MCI a verosimile fenotipo FTD: un caso clinico ad esordio tardivo

Una paziente di 75 anni, giungeva in visita geriatrica nel settembre 2013, lamentando sintomatologia ansiosa ingravescente, perdita d\u2019interessi e paure per situazioni non conosciute, esordite dal 2011. In anamnesi si rilevavano una familiarit\ue0 per demenza (ad esordio tardivo) e un episodio di depressione reattiva alla morte del padre. Le scale di valutazione funzionale mostravano una completa preservazione dell\u2019autonomia (ADL 6/6, IADL 8/8), i test cognitivi di screening erano nella norma (MMSE 30/30, CDT 4/5), mentre si obiettivava una deflessione del tono dell'umore (GDS 14/30). Venivano effettuati: test neuropsicologici conclusivi per MCI non amnesico a dominio singolo dis-esecutivo, TC encefalo (lieve ampliamento dei corni frontali dei ventricoli laterali e lieve vasculopatia), RMN encefalo (iniziale atrofia corticale, lieve vasculopatia), PET cerebri (moderato ipometabolismo glucidico corticale bilaterale pre-frontale), genotipizzazione dell\u2019ApoE (e3/e3) e del gene C9ORF72 (assenza di ripetizioni), dosaggio della progranulina (nella norma). Si poneva diagnosi preliminare di MCI in sospetta FTD. La sintomatologia ansioso-depressiva della paziente, risultata resistente a numerose terapie (bromazepam, alprazolam, sertralina, escitalopram, levosulpiride), migliorava con l\u2019introduzione di paroxetina. \ua0 La diagnosi clinica di MCI FTD \ue8 molto complessa, in quanto i sintomi d\u2019esordio sono spesso sovrapponibili a quelli riscontrati in varie patologie psichiatriche. I test neuropsicologici sono fondamentali per una diagnosi precoce, le prove che valutano le funzioni esecutive frontali e/o il linguaggio, possono essere infatti alterate sin dagli stadi precoci. La RMN encefalo permette di escludere patologie organiche che potrebbero essere la causa dei disturbi lamentati dai pazienti (es. tumori o esiti ischemici in sede frontale) e avvalora la diagnosi di FTD nel caso in cui si evidenzi un\u2019atrofia focale dei lobi frontali e/o temporali. Tuttavia, negli stadi iniziali della malattia tale reperto non \ue8 sempre rilevabile, pertanto per supportare la diagnosi si utilizza la PET che pu\uf2 evidenziare un ipometabolismo glucidico in sede fronto-temporale anche quando il parenchima cerebrale \ue8 ancora volumetricamente integro. Ad oggi non esiste un trattamento farmacologico in grado di impedire o di rallentare la progressione di questa patologia neurodegenerativa. La terapia \ue8 pertanto volta al controllo dei disturbi comportamentali e si avvale principalmente degli inibitori selettivi del reuptake della serotonina (SSRI), in quanto nella FTD vi \ue8 una riduzione della concentrazione di serotonina a livello dei circuiti frontali sottocorticali. La diagnosi precoce di FTD \ue8 di fondamentale importanza perch\ue9 consente un approccio terapeutico in grado di migliorare la qualit\ue0 di vita dei pazienti e dei familiari

Diversity and ethics in trauma and acute care surgery teams: results from an international survey

Background: Investigating the context of trauma and acute care surgery, the article aims at understanding the factors that can enhance some ethical aspects, namely the importance of patient consent, the perceptiveness of the ethical role of the trauma leader, and the perceived importance of ethics as an educational subject. Methods: The article employs an international questionnaire promoted by the World Society of Emergency Surgery. Results: Through the analysis of 402 fully filled questionnaires by surgeons from 72 different countries, the three main ethical topics are investigated through the lens of gender, membership of an academic or non-academic institution, an official trauma team, and a diverse group. In general terms, results highlight greater attention paid by surgeons belonging to academic institutions, official trauma teams, and diverse groups. Conclusions: Our results underline that some organizational factors (e.g., the fact that the team belongs to a university context or is more diverse) might lead to the development of a higher sensibility on ethical matters. Embracing cultural diversity forces trauma teams to deal with different mindsets. Organizations should, therefore, consider those elements in defining their organizational procedures. Level of evidence: Trauma and acute care teams work under tremendous pressure and complex circumstances, with their members needing to make ethical decisions quickly. The international survey allowed to shed light on how team assembly decisions might represent an opportunity to coordinate team member actions and increase performance

Weaning practices in phenylketonuria vary between health professionals in Europe

Background: In phenylketonuria (PKU), weaning is considered more challenging when compared to feeding healthy infants. The primary aim of weaning is to gradually replace natural protein from breast milk or standard infant formula with solids containing equivalent phenylalanine (Phe). In addition, a Phe-free second stage L-amino acid supplement is usually recommended from around 6 months to replace Phe-free infant formula. Our aim was to assess different weaning approaches used by health professionals across Europe. Methods: A cross sectional questionnaire (survey monkey (R)) composed of 31 multiple and single choice questions was sent to European colleagues caring for inherited metabolic disorders (IMD). Centres were grouped into geographical regions for analysis. Results: Weaning started at 17-26 weeks in 85% (n=81/95) of centres, > 26 weeks in 12% (n=11/95) and 26 weeks. First solids were mainly low Phe vegetables (59%, n=56/95) and fruit (34%, n=32/95). A Phe exchange system to allocate dietary Phe was used by 52% (n=49/95) of centres predominantly from Northern and Southern Europe and 48% (n=46/95) calculated most Phe containing food sources (all centres in Eastern Europe and the majority from Germany and Austria). Some centres used a combination of both methods. A second stage Phe-free L-amino acid supplement containing a higher protein equivalent was introduced by 41% (n=39/95) of centres at infant age 26-36 weeks (mainly from Germany, Austria, Northern and Eastern Europe) and 37% (n=35/95) at infant age > 1y mainly from Southern Europe. 53% (n=50/95) of centres recommended a second stage Phe-free L-amino acid supplement in a spoonable or semi-solid form. Conclusions: Weaning strategies vary throughout European PKU centres. There is evidence to suggest that different infant weaning strategies may influence longer term adherence to the PKU diet or acceptance of Phe-free L-amino acid supplements; rendering prospective long-term studies important. It is essential to identify an effective weaning strategy that reduces caregiver burden but is associated with acceptable dietary adherence and optimal infant feeding development.Peer reviewe

Early feeding practices in infants with phenylketonuria across Europe

Background: In infants with phenylketonuria (PKU), dietary management is based on lowering and titrating phenylalanine (Phe) intake from breast milk or standard infant formula in combination with a Phe-free infant formula in order to maintain blood Phe levels within target range. Professionals use different methods to feed infants with PKU and our survey aimed to document practices across Europe. Methods: We sent a cross sectional, survey monkey (R) questionnaire to European health professionals working in IMD. It contained 31 open and multiple-choice questions. The results were analysed according to different geographical regions. Results: Ninety-five centres from 21 countries responded. Over 60% of centres commenced diet in infants by age 10 days, with 58% of centres implementing newborn screening by day 3 post birth. At diagnosis, infant hospital admission occurred in 61% of metabolic centres, mainly in Eastern, Western and Southern Europe. Breastfeeding fell sharply following diagnosis with only 30% of women still breast feeding at 6 months. 53% of centres gave pre-measured Phe-free infant formula before each breast feed and 23% alternated breast feeds with Phe-free infant formula. With standard infant formula feeds, measured amounts were followed by Phe-free infant formula to satiety in 37% of centres (n = 35/95), whereas 44% (n = 42/95) advised mixing both formulas together. Weaning commenced between 17 and 26 weeks in 85% centres, >= 26 weeks in 12% and <17 weeks in 3%. Discussion: This is the largest European survey completed on PKU infant feeding practices. It is evident that practices varied widely across Europe, and the practicalities of infant feeding in PKU received little focus in the PKU European Guidelines (2017). There are few reports comparing different feeding techniques with blood Phe control, Phe fluctuations and growth. Controlled prospective studies are necessary to assess how different infant feeding practices may influence longer term feeding development.Peer reviewe

Diversity and ethics in trauma and acute care surgery teams: results from an international survey

Background Investigating the context of trauma and acute care surgery, the article aims at understanding the factors that can enhance some ethical aspects, namely the importance of patient consent, the perceptiveness of the ethical role of the trauma leader, and the perceived importance of ethics as an educational subject. Methods The article employs an international questionnaire promoted by the World Society of Emergency Surgery. Results Through the analysis of 402 fully filled questionnaires by surgeons from 72 different countries, the three main ethical topics are investigated through the lens of gender, membership of an academic or non-academic institution, an official trauma team, and a diverse group. In general terms, results highlight greater attention paid by surgeons belonging to academic institutions, official trauma teams, and diverse groups. Conclusions Our results underline that some organizational factors (e.g., the fact that the team belongs to a university context or is more diverse) might lead to the development of a higher sensibility on ethical matters. Embracing cultural diversity forces trauma teams to deal with different mindsets. Organizations should, therefore, consider those elements in defining their organizational procedures. Level of evidence Trauma and acute care teams work under tremendous pressure and complex circumstances, with their members needing to make ethical decisions quickly. The international survey allowed to shed light on how team assembly decisions might represent an opportunity to coordinate team member actions and increase performance

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Atrial fibrillation: possible influences of rate/rhytm control strategy on cognitive performance

Growing evidence suggests that cognitive impairment and the severity of dementia are amplified in patients with atrial fibrillation (AF), independent of clinical stroke and other co-morbid conditions (1). This link is probably multifactorial with emboli, micro-bleedings, decreased cerebral perfusion (secondary to reduced cardiac output and heart rate variability), and inflammation potentially being involved (2). Rhythm control [through electrical cardioversion (3) or ablate-and-pace strategy (4)] seems to improve cardiac output, cerebral blood flow (3), and cognitive function (4). At the same time, heart rate control strategy can also exert protective effects on cognition. In fact, the reduction of the heart rate variability and the achievement of an optimal heart rate may guarantee an improved cerebral perfusion. It has been demonstrated that both low and high ventricular response rates are predictive of dementia (5). We hypothesize that cognition might be differently affected with the therapeutic choice of controlling rate versus rhythm in older persons with AF. Thus, in the present study, we analyse whether rate or rhythm control strategy may have an impact on cognition in older patients with AF, taking advantage of a large cohort of hospitalized persons. Retrospective analysis of the REPOSI database (6). People aged 65 years or more affected by AF prior to hospital admission to Italian internal medicine and geriatric wards in the years 2010, 2012, 2014 were enrolled. Patients with AF and/or atrial flutter were selected according to the diagnosis or indication for anti-arrhythmic drugs at their hospital admission. Patients diagnosed for the first time with AF during the hospitalization were excluded from the analyses. Patients with AF were classified into 3 groups: rate control, rhythm control (including patients on rhythm control therapy and those receiving drugs for both rhythm and rate control), and no therapy of interest (i.e., patients taking neither rate nor rhythm control drugs). Cognitive performance was evaluated with short blessed test (SBT). The patient socio-demographic characteristics were compared using univariate analysis by means of Chi-squared tests for categorical variables, and ANOVA for continuous variables. Logistic regression models adjusted for age, sex, education, anticoagulant/antiplatelet therapy, and comorbidities were used. RISULTATI: The study sample included 1,082 patients. Figure\ua01 shows the main characteristics of the study population. Less than half of the patients were treated with an oral anticoagulant both in the total sample (n=436, 40.3%) as well as in the different rhythm/rate control strategy groups (rhythm control n=86, 31.7%; rate control n=162, 48.9%; no therapy of interest n=188, 39.2%). Rhythm control strategy was protective versus the development of cognitive impairment (OR 0.56, 95%CI 0.40\u20130.79, p=0.001). Older age was associated with an increased risk of presenting cognitive impairment (adjusted OR 2.87, 95%CI 1.93-4.27; p<0.001), whereas education was protective (adjusted OR 0.50, 95%CI 0.35\u20130.62; p<0.001). Anticoagulant and/or anti-platelet therapy was associated to a non-statistically significant reduction in the risk of cognitive impairment. Results were similar using both SBT cut points. Our study shows that rhythm control strategy is associated with a lower risk of cognitive impairment. To date, only a sub-study of the AFFIRM trial\ua0(7) has explored the differences between pharmacological rhythm and rate control strategy on cognition, without founding significant results between the two groups. However, the population of the AFFIRM trial was younger (69.8\ub18.8 years vs 80.6\ub17 years) and with a better cognitive performance (MMSE score: 28.3\ub12.2 in the rate control group and 27.3\ub12.6 in the rhythm control group) whereas in our sample patients in all groups had a mean SBT score consistent with at least a questionable cognitive impairment. Moreover, on the contrary of what found in our study, anticoagulation was elevated in the AFFIRM trial, thus limiting the possible deleterious effects of microembolizations and strokes on cognition. Differently from what previously reported (5), rate control did not seem to play a protective effect on cognition in our sample. However, whereas in the AFFIRM trial participants in the rate control group had to achieve specific heart rate targets, we are unable to speculate on heart frequency of our sample. Inadequate heart frequency (both too high or too low) may explain the worse cognitive function detected in the rate control compared to other groups. The possible protective effect of rhythm control on cognition is even more relevant if it is taken into account the fact that the rhythm control group in our study was the one with the lowest prevalence of anticoagulant use

Repeated CSF removal procedures in older patients with iNPH ineligible for surgical treatment

Introduction: shunt interventions represent the key treatment of Idiopathic Normotensive Hydrocephalus (iNPH)[1], but are complicated by high costs, risk of complications[2,3], and temporary benefits[4,5], especially in frail older people. Consecutive cerebral spinal fluid removal procedures (CSF TAP test) have been used to relieve patients\u2019 symptoms and predict surgery responsiveness. We evaluated the effect of repeated CSF TAP tests in older iNPH patients ineligible for surgery. Methods: prospective, monocentric, pilot study performed in a tertiary hospital of Milan, between 2011 and 2016. Inclusion criteria: age 65 75 years; positive criteria for probable iNPH[6]; ineligibility for surgery. Exclusion criteria: secondary hydrocephalus, Mini Mental State Examination (MMSE) < 20, gait disorders secondary to other causes. Pre-CSF TAP test evaluation included: Barthel index, continence, Performance-Oriented Mobility Assessment (POMA), Timed Up and Go (TUG) test, and MMSE. All the tests were periodically repeated during the follow-up. Every peri-procedural adverse event was recorded Results: Twenty-eight of the 39 enrolled patients (mean age 82.5 \ub14.7 years; women 43.5%) showed an improvement in Barthel, TUG, POMA and MMSE scores after the drainage procedures, whereas continence was poorly influenced over the follow-up (median 31 months). No major adverse event was recorded from the total 83 procedures. The mean period of functional benefit between procedures was 7 months. Patients who chose to interrupt the study for subjective reasons showed a more rapid worsening of the health status over time. Key conclusions: periodic CSF TAP tests are safe, allow to control iNPH symptoms and improve functional status in geriatric patients

Contrast-enhanced versus conventional and color doppler sonography for the detection of thrombosis of the portal and hepatic venous systems

We conducted a prospective study to compare sonography, color Doppler sonography, and contrast-enhanced sonography for the detection and characterization of portal and hepatic vein thrombosis complicating hepatic malignancies. SUBJECTS AND METHODS: Three hundred sixteen patients with biopsy-proved hepatic tumors were studied at baseline and 3 months later with sonography, color Doppler sonography, and contrast-enhanced sonography. Thrombosis was defined as the presence of intraluminal echogenic material at sonography, absence of intraluminal color signals at color Doppler sonography, and presence of nonenhancing intraluminal area at contrast-enhanced sonography. Thrombi were considered malignant if they displayed continuity with tumor tissue at sonography, intrathrombus color signals at color Doppler sonography, and enhancing signals at contrast-enhanced sonography, both having arterial waveforms at Doppler spectral examination. Definitive diagnoses were obtained by sonographically guided biopsy except for thrombi displaying at conventional sonography unequivocal continuity with tumor tissue. RESULTS: Thrombosis was detected in 79 (25.0%) of 316 patients at baseline and in 83 (26.3%) of 316 patients after 3 months. Eighty-one (97.6%) of the 83 thrombi were malignant. Definitive diagnosis was performed by imaging in 60 (72.3%) of the 83 cases and by biopsy in 23 cases (27.7%). For thrombus detection, contrast-enhanced sonography displayed significantly higher sensitivity than color Doppler sonography (p = 0.004) and borderline superiority over sonography (p = 0.058). For thrombus characterization, contrast-enhanced sonography was significantly more sensitive than color Doppler sonography (p < 0.0005) and conventional sonography (p = 0.02). CONCLUSION: Contrast-enhanced sonography is superior to sonography and color Doppler sonography for the detection and characterization of portal and hepatic vein thrombosis complicating hepatic malignancie