Gene specific effects on brain volume and cognition of TMEM106B in frontotemporal lobar degeneration.

Background and Objectives: TMEM106B has been proposed as a modifier of disease risk in FTLD-TDP, particularly in GRN mutation carriers. Furthermore, TMEM106B has been investigated as a disease modifier in the context of healthy aging and across multiple neurodegenerative diseases. The objective of this study is to evaluate and compare the effect of TMEM106B on gray matter volume and cognition in each of the common genetic FTD groups and in sporadic FTD patients. Methods: Participants were enrolled through the ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, which includes symptomatic and presymptomatic individuals with a pathogenic mutation in C9orf72, GRN, MAPT, VCP, TBK1, TARDBP, symptomatic non-mutation carriers, and non-carrier family controls. All participants were genotyped for the TMEM106B rs1990622 SNP. Cross-sectionally, linear mixed-effects models were fitted to assess an association between TMEM106B and genetic group interaction with each outcome measure (gray matter volume and UDS3-EF for cognition), adjusting for education, age, sex and CDR®+NACC-FTLD sum of boxes. Subsequently, associations between TMEM106B and each outcome measure were investigated within the genetic group. For longitudinal modeling, linear mixed-effects models with time by TMEM106B predictor interactions were fitted. Results: The minor allele of TMEM106B rs1990622, linked to a decreased risk of FTD, associated with greater gray matter volume in GRN mutation carriers under the recessive dosage model. This was most pronounced in the thalamus in the left hemisphere, with a retained association when considering presymptomatic GRN mutation carriers only. The minor allele of TMEM106B rs1990622 also associated with greater cognitive scores among all C9orf72 mutation carriers and in presymptomatic C9orf72 mutation carriers, under the recessive dosage model. Discussion: We identified associations of TMEM106B with gray matter volume and cognition in the presence of GRN and C9orf72 mutations. This further supports TMEM106B as modifier of TDP-43 pathology. The association of TMEM106B with outcomes of interest in presymptomatic GRN and C9orf72 mutation carriers could additionally reflect TMEM106B's impact on divergent pathophysiological changes before the appearance of clinical symptoms.

Anterior insula is more vulnerable than posterior insula to TDP-43 pathology in common dementias and ALS.

Based on the anatomic proximity, connectivity, and functional similarities between the anterior insula and amygdala, we tested the hypothesis that the anterior insula is an important focus in the progression of TDP-43 pathology in LATE-NC. Blinded to clinical and neuropathologic data, phospho-TDP (pTDP) inclusion pathology was assessed in paired anterior and posterior insula samples in 105 autopsied patients with Alzheimer disease, Lewy body disease, LATE-NC and hippocampal sclerosis (HS), amyotrophic lateral sclerosis (ALS), and other conditions. Insular pTDP pathology was present in 34.3% of the study cohort, most commonly as neuronal inclusions and/or short neurites in lamina II, and less commonly as subpial processes resembling those described in the amygdala region. Among positive samples, pTDP pathology was limited to the anterior insula (41.7%), or occurred in both anterior and posterior insula (58.3%); inclusion density was greater in anterior insula across all diseases (p < .001). pTDP pathology occurred in 46.7% of ALS samples, typically without a widespread TDP-43 proteinopathy. In LATE-NC, it was seen in 30.4% of samples (mostly LATE-NC stages 2 and 3), often co-occurring with basal forebrain pathology and comorbid HS, suggesting this is an important step in the evolution of this pathology beyond the medial temporal lobe.

Reliability and Validity of Smartphone Cognitive Testing for Frontotemporal Lobar Degeneration.

Importance: Frontotemporal lobar degeneration (FTLD) is relatively rare, behavioral and motor symptoms increase travel burden, and standard neuropsychological tests are not sensitive to early-stage disease. Remote smartphone-based cognitive assessments could mitigate these barriers to trial recruitment and success, but no such tools are validated for FTLD. Objective: To evaluate the reliability and validity of smartphone-based cognitive measures for remote FTLD evaluations. Design, Setting, and Participants: In this cohort study conducted from January 10, 2019, to July 31, 2023, controls and participants with FTLD performed smartphone application (app)-based executive functioning tasks and an associative memory task 3 times over 2 weeks. Observational research participants were enrolled through 18 centers of a North American FTLD research consortium (ALLFTD) and were asked to complete the tests remotely using their own smartphones. Of 1163 eligible individuals (enrolled in parent studies), 360 were enrolled in the present study; 364 refused and 439 were excluded. Participants were divided into discovery (n = 258) and validation (n = 102) cohorts. Among 329 participants with data available on disease stage, 195 were asymptomatic or had preclinical FTLD (59.3%), 66 had prodromal FTLD (20.1%), and 68 had symptomatic FTLD (20.7%) with a range of clinical syndromes. Exposure: Participants completed standard in-clinic measures and remotely administered ALLFTD mobile app (app) smartphone tests. Main Outcomes and Measures: Internal consistency, test-retest reliability, association of smartphone tests with criterion standard clinical measures, and diagnostic accuracy. Results: In the 360 participants (mean [SD] age, 54.0 [15.4] years; 209 [58.1%] women), smartphone tests showed moderate-to-excellent reliability (intraclass correlation coefficients, 0.77-0.95). Validity was supported by association of smartphones tests with disease severity (r range, 0.38-0.59), criterion-standard neuropsychological tests (r range, 0.40-0.66), and brain volume (standardized ß range, 0.34-0.50). Smartphone tests accurately differentiated individuals with dementia from controls (area under the curve [AUC], 0.93 [95% CI, 0.90-0.96]) and were more sensitive to early symptoms (AUC, 0.82 [95% CI, 0.76-0.88]) than the Montreal Cognitive Assessment (AUC, 0.68 [95% CI, 0.59-0.78]) (z of comparison, -2.49 [95% CI, -0.19 to -0.02]; P = .01). Reliability and validity findings were highly similar in the discovery and validation cohorts. Preclinical participants who carried pathogenic variants performed significantly worse than noncarrier family controls on 3 app tasks (eg, 2-back ß = -0.49 [95% CI, -0.72 to -0.25]; P < .001) but not a composite of traditional neuropsychological measures (ß = -0.14 [95% CI, -0.42 to 0.14]; P = .32). Conclusions and Relevance: The findings of this cohort study suggest that smartphones could offer a feasible, reliable, valid, and scalable solution for remote evaluations of FTLD and may improve early detection. Smartphone assessments should be considered as a complementary approach to traditional in-person trial designs. Future research should validate these results in diverse populations and evaluate the utility of these tests for longitudinal monitoring.

Research Participants' Perspectives on Precision Diagnostics for Alzheimer's Disease.

BACKGROUND: Understanding research participants' responses to learning Alzheimer's disease (AD) risk information is important to inform clinical implementation of precision diagnostics given rapid advances in disease modifying therapies. OBJECTIVE: We assessed participants' perspectives on the meaning of their amyloid positron emission tomography (PET) imaging results for their health, self-efficacy to understand their results, psychological impact of learning their results, experience receiving their results from the clinical team, and interest in genetic testing for AD risk. METHODS: We surveyed individuals who were being clinically evaluated for AD and received PET imaging six weeks after the return of results. We analyzed responses to close-ended survey items by PET result using Fisher's exact test and qualitatively coded open-ended responses. RESULTS: A total of 88 participants completed surveys, most of whom had mild cognitive impairment due to AD (38.6%), AD (28.4%), or were cognitively unimpaired (21.6%). Participants subjectively understood their results (25.3% strongly agreed, 41.8% agreed), which could help them plan (16.5% strongly agreed, 49.4% agreed). Participants with a negative PET result (n = 25) reported feelings of relief (Fisher's exact p < 0.001) and happiness (p < 0.001) more frequently than those with a positive result. Most participants felt that they were treated respectfully and were comfortable voicing concerns during the disclosure process. Genetic testing was anticipated to be useful for medical care decisions (48.2%) and to inform family members about AD risk (42.9%). CONCLUSIONS: Participants had high subjective understanding and self-efficacy around their PET results and did not experience negative psychological effects. Interest in genetic testing was high.

Malnutrition risk prevalence in hospitalised patients in Castilla-La Mancha: Ten years after the PREDyCES® study.

INTRODUCTION: The PREDyCESR study showed ten years ago that malnutrition is a highly prevalent problem at the hospital level. In the present study we investigate the prevalence of malnutrition in hospitals of Castilla La Mancha and its relationship with complications, mortality and length of hospital stay. METHODS: 433 patients (236 men and 197 women), from 4 hospitals were included and randomised within the first 48 h of admission. Nutritional risk was assessed using the NRS-2002 screening test. RESULTS: The mean age of the patients was 71.3 ±â€¯0.9 years (alpha-trimmed mean ±â€¯insorized standard deviation). Their mean weight was 72.3 ±â€¯0.8 kg and BMI 26.8 ±â€¯0.3 kg/m2. The mean length of hospital stay was 7.2 ±â€¯0.3 days. Of the 433 study patients, 19.4% were defined as 'at-risk' by NRS-2002 > 3. Of the patients at risk, 39.3% received nutritional support. Patients at nutritional risk had an increased length of hospital stay (9.6 vs 6.8 days; p = 0.012) and had more complications and/or higher mortality (40.5% of complications and/or mortality vs 16.4%; p < 0.005). The OR of having a complication and/or death was 3.93 (95% CI: 2.36-6.5); p < 0.005. Regarding the results obtained in the PREDyCES® study, no significant differences were found in the prevalence of nutritional risk at patients' admission (19.4% vs 23%; p = 0.12). CONCLUSIONS: The nutritional risk at hospital admission continues to be high. Patients at nutritional risk have more complications, higher mortality and an increased length of hospital stay.

Feasibility and acceptability of remote smartphone cognitive testing in frontotemporal dementia research.

Introduction: Remote smartphone assessments of cognition, speech/language, and motor functioning in frontotemporal dementia (FTD) could enable decentralized clinical trials and improve access to research. We studied the feasibility and acceptability of remote smartphone data collection in FTD research using the ALLFTD Mobile App (ALLFTD-mApp). Methods: A diagnostically mixed sample of 214 participants with FTD or from familial FTD kindreds (asymptomatic: CDR®+NACC-FTLD = 0 [N = 101]; prodromal: 0.5 [N = 49]; symptomatic ≥1 [N = 51]; not measured [N = 13]) were asked to complete ALLFTD-mApp tests on their smartphone three times within 12 days. They completed smartphone familiarity and participation experience surveys. Results: It was feasible for participants to complete the ALLFTD-mApp on their own smartphones. Participants reported high smartphone familiarity, completed ∼ 70% of tasks, and considered the time commitment acceptable (98% of respondents). Greater disease severity was associated with poorer performance across several tests. Discussion: These findings suggest that the ALLFTD-mApp study protocol is feasible and acceptable for remote FTD research. HIGHLIGHTS: The ALLFTD Mobile App is a smartphone-based platform for remote, self-administered data collection.The ALLFTD Mobile App consists of a comprehensive battery of surveys and tests of executive functioning, memory, speech and language, and motor abilities.Remote digital data collection using the ALLFTD Mobile App was feasible in a multicenter research consortium that studies FTD. Data was collected in healthy controls and participants with a range of diagnoses, particularly FTD spectrum disorders.Remote digital data collection was well accepted by participants with a variety of diagnoses.

Plasma inflammation for predicting phenotypic conversion and clinical progression of autosomal dominant frontotemporal lobar degeneration.

BACKGROUND: Measuring systemic inflammatory markers may improve clinical prognosis and help identify targetable pathways for treatment in patients with autosomal dominant forms of frontotemporal lobar degeneration (FTLD). METHODS: We measured plasma concentrations of IL-6, TNFα and YKL-40 in pathogenic variant carriers (MAPT, C9orf72, GRN) and non-carrier family members enrolled in the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration consortium. We evaluated associations between baseline plasma inflammation and rate of clinical and neuroimaging changes (linear mixed effects models with standardised (z) outcomes). We compared inflammation between asymptomatic carriers who remained clinically normal ('asymptomatic non-converters') and those who became symptomatic ('asymptomatic converters') using area under the curve analyses. Discrimination accuracy was compared with that of plasma neurofilament light chain (NfL). RESULTS: We studied 394 participants (non-carriers=143, C9orf72=117, GRN=62, MAPT=72). In MAPT, higher TNFα was associated with faster functional decline (B=0.12 (0.02, 0.22), p=0.02) and temporal lobe atrophy. In C9orf72, higher TNFα was associated with faster functional decline (B=0.09 (0.03, 0.16), p=0.006) and cognitive decline (B=-0.16 (-0.22, -0.10), p<0.001), while higher IL-6 was associated with faster functional decline (B=0.12 (0.03, 0.21), p=0.01). TNFα was higher in asymptomatic converters than non-converters (ß=0.29 (0.09, 0.48), p=0.004) and improved discriminability compared with plasma NfL alone (ΔR2=0.16, p=0.007; NfL: OR=1.4 (1.03, 1.9), p=0.03; TNFα: OR=7.7 (1.7, 31.7), p=0.007). CONCLUSIONS: Systemic proinflammatory protein measurement, particularly TNFα, may improve clinical prognosis in autosomal dominant FTLD pathogenic variant carriers who are not yet exhibiting severe impairment. Integrating TNFα with markers of neuronal dysfunction like NfL could optimise detection of impending symptom conversion in asymptomatic pathogenic variant carriers and may help personalise therapeutic approaches.

Cellular and environmental dynamics influence species-specific extents of organelle gene retention.

Mitochondria and plastids rely on many nuclear-encoded genes, but retain small subsets of the genes they need to function in their own organelle DNA (oDNA). Different species retain different numbers of oDNA genes, and the reasons for these differences are not completely understood. Here, we use a mathematical model to explore the hypothesis that the energetic demands imposed by an organism's changing environment influence how many oDNA genes it retains. The model couples the physical biology of cell processes of gene expression and transport to a supply-and-demand model for the environmental dynamics to which an organism is exposed. The trade-off between fulfilling metabolic and bioenergetic environmental demands, and retaining genetic integrity, is quantified for a generic gene encoded either in oDNA or in nuclear DNA. Species in environments with high-amplitude, intermediate-frequency oscillations are predicted to retain the most organelle genes, whereas those in less dynamic or noisy environments the fewest. We discuss support for, and insight from, these predictions with oDNA data across eukaryotic taxa, including high oDNA gene counts in sessile organisms exposed to day-night and intertidal oscillations (including plants and algae) and low counts in parasites and fungi.

In Alzheimer-prone brain regions, metabolism and risk-gene expression are strongly correlated.

Neuroimaging in the preclinical phase of Alzheimer's disease provides information crucial to early intervention, particularly in people with a high genetic risk. Metabolic network modularity, recently applied to the study of dementia, is increased in Alzheimer's disease patients compared with controls, but network modularity in cognitively unimpaired elderly with various risks of developing Alzheimer's disease needs to be determined. Based on their 5-year cognitive progression, we stratified 117 cognitively normal participants (78.3 ± 4.0 years of age, 52 women) into three age-matched groups, each with a different level of risk for Alzheimer's disease. From their fluorodeoxyglucose PET we constructed metabolic networks, evaluated their modular structures using the Louvain algorithm, and compared them between risk groups. As the risk for Alzheimer's disease increased, the metabolic connections among brain regions weakened and became more modular, indicating network fragmentation and functional impairment of the brain. We then set out to determine the correlation between regional brain metabolism, particularly in the modules derived from the previous analysis, and the regional expression of Alzheimer-risk genes in the brain, obtained from the Allen Human Brain Atlas. In all risk groups of this elderly population, the regional brain expression of most Alzheimer-risk genes showed a strong correlation with brain metabolism, particularly in the module that corresponded to regions of the brain that are affected earliest and most severely in Alzheimer's disease. Among the genes, APOE and CD33 showed the strongest negative correlation and SORL1 showed the strongest positive correlation with brain metabolism. The Pearson correlation coefficients remained significant when contrasted against a null-hypothesis distribution of correlation coefficients across the whole transcriptome of 20 736 genes (SORL1: P = 0.0130; CD33, P = 0.0136; APOE: P = 0.0093). The strong regional correlation between Alzheimer-related gene expression in the brain and brain metabolism in older adults highlights the role of brain metabolism in the genesis of dementia.

Niveles de riesgo en adolescentes en consumo de tabaco y en actitudes hacia el consumo de drogas después de la intervención preventiva “Programa de Competencia Familiar” / Risk levels among adolescents in tobacco use and in substance use attitudes after the preventive intervention “Family Competence Program”

Introducción: el Programa de Competencia Familiar Universal (PCF-U) es un programa preventivo basado en la evidencia para familias con hijos entre 11 y 14 años. Los objetivos son la reducción o prevención del consumo, la promoción de las relaciones familiares, la promoción de las habilidades parentales y un aumento de las habilidades sociales y personales de los hijos.Método: Diseño cuasi-experimental con grupo control. La muestra final son 305 padres y 262 hijos. La evaluación incluye el Cuestionario sobre Actitudes hacia las Drogas. La evaluación también contiene preguntas sobre el consumo de tabaco y alcohol. Se lleva a cabo un análisis de conglomerados sobre el consumo de tabaco y sobre las actitudes hacia el consumo de drogas.Resultados: el consumo de tabaco desciende después de la intervención. El estadístico sobre las declaraciones sobre consumo de alcohol no es fiable. En actitudes hacia las drogas, la predisposiciónhacia el consumo desciende después de la intervención, pero no es significativa. Las creencias normativas y erróneas cambian, pero no de manera significativa. Sobre los conglomerados, se identificantres niveles de riesgo, 4.7% de los adolescentes pertenecerían al riesgo alto, 24.3% pertenecerían al riesgo medio/medio-bajo y 70.9% pertenecerían al riesgo bajo. Discusión: los resultados generales del PCF-U 11-14 presentados en otros estudios muestran buenos resultados en parentalidad y habilidades familiares. Sin embargo, en consumo de tabaco y alcohol y en actitudes hacia las drogas, sólo el consumo de tabaco tiene un cambio significativo. Quizás el programa es limitado para niveles de riesgo medio y alto. (AU)

Introduction: Universal Family Competence Program is an evidence-based drug preventive intervention in Spain, working with families with children between 11 and 14 years old. Their objectives arereduction or prevention of substance use, promotion of family relationships, promotion of parenting skills, and increase of children personal and social skills. Method: Cuasi-experimental design with control group. Final sample of this study was 305 parents and 262 children. Evaluation instrument includes the Questionnaire about Drug Attitudes, measuring readiness towards substance use, wrong beliefs and normative beliefs. The instrument also contains questions about tobacco and alcohol use. Cluster analysis on tobacco and alcohol use, and drug attitudes is calculated.Results: tobacco use descends after program intervention. Declarations on alcohol use are not reliable. On drug attitudes, readiness towards substance use descends after intervention, but it is notsignificant. Wrong beliefs on drugs decrease, but not in a significant way. Normative beliefs increase, nevertheless not significantly. Regarding cluster analysis, according to their responses to tobacco use and drug attitudes, it is possible to identify three levels of risk. 4.7% of the adolescents interviewed would belong to the high risk level, 24.3% would belong to the middle or middle down level and70.9% would belong to the low risk level.Discussion: general results of the PCF-U 11-14 show good results in family and parenting skills (investigated elsewhere). Nevertheless, when it takes to tobacco and alcohol use and to drug attitudes, only tobacco use results are significant. The program might be slightly short for high and medium risk levels. (AU)

Imaging Neuroinflammation in Neurodegenerative Disorders.

Neuroinflammation plays a major role in the etiopathology of neurodegenerative diseases, including Alzheimer and Parkinson diseases, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis. In vivo monitoring of neuroinflammation using PET is critical to understand this process, and data are accumulating in this regard, thus a review is useful. From PubMed, we retrieved publications using any of the available PET tracers to image neuroinflammation in humans as well as selected articles dealing with experimental animal models or the chemistry of currently used or potential radiotracers. We reviewed 280 articles. The most common PET neuroinflammation target, translocator protein (TSPO), has limitations, lacking cellular specificity and the ability to separate neuroprotective from neurotoxic inflammation. However, TSPO PET is useful to define the amount and location of inflammation in the brain of people with neurodegenerative disorders. We describe the characteristics of TSPO and other potential PET neuroinflammation targets and PET tracers available or in development. Despite target and tracer limitations, in recent years there has been a sharp increase in the number of reports of neuroinflammation PET in humans. The most studied has been Alzheimer disease, in which neuroinflammation seems initially neuroprotective and neurotoxic later in the progression of the disease. We describe the findings in all the major neurodegenerative disorders. Neuroinflammation PET is an indispensable tool to understand the process of neurodegeneration, particularly in humans, as well as to validate target engagement in therapeutic clinical trials.

Comprehensive cross-sectional and longitudinal analyses of plasma neurofilament light across FTD spectrum disorders.

Frontotemporal dementia (FTD) therapy development is hamstrung by a lack of susceptibility, diagnostic, and prognostic biomarkers. Blood neurofilament light (NfL) shows promise as a biomarker, but studies have largely focused only on core FTD syndromes, often grouping patients with different diagnoses. To expedite the clinical translation of NfL, we avail ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study resources and conduct a comprehensive investigation of plasma NfL across FTD syndromes and in presymptomatic FTD mutation carriers. We find plasma NfL is elevated in all studied syndromes, including mild cases; increases in presymptomatic mutation carriers prior to phenoconversion; and associates with indicators of disease severity. By facilitating the identification of individuals at risk of phenoconversion, and the early diagnosis of FTD, plasma NfL can aid in participant selection for prevention or early treatment trials. Moreover, its prognostic utility would improve patient care, clinical trial efficiency, and treatment outcome estimations.

Proposed research criteria for prodromal behavioural variant frontotemporal dementia.

At present, no research criteria exist for the diagnosis of prodromal behavioural variant frontotemporal dementia (bvFTD), though early detection is of high research importance. Thus, we sought to develop and validate a proposed set of research criteria for prodromal bvFTD, termed 'mild behavioural and/or cognitive impairment in bvFTD' (MBCI-FTD). Participants included 72 participants deemed to have prodromal bvFTD; this comprised 55 carriers of a pathogenic mutation known to cause frontotemporal lobar degeneration, and 17 individuals with autopsy-confirmed frontotemporal lobar degeneration. All had mild behavioural and/or cognitive changes, as judged by an evaluating clinician. Based on extensive clinical workup, the prodromal bvFTD group was divided into a Development Group (n = 22) and a Validation Group (n = 50). The Development Group was selected to be the subset of the prodromal bvFTD group for whom we had the strongest longitudinal evidence of conversion to bvFTD, and was used to develop the MBCI-FTD criteria. The Validation Group was the remainder of the prodromal bvFTD group and was used as a separate sample on which to validate the criteria. Familial non-carriers were included as healthy controls (n = 165). The frequencies of behavioural and neuropsychiatric features, neuropsychological deficits, and social cognitive dysfunction in the prodromal bvFTD Development Group and healthy controls were assessed. Based on sensitivity and specificity analyses, seven core features were identified: apathy without moderate-severe dysphoria, behavioural disinhibition, irritability/agitation, reduced empathy/sympathy, repetitive behaviours (simple and/or complex), joviality/gregariousness, and appetite changes/hyperorality. Supportive features include a neuropsychological profile of impaired executive function or naming with intact orientation and visuospatial skills, reduced insight for cognitive or behavioural changes, and poor social cognition. Three core features or two core features plus one supportive feature are required for the diagnosis of possible MBCI-FTD; probable MBCI-FTD requires imaging or biomarker evidence, or a pathogenic genetic mutation. The proposed MBCI-FTD criteria correctly classified 95% of the prodromal bvFTD Development Group, and 74% of the prodromal bvFTD Validation Group, with a false positive rate of <10% in healthy controls. Finally, the MBCI-FTD criteria were tested on a cohort of individuals with prodromal Alzheimer's disease, and the false positive rate of diagnosis was 11-16%. Future research will need to refine the sensitivity and specificity of these criteria, and incorporate emerging biomarker evidence.

The contribution of behavioral features to caregiver burden in FTLD spectrum disorders.

INTRODUCTION: Caregivers of patients with frontotemporal lobar degeneration (FTLD) spectrum disorders experience tremendous burden, which has been associated with the neuropsychiatric and behavioral features of the disorders. METHODS: In a sample of 558 participants with FTLD spectrum disorders, we performed multiple-variable regressions to identify the behavioral features that were most strongly associated with caregiver burden, as measured by the Zarit Burden Interview, at each stage of disease. RESULTS: Apathy and disinhibition, as rated by both clinicians and caregivers, as well as clinician-rated psychosis, showed the strongest associations with caregiver burden, a pattern that was consistent when participants were separated cross-sectionally by disease stage. In addition, behavioral features appeared to contribute most to caregiver burden in patients with early dementia. DISCUSSION: Caregivers should be provided with early education on the management of the behavioral features of FTLD spectrum disorders. Interventions targeting apathy, disinhibition, and psychosis may be most useful to reduce caregiver burden.

Recognition memory and divergent cognitive profiles in prodromal genetic frontotemporal dementia.

Although executive dysfunction is the characteristic cognitive marker of behavioral variant frontotemporal dementia (bvFTD), episodic memory deficits are relatively common, and may be present even during the prodromal disease phase. In a cohort of mutation carriers with mild behavioral and/or cognitive symptoms consistent with prodromal bvFTD, we aimed to investigate patterns of performance on an abbreviated list learning task, with a particular focus on recognition memory. We further aimed to characterize the cognitive prodromes associated with the three major genetic causes of frontotemporal dementia, as emerging evidence suggests there may be subtle differences in cognitive profiles among carriers of different genetic mutations. Participants included 57 carriers of a pathogenic mutation in microtubule-associated protein tau (MAPT, N = 23), or progranulin (GRN, N = 15), or a or a hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72, N = 19), with mild cognitive and/or behavioral symptoms consistent with prodromal bvFTD. Familial non-carriers were included as controls (N = 143). All participants completed a comprehensive neuropsychological examination, including an abbreviated list learning test assessing episodic memory recall and recognition. MAPT mutation carriers performed worse than non-carriers in terms of list recall, and had difficulty discriminating targets from distractors on the recognition memory task, primarily due to the endorsement of distractors as targets. MAPT mutation carriers also showed nonverbal episodic memory and semantic memory dysfunction (object naming). GRN mutation carriers were variable in performance and overall the most dysexecutive. Slowed psychomotor speed was evident in C9orf72 repeat expansion carriers. Identifying the earliest cognitive indicators of bvFTD is of critical clinical and research importance. List learning may be a sensitive cognitive marker for incipient dementia in MAPT and potentially a subset of GRN carriers. Our results highlight that distinct cognitive profiles may be evident in carriers of the three disease-causing genes during the prodromal disease stage.

The Influence of the Competences of the Professionals in Charge of Family Evidence-Based Programmes on Internalizing and Externalizing Symptoms in Adolescents.

This study analyses the influence of trainers' intrapersonal and group management competences on the effectiveness of the Universal Strengthening Families Program 11-14 (SFP 11-14). More specifically, it assesses the effect of these competences on internalizing and externalizing symptoms in adolescents. The analysed data is made up of ratings given by the 174 mothers participating in SFP 11-14. The results confirm the effectiveness of SFP 11-14 in reducing internalizing and externalizing symptoms in adolescents. Using linear regression models, evidence is provided of the influence of the trainers' expertise, in terms of their competences, in improving internalizing symptoms in adolescents (through a reduction in levels of anxiety, depression, and somatization and in the global internalization scale). Emphasis is placed on how trainer competences can impact on the effectiveness of evidence-based programmes, stressing that this should be taken into account by the public authorities and other stakeholders in the assessment and design of family evidence-based programmes.

Neuroinflammation is highest in areas of disease progression in semantic dementia.

Despite epidemiological and genetic data linking semantic dementia to inflammation, the topography of neuroinflammation in semantic dementia, also known as the semantic variant of primary progressive aphasia, remains unclear. The pathology starts at the tip of the left temporal lobe where, in addition to cortical atrophy, a strong signal appears with the tau PET tracer 18F-flortaucipir, even though the disease is not typically associated with tau but with TDP-43 protein aggregates. Here, we characterized the topography of inflammation in semantic variant primary progressive aphasia using high-resolution PET and the tracer 11C-PBR28 as a marker of microglial activation. We also tested the hypothesis that inflammation, by providing non-specific binding targets, could explain the 18F-flortaucipir signal in semantic variant primary progressive aphasia. Eight amyloid-PET-negative patients with semantic variant primary progressive aphasia underwent 11C-PBR28 and 18F-flortaucipir PET. Healthy controls underwent 11C-PBR28 PET (n = 12) or 18F-flortaucipir PET (n = 12). Inflammation in PET with 11C-PBR28 was analysed using Logan graphical analysis with a metabolite-corrected arterial input function. 18F-flortaucipir standardized uptake value ratios were calculated using the cerebellum as the reference region. Since monoamine oxidase B receptors are expressed by astrocytes in affected tissue, selegiline was administered to one patient with semantic variant primary progressive aphasia before repeating 18F-flortaucipir scanning to test whether monoamine oxidase B inhibition blocked flortaucipir binding, which it did not. While 11C-PBR28 uptake was mostly cortical, 18F-flortaucipir uptake was greatest in the white matter. The uptake of both tracers was increased in the left temporal lobe and in the right temporal pole, as well as in regions adjoining the left temporal pole such as insula and orbitofrontal cortex. However, peak uptake of 18F-flortaucipir localized to the left temporal pole, the epicentre of pathology, while the peak of inflammation 11C-PBR28 uptake localized to a more posterior, mid-temporal region and left insula and orbitofrontal cortex, in the periphery of the damage core. Neuroinflammation, greatest in the areas of progression of the pathological process in semantic variant primary progressive aphasia, should be further studied as a possible therapeutic target to slow disease progression.

Parametric Mapping for TSPO PET Imaging with Spectral Analysis Impulsive Response Function.

PURPOSE: The aim of this study was to investigate the use of spectral analysis (SA) for voxel-wise analysis of TSPO PET imaging studies. TSPO PET quantification is methodologically complicated by the heterogeneity of TSPO expression and its cell-dependent modulation during neuroinflammatory response. Compartmental models to account for this complexity exist, but they are unreliable at the high noise typical of voxel data. On the contrary, SA is noise-robust for parametric mapping and provides useful information about tracer kinetics with a free compartmental structure. PROCEDURES: SA impulse response function (IRF) calculated at 90 min after tracer injection was used as main parameter of interest in 3 independent PET imaging studies to investigate its sensitivity to (1) a TSPO genetic polymorphism (rs6971) known to affect tracer binding in a cross-sectional analysis of healthy controls scanned with [11C]PBR28 PET; (2) TSPO density with [11C]PBR28 in a competitive blocking study with a TSPO blocker, XBD173; and (3) the higher affinity of a second radiotracer for TSPO, by using data from a head-to-head comparison between [11C]PBR28 and [11C]ER176 scans. RESULTS: SA-IRF produced parametric maps of visually good quality. These were sensitive to TSPO genotype (mean relative difference between high- and mixed-affinity binders = 25 %) and TSPO availability (mean signal displacement after 90 mg oral administration of XBD173 = 39 %). Regional averages of voxel-wise IRF estimates were strongly associated with regional total distribution volume (VT) estimated with a 2-tissue compartmental model with vascular compartment (Pearson's r = 0.86 ± 0.11) but less strongly with standard 2TCM-VT (Pearson's r = 0.76 ± 0.32). Finally, SA-IRF estimates for [11C]ER176 were significantly higher than [11C]PBR28 ones, consistent with the higher amount of specific binding of the former tracer. CONCLUSIONS: SA-IRF can be used for voxel-wise quantification of TSPO PET data because it generates high-quality parametric maps, it is sensitive to TSPO availability and genotype, and it accounts for the complexity of TSPO tracer kinetics with no additional assumptions.

Morbimortalidad asociada a la disfagia en pacientes ingresados en un hospital general universitario

RESUMEN Introducción: La disfagia tiene una morbimortalidad importante en pacientes hospitalizados. Objetivos: principal; describir las características de los pacientes con disfagia hospitalizados y, secundarios; cuantificar y analizar la prevalencia de mortalidad y de reingresos. Metodología: Estudio transversal descriptivo de las hospitalizaciones por disfagia durante el año 2015 en un Hospital General Universitario. Resultados: Se evaluaron 431 historias clínicas. La edad de los pacientes fue de 83,21 (DE 11,4) años, el 52,5% fueron mujeres y el 47,2% varones; la estancia media fue de 11,1 (DE 7,99) días. En el 71,2 % de los casos la disfagia fue por afectación de la fase orofaríngea. En el 80,51% de los casos se diagnosticaron complicaciones respiratorias: 48,12% neumonía aspirativa por líquidos, 40,05 % neumonitis química por aspiración y 11,81% neumonía aspirativa por sólidos. La mortalidad general asociada a las complicaciones respiratorias respecto del total de los casos de disfagia fue del 24,49%. El 50,48% de los pacientes con neumonía aspirativa fallecieron. La principal causa de la disfagia fue las enfermedades neurológicas (un 77,25%). La mortalidad fue significativamente mayor en las mujeres - 42,3% frente al 7,8% - (p < 0,01) y esta diferencia se mantuvo tras ajustar el resultado por edad: OR 9,937, IC95%: 5,446; 18,131. El 13,10% de los pacientes reingresaron al menos en una ocasión. Los pacientes de geriatría presentaron un mayor número de reingresos por número de ingresos. Discusión: las enfermedades neurológicas fueron la principal causa de disfagia. La mortalidad fue significativamente mayor en las mujeres.

ABSTRACT Introduction: Dysphagia is an important associated morbidity and mortality in hospitalized patient. Objectives: Main; to describe the characteristics of patients admitted for dysphagia and secondary; quantify and analyze the prevalence of mortality and readmissions. Methodology: Cross-sectional study descriptive revenues by dysphagia during the year 2015 in a University General Hospital. Results: 431 records were evaluated. The age of the patients was 83,21 (11.4), 52.5% women and 47.2% male; the average stay was 11.1 (7.99) days. In 71,2% of cases the dysphagia was involvement of the oropharyngeal phase. 80.51% of cases were diagnosed respiratory complications. The percentage distribution of these complications were: in 48.12% aspiration pneumonia due to fluids, in 40.05% chemical aspiration pneumonitis and in 11.81% aspiration pneumonia due to solids. The overall mortality associated with respiratory complications compared to the total of cases of dysphagia was 24.49%. 50.48% of patients diagnosed with aspiration pneumonia died. The main cause of dysphagia was neurological diseases (77.25%). Mortality was significantly higher in women - 42.3% of women compared with 7.8% of males - (p < 0.01) and this difference remained after adjusting the result by age: OR 9,937, 95% CI: 5,446; 18,131. 13.10% of patients re-entered at least on one occasion. Patients of geriatric unit that presented in greater number of readmissions by admissions. Discussion: neurological diseases were the main cause of dysphagia. Mortality was significantly higher in women