types of depression.

Objective The frontal assessment battery (FAB) is a quick and reliable method of screening to evaluate frontal lobe dysfunction in amyotrophic lateral sclerosis (ALS). However, previous studies were generally conducted on small samples representing different stages of disease and severity. We assessed the diagnostic accuracy of the FAB in detecting executive functions and its association with demographic and clinical features in ALS without dementia. Design Retrospective observational study. Setting A multidisciplinary tertiary centre for motor neuron disease. Participants We enrolled 95 consecutive patients with ALS diagnosed with El Escorial criteria in the period between January 2006 and December 2010. Main outcome measures We screened the patients with ALS using the FAB. An Executive Index (EI) was also calculated by averaging the Z scores of analytic executive tests evaluating information-processing speed (Symbol Digit Modalities Test—Oral version), selective attention (Stroop test) and semantic memory (Verbal Fluency Test). Results The FAB detected executive dysfunction in 13.7% of the patients with ALS. Moreover, using the EI standardised cut-off, 37.9% of the patients with ALS showed executive dysfunction. The receiver-operating characteristic curve showed that the optimal cut-off for the FAB in the whole sample was 16, with a sensitivity of 0.889 (95% CIs 0.545 to 1.000), a specificity of 0.593 (95% CI 0.450 to 0.907) and a moderate overall discriminatory power of 0.809. Different levels of respiratory function, duration of disease and depressive symptoms did not affect the FAB validity. Conclusions In patients with ALS without dementia, a high prevalence of executive dysfunction was present. The FAB showed good validity as a screening instrument to detect executive dysfunction in these patients and may be used when a complete neuropsychological assessment is not possible.

Introduction The prevalence of Anxiety Disorders (ADs) among the elderly (65 plus) varies across studies, because of differences in diagnostic criteria's definition and the heterogeneity of clinical presentation. Furthermore the comorbidity of anxiety with affective disorders is controversial. Objectives Estimate the prevalence of ADs in 65 years plus subjects in a random sampling of the general population and provide current estimates of comorbidity with affective disorders. Methods The sample was collected in the Great Age study, a population-based study conducted in a random sampling of the elderly residents in Castellana, South-East Italy. It includes 719 participants (56,33% males). Through the SCID-IVTR interview performed by a psychiatrist, ADs diagnosis and classification in subtypes (phobia, generalized anxiety disorder, OCD, panic disorder, post-traumatic stress disorder, adjustment disorder and AD nos) were assessed. Results The 30,25% of females and 15,30% of males were positive for any DSM-VI disorder. The ADs prevalence was 10,43% (14,97% of women; 6,91% of men; mean age at interview 72 years). Rates prevalence in 65-74 age stratum was 11,78%; 8,1% in 75-84 and 10,26% in the oldest age. The ADs were classified as phobia (1,49%), GAD (2,22%), OCD (0,28%), panic disorder (0,7%), PTSD (0,55%), adjustment disorder (1,67%) and AD nos (3,75%). 21,33% of the ADs had apparently new-onset (Late OnsetADs). Affective disorders occur in 25,33% of ADs. Conclusions The prevalence rates of ADs in late life tend to decline, but remain the most common psychiatric disorders, especially in women. Anxiety co-occurs with affective disorders in similar rate to Late OnsetADs. Founding: PRIN2009E4RM4Z