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Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10-12, OR = 1.27) and APOE (rs6857; p = 1.31 × 10-12, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10-8, OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex.
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Apolipoproteínas E , Demencia Frontotemporal , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Proteínas tau , Humanos , Demencia Frontotemporal/genética , Proteínas tau/genética , Apolipoproteínas E/genética , Masculino , Femenino , Anciano , Polimorfismo de Nucleótido Simple , Sitios Genéticos , Persona de Mediana Edad , Estudios de Casos y Controles , Proteínas de la MielinaRESUMEN
Genetic repeat expansions cause neuronal degeneration in amyotrophic lateral sclerosis as well as other neurodegenerative disorders such as spinocerebellar ataxia, Huntington's disease and Kennedy's disease. Repeat expansions in the same gene can cause multiple clinical phenotypes. We aimed to characterize repeat expansions in a Norwegian amyotrophic lateral sclerosis cohort. Norwegian amyotrophic lateral sclerosis patients (n = 414) and neurologically healthy controls adjusted for age and gender (n = 713) were investigated for repeat expansions in AR, ATXN1, ATXN2 and HTT using short read exome sequencing and the ExpansionHunter software. Five amyotrophic lateral sclerosis patients (1.2%) and two controls (0.3%) carried ≥36 repeats in HTT (P = 0.032), and seven amyotrophic lateral sclerosis patients (1.7%) and three controls (0.4%) carried ≥29 repeats in ATXN2 (P = 0.038). One male diagnosed with amyotrophic lateral sclerosis carried a pathogenic repeat expansion in AR, and his diagnosis was revised to Kennedy's disease. In ATXN1, 50 amyotrophic lateral sclerosis patients (12.1%) and 96 controls (13.5%) carried ≥33 repeats (P = 0.753). None of the patients with repeat expansions in ATXN2 or HTT had signs of Huntington's disease or spinocerebellar ataxia type 2, based on a re-evaluation of medical records. The diagnosis of amyotrophic lateral sclerosis was confirmed in all patients, with the exception of one patient who had primary lateral sclerosis. Our findings indicate that repeat expansions in HTT and ATXN2 are associated with increased likelihood of developing amyotrophic lateral sclerosis. Further studies are required to investigate the potential relationship between HTT repeat expansions and amyotrophic lateral sclerosis.
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Staging amyloid-beta (Aß) pathophysiology according to the intensity of neurodegeneration could identify individuals at risk for cognitive decline in Alzheimer's disease (AD). In blood, phosphorylated tau (p-tau) associates with Aß pathophysiology but an AD-type neurodegeneration biomarker has been lacking. In this multicenter study (n = 1076), we show that brain-derived tau (BD-tau) in blood increases according to concomitant Aß ("A") and neurodegeneration ("N") abnormalities (determined using cerebrospinal fluid biomarkers); We used blood-based A/N biomarkers to profile the participants in this study; individuals with blood-based p-tau+/BD-tau+ profiles had the fastest cognitive decline and atrophy rates, irrespective of the baseline cognitive status. Furthermore, BD-tau showed no or much weaker correlations with age, renal function, other comorbidities/risk factors and self-identified race/ethnicity, compared with other blood biomarkers. Here we show that blood-based BD-tau is a biomarker for identifying Aß-positive individuals at risk of short-term cognitive decline and atrophy, with implications for clinical trials and implementation of anti-Aß therapies.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Proteínas tau/líquido cefalorraquídeo , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Biomarcadores/líquido cefalorraquídeo , AtrofiaRESUMEN
BACKGROUND: Brain innate immune activation is associated with Alzheimer's disease (AD), but degrees of activation may vary between disease stages. Thus, brain innate immune activation must be assessed in longitudinal clinical studies that include biomarker negative healthy controls and cases with established AD pathology. Here, we employ longitudinally sampled cerebrospinal fluid (CSF) core AD, immune activation and glial biomarkers to investigate early (predementia stage) innate immune activation levels and biomarker profiles. METHODS: We included non-demented cases from a longitudinal observational cohort study, with CSF samples available at baseline (n = 535) and follow-up (n = 213), between 1 and 6 years from baseline (mean 2.8 years). We measured Aß42/40 ratio, p-tau181, and total-tau to determine Ab (A+), tau-tangle pathology (T+), and neurodegeneration (N+), respectively. We classified individuals into these groups: A-/T-/N-, A+/T-/N-, A+/T+ or N+, or A-/T+ or N+. Using linear and mixed linear regression, we compared levels of CSF sTREM2, YKL-40, clusterin, fractalkine, MCP-1, IL-6, IL-1, IL-18, and IFN-γ both cross-sectionally and longitudinally between groups. A post hoc analysis was also performed to assess biomarker differences between cognitively healthy and impaired individuals in the A+/T+ or N+ group. RESULTS: Cross-sectionally, CSF sTREM2, YKL-40, clusterin and fractalkine were higher only in groups with tau pathology, independent of amyloidosis (p < 0.001, A+/T+ or N+ and A-/T+ or N+, compared to A-/T-/N-). No significant group differences were observed for the cytokines CSF MCP-1, IL-6, IL-10, IL18 or IFN-γ. Longitudinally, CSF YKL-40, fractalkine and IFN-γ were all significantly lower in stable A+/T-/N- cases (all p < 0.05). CSF sTREM2, YKL-40, clusterin, fractalkine (p < 0.001) and MCP-1 (p < 0.05) were all higher in T or N+, with or without amyloidosis at baseline, but remained stable over time. High CSF sTREM2 was associated with preserved cognitive function within the A+/T+ or N+ group, relative to the cognitively impaired with the same A/T/N biomarker profile (p < 0.01). CONCLUSIONS: Immune hypoactivation and reduced neuron-microglia communication are observed in isolated amyloidosis while activation and increased fractalkine accompanies tau pathology in predementia AD. Glial hypo- and hyperactivation through the predementia AD continuum suggests altered glial interaction with Ab and tau pathology, and may necessitate differential treatments, depending on the stage and patient-specific activation patterns.
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Enfermedad de Alzheimer , Amiloidosis , Humanos , Enfermedad de Alzheimer/patología , Proteína 1 Similar a Quitinasa-3 , Quimiocina CX3CL1 , Clusterina , Péptidos beta-Amiloides/líquido cefalorraquídeo , Interleucina-6 , Biomarcadores/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeoRESUMEN
BACKGROUND: Alcohol consumption is widespread in student environments. The objective of the study was to examine alcohol use among students at the Norwegian University of Science and Technology (NTNU) in a twelve-year perspective. MATERIAL AND METHOD: The study is cross-sectional, based on two questionnaire surveys conducted in lecture breaks at NTNU in 2007 and 2019. Participation was voluntary and anonymous. The questionnaire surveyed background variables and alcohol use, and included questions from the Alcohol Use Disorders Identification Test (AUDIT). The respondents were categorised into risk profiles based on their results. An AUDIT score of ≥ 8 was used as the threshold value for risky/potentially harmful alcohol use. RESULTS: The study included 2,247 students: 857 from 2007 and 1,390 from 2019. The proportion of women was 42.3 % in 2007 and 54.9 % in 2019. The average age was 21.5 years (2007) and 22.5 years (2019). The average AUDIT score was 10.7 in 2007 and 8.5 in 2019. A total of 937 students (67.6 %) consumed alcohol two to four times per month or more in 2019, a reduction of 9.8 % from 2007. Altogether 885 students (67.8 %) consumed five or more alcohol units on a typical drinking day in 2019, a reduction of 12.8 % from 2007. INTERPRETATION: A considerable one-fifth reduction in the proportion of students with risky alcohol use occurred from 2007 to 2019. However, the alcohol use of more than half of the students may still pose a long-term risk.
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Alcoholismo , Humanos , Femenino , Adulto Joven , Adulto , Estudios Transversales , Consumo de Bebidas Alcohólicas/efectos adversos , Consumo de Bebidas Alcohólicas/epidemiología , Estudiantes , Encuestas y Cuestionarios , UniversidadesRESUMEN
The FAS phonemic fluency test is a commonly used neuropsychological test of executive function and processing speed. Although Norwegian discrete norms have been developed for the FAS test, American regression-based norms are frequently used by clinicians in Norway.However, language and cultural differences impact performance on the FAS test, and using foreign norms may not be appropriate. Moreover, while discrete norming relies on stratified subgroups of demographics, regression-based norming uses the entire sample to estimate the influence of demographics on performance and may thus improve normative estimates. Here we develop regression-based norms for the FAS phonemic fluency test based on n = 204 healthy Norwegian controls between the ages 40-84 from the Norwegian Dementia Disease Initiation cohort (DDI). We compare the proposed regression norms to published Norwegian discrete norms and American regression-based norms in an independent sample of n = 182 cognitively healthy adults reporting subjective cognitive decline (SCD). We found that years of education was the only significant predictor of FAS performance in our normative sample, accounting for 14.9% of the variance. Both the proposed regression-based norms and previously published discrete norms adequately adjusted for demographics in the independent sample. In contrast, the American norms underestimated the effect of education and overestimated the effect of age. While both the proposed Norwegian regression norms and the previously published discrete norms are suitable for use in Norway, the proposed regression norms may be less vulnerable to sub-stratification sample characteristics posed by discrete norming procedures, and thereby improve normative estimation.
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Disfunción Cognitiva , Pruebas Neuropsicológicas , Adulto , Anciano , Anciano de 80 o más Años , Humanos , Persona de Mediana Edad , Cognición , Disfunción Cognitiva/psicología , Lenguaje , Pruebas Neuropsicológicas/normas , Valores de Referencia , SemánticaRESUMEN
INTRODUCTION: Given that exercise training reduces the risk of developing Alzheimer's disease (AD), induces changes in the blood composition and has widespread systemic benefits, it is reasonable to hypothesise that exercised plasma (ExPlas) may have rejuvenative properties. The main objective is to test safety and tolerability of transfusing ExPlas from young, healthy, fit adults to patients with mild cognitive impairment (MCI) or early AD. The study is a pilot for a future efficacy study. The key secondary objectives are examining the effect of plasma transfusions on cognitive function, fitness level, vascular risk profile, assessment of cerebral blood flow and hippocampal volume, quality of life, functional connectivity assessed by resting state functional MRI and biomarkers in blood and cerebrospinal fluid. METHODS AND ANALYSIS: ExPlas is a double-blinded, randomised controlled clinical single-centre trial. Patients up to 75 years of age with diagnosis early symptomatic phase AD will be recruited from two Norwegian hospitals. ExPlas is plasma drawn by plasmapheresis once a month for 4 months, from a total of 30 fit male donors (aged 18-40, BMI≤27 kg/m2 and maximal oxygen uptake>55 mL/kg/min). All units will be virus inactivated by the Intercept method in accordance with procedures at St. Olavs University Hospital. Comparison with isotonic saline allows differentiation from a non-blood product. The main study consists of 6 rounds of examinations in addition to 12 plasma transfusions divided over three 4-week periods during study year-1. It is also planned to conduct follow-up examinations 2 and 5 years after baseline ETHICS AND DISSEMINATION: Written informed consent will be obtained from all participants and participation is voluntary. All participants have a next of kin who will follow them throughout the study to represent the patient's interest. The study is approved by the Regional Committee for Medical and Health Research Ethics (REK 2018/702) and the Norwegian Medicines Agency (EudraCT No. 2018-000148-24). The study will be published in an open access journal and results will be presented at numerous national and international meetings as well as on social media platforms. TRIAL REGISTRATION NUMBER: EudraCT No. 2018-000148-24. CLINICALTRIALS: gov, NCT05068830.
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Enfermedad de Alzheimer , COVID-19 , Adulto , Humanos , Masculino , SARS-CoV-2 , Enfermedad de Alzheimer/terapia , Transfusión de Componentes Sanguíneos , Calidad de Vida , Plasma , Resultado del Tratamiento , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Importance: Identification of proteins and genetic factors that reduce Alzheimer disease (AD) pathology is of importance when searching for novel AD treatments. Heterozygosity of the KL-VS haplotype has been associated with reduced amyloid and tau burden. Whether this association is mediated by the Klotho protein remains unclear. Objectives: To assess concentrations of Klotho in cerebrospinal fluid (CSF) and plasma among cognitively healthy controls and patients with AD and to correlate these findings with KL-VS heterozygosity status and amyloid and tau burden. Design, Setting, and Participants: This case-control study combined 2 independent case-control AD cohorts consisting of 243 referred patients with AD and volunteer controls recruited from January 1, 2009, to December 31, 2018. Klotho levels were measured in CSF and plasma and correlated with KL-VS heterozygosity status and levels of CSF amyloid-ß 42 (Aß42), total tau, and phosphorylated tau. Statistical analysis was performed from January 1, 2021, to March 1, 2022. Main Outcomes and Measures: Associations of Klotho levels in CSF and plasma with levels of CSF biomarkers were analyzed using linear regression. Association analyses were stratified separately by clinical groups, APOE4 status, and KL-VS heterozygosity. Pearson correlation was used to assess the correlation between CSF and plasma Klotho levels. Results: A total of 243 participants were included: 117 controls (45 men [38.5%]; median age, 65 years [range, 41-84 years]), 102 patients with mild cognitive impairment due to AD (AD-MCI; 59 men [57.8%]; median age, 66 years [range, 46-80 years]), and 24 patients with dementia due to AD (AD-dementia; 12 men [50.0%]; median age, 64.5 years [range, 54-75 years]). Median CSF Klotho levels were higher in controls (1236.4 pg/mL [range, 20.4-1726.3 pg/mL]; ß = 0.103; 95% CI, 0.023-0.183; P = .01) and patients with AD-MCI (1188.1 pg/mL [range, 756.3-1810.3 pg/mL]; ß = 0.095; 95% CI, 0.018-0.172; P = .02) compared with patients with AD-dementia (1073.3 pg/mL [range, 698.2-1661.4 pg/mL]). Higher levels of CSF Klotho were associated with lower CSF Aß42 burden (ß = 0.519; 95% CI, 0.201-0.836; P < .001) and tau burden (CSF total tau levels: ß = -0.884; 95% CI, 0.223 to -0.395; P < .001; CSF phosphorylated tau levels: ß = -0.672; 95% CI, -1.022 to -0.321; P < .001) independent of clinical, KL-VS heterozygosity, or APOE4 status. There was a weak correlation between Klotho CSF and plasma levels among the entire cohort (Pearson correlation r = 0.377; P < .001). Conclusions and Relevance: The findings of this case-control study suggest that Klotho protein levels were associated with clinical stages of AD, cognitive decline, and amyloid and tau burden and that these outcomes were more clearly mediated by the protein directly rather than the KL-VS heterozygosity variant. When selecting individuals at risk for clinical trials, the Klotho protein level and not only the genetic profile should be considered.
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Enfermedad de Alzheimer , Anciano , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides , Apolipoproteína E4 , Estudios de Casos y Controles , Proteínas Klotho , Proteínas tau , Heterocigoto , Femenino , Adulto , Anciano de 80 o más AñosRESUMEN
Cerebrospinal fluid (CSF) ß-site amyloid precursor protein cleaving enzyme 1 (BACE1), neurogranin and the neurogranin/BACE1 ratio are proposed markers for Alzheimer's disease. BACE1 is also a drug target. However, CSF levels may differ between early-stage amyloid plaque formation (A) and later stage downstream tau-tangle pathology (T) and neurodegeneration (N) and may be expressed as an A/T/N stage (e.g. A+/T-/N or A+/T+/N+). Whether BACE1 and neurogranin levels are persistent traits or change with disease progression is unknown. The aim of this study was to investigate whether CSF neurogranin and BACE1 concentrations differ between A/T/N stages, whether these change over time and correlate with memory decline. This may have implications for patient selection in future trials. We used CSF markers to determine A/T/N stage using amyloid beta42/40 ratio, p-tau181 and total-tau respectively in predementia Alzheimer's disease cases (n = 176) [including cases that progressed to dementia (n = 10)] and controls (n = 74) from the Norwegian Dementia Disease Initiation cohort. We selected cases at the presumed early (A+/T-/N-, n = 86) and late stages (A+/T+/N+, n = 90) of the Alzheimer's disease continuum and controlled with normal markers (A-/T-/N-, n = 74). A subset of subjects in all A/T/N groups underwent repeat CSF sampling at approximately 2-year intervals up to 6 years from baseline. Using linear mixed models, longitudinal measurements of CSF BACE1 and neurogranin levels in A+/T-/N- and A+/T+/N+ as compared to A-/T-/N- healthy controls were performed. Next, we measured changes in CSF BACE1 and neurogranin levels in cases that progressed from A-/T-/N- to A+/T-/N- (n = 12), from A+/T-/N- to A+/T or N+ (n = 12), remained stable A+/T-/N- (n = 26), remained stable A+/T+/N+ (n = 28) compared with controls remaining stable A-/T-/N- (n = 33). Lastly, associations between these markers and memory decline were assessed. Compared with A-/T-/N- healthy controls, neurogranin was unaltered in A+/T-/N- (n.s.) but higher in A+/T+/N+ (P < 0.0001). In contrast, BACE1 was lower in A+/T-/N- (P < 0.05) and higher in A+/T+/N+ (P < 0.0001). The neurogranin/BACE1 ratio was increased in both A+/T-/N- (P < 0.05) and A+/T+/N+ (P < 0.0001) groups as compared to A-/T-/N- healthy controls and was more strongly associated with memory decline (b = -0.29, P = 0.0006) than neurogranin (b = -0.20, P = 0.002) and BACE1 (b = -0.13, P = 0.046). Neurogranin and BACE1 level differences remained stable over time not only within A/T/N groups but also in patients progressing to more pathological A/T/N stages (e.g. progressing from A+/T-/N- to A + T or N+) and in cases progressing to dementia. Our results suggest that neurogranin and BACE1 levels may differentiate pathomechanistic Alzheimer's disease subgroups, putatively with different options for treatment.
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PURPOSE: To study the prevalence and directionality of comorbid epilepsy and psychosis in Norway. METHODS: The Norwegian Prescription Database (NorPD) provided individual-based information on all antiseizure medications (ASMs) and antipsychotic drugs (APDs) dispensed during 2004-2017. Subjects were ≥18 years of age at the end of the study period. Diagnosis-specific reimbursement codes from the 10th revision of the International Classification of Diseases/2nd edition of the International Classification of Primary Care (ICD-10/ICPC-2) combined with ATC codes were used as indicators of diagnosis. Subjects had collected ASMs for epilepsy or APDs for psychosis at least four times, at least once issued with an ICD-10 code from the specialist healthcare service. Directionality was analyzed in subjects receiving both treatments. To reduce prevalent comorbidity bias, we employed a four-year comorbidity-free period (2004-2007). The use of specific ASMs and APDs was analyzed. RESULTS: A total of 31,289 subjects had collected an ASM for epilepsy at least four times, 28,889 an APD for psychosis. Both the prevalence of treatment for epilepsy and of treatment for psychosis was 0.8%. Further, 891 subjects had been treated for both conditions; 2.8% with epilepsy had been treated for psychosis, and 3.1% with psychosis had been treated for epilepsy. Among 558 subjects included in the analyses of directionality, 56% had collected the first APD before an ASM, whereas 41% had collected an ASM first. During the last year prior to comorbidity onset, levetiracetam, topiramate, or zonisamide had been used for epilepsy by approximately 40%, whereas olanzapine and quetiapine were most used in patients with psychosis, and clozapine in 13%. CONCLUSION: The proportion of patients with prior antipsychotic treatment at onset of epilepsy is higher than previously acknowledged, as demonstrated in this nation-wide study. Apart from a shared neurobiological susceptibility, the bidirectionality of epilepsy and psychosis may be influenced by various environmental factors, including the interaction of pharmacodynamic effects. APDs may facilitate seizures; ASMs may induce psychiatric symptoms. In patients with combined treatment, these potential drug effects should receive ample attention, along with the psychosocial consequences of the disorders. A prudent multi-professional approach is required.
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Antipsicóticos , Epilepsia , Trastornos Psicóticos , Humanos , Antipsicóticos/uso terapéutico , Trastornos Psicóticos/tratamiento farmacológico , Trastornos Psicóticos/epidemiología , Epilepsia/tratamiento farmacológico , Epilepsia/epidemiología , Levetiracetam/uso terapéutico , Zonisamida/uso terapéutico , Anticonvulsivantes/uso terapéuticoRESUMEN
BACKGROUND: Low levels of plasma apolipoprotein E (apoE) and presence of the APOE ε4 allele are associated with an increased risk of Alzheimer's disease (AD). Although the increased risk of AD in APOE ε4-carriers is well-established, the protein levels have received limited attention. METHODS: We here report the total plasma apoE and apoE isoform levels at baseline from a longitudinally (24 months) followed cohort including controls (n = 39), patients with stable amnestic mild cognitive impairment during 24 months follow up (MCI-MCI, n = 30), patients with amnestic MCI (aMCI) that during follow-up were clinically diagnosed with AD with dementia (ADD) (MCI-ADD, n = 28), and patients with AD with dementia (ADD) at baseline (ADD, n = 28). We furthermore assessed associations between plasma apoE levels with cerebrospinal fluid (CSF) AD biomarkers and α-synuclein, as well as both CSF and plasma neurofilament light chain (NfL), YKL-40 and kallikrein 6. RESULTS: Irrespective of clinical diagnosis, the highest versus the lowest apoE levels were found in APOE ε2/ε3 versus APOE ε4/ε4 subjects, with the most prominent differences exhibited in females. Total plasma apoE levels were 32% and 21% higher in the controls versus MCI-ADD and ADD patients, respectively. Interestingly, MCI-ADD patients exhibited a 30% reduction in plasma apoE compared to MCI-MCI patients. This decrease appeared to be associated with brain amyloid-ß (Aß42) pathology regardless of disease status as assessed using the Amyloid, Tau, and Neurodegeneration (A/T/N) classification. In addition to the association between low plasma apoE and low levels of CSF Aß42, lower apoE levels were also related to higher levels of CSF total tau (t-tau) and tau phosphorylated at Threonine 181 residue (p-tau) and NfL as well as a worse performance on the mini-mental-state-examination. In MCI-ADD patients, low levels of plasma apoE were associated with higher levels of CSF α-synuclein and kallikrein 6. No significant correlations between plasma apoE and the astrocytic inflammatory marker YKL40 were observed. CONCLUSIONS: Our results demonstrate important associations between low plasma apoE levels, Aß pathology, and progression from aMCI to a clinical ADD diagnosis.
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Enfermedad de Alzheimer , Apolipoproteínas E , Disfunción Cognitiva , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides/líquido cefalorraquídeo , Apolipoproteína E3/líquido cefalorraquídeo , Apolipoproteína E3/genética , Apolipoproteína E4/líquido cefalorraquídeo , Apolipoproteína E4/genética , Apolipoproteínas E/líquido cefalorraquídeo , Apolipoproteínas E/genética , Biomarcadores/líquido cefalorraquídeo , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/diagnóstico , Femenino , Humanos , Calicreínas , Fragmentos de Péptidos/líquido cefalorraquídeo , alfa-Sinucleína , Proteínas tau/líquido cefalorraquídeoRESUMEN
BACKGROUND: Polygenic hazard scores (PHS) estimate age-dependent genetic risk of late-onset Alzheimer's disease (AD), but there is limited information about the performance of PHS on real-world data where the population of interest differs from the model development population and part of the model genotypes are missing or need to be imputed. OBJECTIVE: The aim of this study was to estimate age-dependent risk of late-onset AD using polygenic predictors in Nordic populations. METHODS: We used Desikan PHS model, based on Cox proportional hazards assumption, to obtain age-dependent hazard scores for AD from individual genotypes in the Norwegian DemGene cohort (nâ=â2,772). We assessed the risk discrimination and calibration of Desikan model and extended it by adding new genotype markers (the Desikan Nordic model). Finally, we evaluated both Desikan and Desikan Nordic models in two independent Danish cohorts: The Copenhagen City Heart Study (CCHS) cohort (nâ=â7,643) and The Copenhagen General Population Study (CGPS) cohort (nâ=â10,886). RESULTS: We showed a robust prediction efficiency of Desikan model in stratifying AD risk groups in Nordic populations, even when some of the model SNPs were missing or imputed. We attempted to improve Desikan PHS model by adding new SNPs to it, but we still achieved similar risk discrimination and calibration with the extended model. CONCLUSION: PHS modeling has the potential to guide the timing of treatment initiation based on individual risk profiles and can help enrich clinical trials with people at high risk to AD in Nordic populations.
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Enfermedad de Alzheimer , Edad de Inicio , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/genética , Genotipo , Humanos , Herencia Multifactorial/genética , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
Background: Pediatric investigation plans (PIPs) describe how adult drugs can be studied in children. In 2015, PIPs for Amyotrophic Lateral Sclerosis (ALS) became mandatory for European marketing-authorization of adult treatments, unless a waiver is granted by the European Medicines Agency (EMA).Objective: To assess the feasibility of clinical studies on the effect of therapy in children (<18 years) with ALS in Europe.Methods: The EMA database was searched for submitted PIPs in ALS. A questionnaire was sent to 58 European ALS centers to collect the prevalence of pediatric ALS during the past ten years, the recruitment potential for future pediatric trials, and opinions of ALS experts concerning a waiver for ALS.Results: Four PIPs were identified; two were waived and two are planned for the future. In total, 49 (84.5%) centers responded to the questionnaire. The diagnosis of 44,858 patients with ALS was reported by 46 sites; 39 of the patients had an onset < 18 years (prevalence of 0.008 cases per 100,000 or 0.087% of all diagnosed patients). The estimated recruitment potential (47 sites) was 26 pediatric patients within five years. A majority of ALS experts (75.5%) recommend a waiver should apply for ALS due to the low prevalence of pediatric ALS.Conclusions: ALS with an onset before 18 years is extremely rare and may be a distinct entity from adult ALS. Conducting studies on the effect of disease-modifying therapy in pediatric ALS may involve lengthy recruitment periods, high costs, ethical/legal implications, challenges in trial design and limited information.
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Esclerosis Amiotrófica Lateral , Adulto , Niño , Humanos , Esclerosis Amiotrófica Lateral/diagnóstico , Esclerosis Amiotrófica Lateral/epidemiología , Esclerosis Amiotrófica Lateral/terapia , Estudios de Factibilidad , Europa (Continente) , Bases de Datos Factuales , PrevalenciaRESUMEN
Careful brain monitoring saves lives and is beneficial to patients' health. Nevertheless, Norway lacks guidelines for brain monitoring in hospitals.
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Encéfalo , Hospitales , Encéfalo/diagnóstico por imagen , Humanos , NoruegaRESUMEN
Late-onset Alzheimer's disease is a prevalent age-related polygenic disease that accounts for 50-70% of dementia cases. Currently, only a fraction of the genetic variants underlying Alzheimer's disease have been identified. Here we show that increased sample sizes allowed identification of seven previously unidentified genetic loci contributing to Alzheimer's disease. This study highlights microglia, immune cells and protein catabolism as relevant to late-onset Alzheimer's disease, while identifying and prioritizing previously unidentified genes of potential interest. We anticipate that these results can be included in larger meta-analyses of Alzheimer's disease to identify further genetic variants that contribute to Alzheimer's pathology.
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Enfermedad de Alzheimer/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Humanos , Microglía/citología , Herencia Multifactorial/genética , Polimorfismo de Nucleótido Simple/genética , Proteínas/metabolismo , Proteolisis , Tamaño de la MuestraRESUMEN
Neurofilament light (NfL) is a promising biomarker of neurodegeneration in Alzheimer's disease (AD). In this study, cerebrospinal fluid (CSF) NfL was measured in a 24-month longitudinal cohort consisting of control (n = 52), amnestic mild cognitive impairment (aMCI) (n = 55), and probable AD dementia (n = 28) individuals. The cohort was reevaluated after 6-10 years. Baseline CSF NfL was significantly elevated in aMCI and probable AD dementia groups compared to controls (p < 0.0001). CSF NfL was significantly lower in stable aMCI patients compared to aMCI patients who converted to probable AD dementia within the 24-month period (p = 0.004). Substituting T-tau for NfL in the core AD biomarkers model (Aß42/P-tau/T-tau) did not improve ability to separate control and AD, or stable and converter aMCI patients. Our results support that elevated CSF NfL could predict progression in aMCI patients, but its utility cannot improve the core AD biomarkers.
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Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/etiología , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/etiología , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Anciano , Biomarcadores/líquido cefalorraquídeo , Progresión de la Enfermedad , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Factores de TiempoRESUMEN
BACKGROUND: Young onset dementia is associated with a longer time to diagnosis compared to late onset dementia. Earlier publications have indicated that atypical presentation is a key contributing factor to the diagnostic delay. Our hypothesis was that even the most common presentation of Alzheimer's disease is associated with a substantial diagnostic delay in patientsâ<â65 years. OBJECTIVE: To determine the time to diagnosis, and time lags in the diagnostic pathway in typical young onset Alzheimer's disease in central Norway. METHODS: The main sources of patients were the databases at the Department of Neurology, University Hospital of Trondheim (St. Olav's Hospital), and Department of Psychiatry, Levanger Hospital. Other sources included key persons in the communities, collaborating hospital departments examining patients with suspected cognitive impairment, and review of hospital records of all three hospitals in the area. Information on the time lags, and the clinical assessment, including the use of biomarkers, was collected from hospital notes. Caregivers were interviewed by telephone. RESULTS: Time from first symptom to diagnosis in typical young onset Alzheimer's disease was 5.5 years (nâ=â223, SD 2.8). Time from onset to contact with healthcare services (usually a general practitioner) was 3.4 years (SD 2.3). Time from contact with healthcare services to the first visit at a hospital was 10.3 months (SD 15.5). Time from first visit at a hospital to diagnosis was 14.8 months (SD 22.6). The analysis of cerebrospinal fluid core biomarkers was performed after 8.3 months (SD 20.9). CONCLUSION: Typical Alzheimer's disease is associated with a substantial diagnostic delay in younger patients. Raising public awareness, and education of healthcare professionals on the aspects of young onset Alzheimer's disease is warranted. CSF core biomarkers should be performed earlier in the hospital evaluation process.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/psicología , Diagnóstico Tardío , Progresión de la Enfermedad , Pruebas de Estado Mental y Demencia , Vigilancia de la Población , Anciano , Enfermedad de Alzheimer/epidemiología , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Noruega/epidemiología , Vigilancia de la Población/métodosRESUMEN
A patterned spread of proteinopathy represents a common characteristic of many neurodegenerative diseases. In Parkinson's disease (PD), misfolded forms of α-synuclein proteins accumulate in hallmark pathological inclusions termed Lewy bodies and Lewy neurites. Such protein aggregates seem to affect selectively vulnerable neuronal populations in the substantia nigra and to propagate within interconnected neuronal networks. Research findings suggest that these proteinopathic inclusions are present at very early time points in disease development, even before clear behavioral symptoms of dysfunction arise. In this study, we investigate the early pathophysiology developing after induced formation of such PD-related α-synuclein inclusions in a physiologically relevant in vitro setup using engineered human neural networks. We monitor the neural network activity using multielectrode arrays (MEAs) for a period of 3 wk following proteinopathy induction to identify associated changes in network function, with a special emphasis on the measure of network criticality. Self-organized criticality represents the critical point between resilience against perturbation and adaptational flexibility, which appears to be a functional trait in self-organizing neural networks, both in vitro and in vivo. We show that although developing pathology at early onset is not clearly manifest in standard measurements of network function, it may be discerned by investigating differences in network criticality states.