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Early-onset dementia (EOD), with symptom onset before age 65, has a strong genetic burden. Due to genetic and clinical overlaps between different types of dementia, whole-exome sequencing (WES) has emerged as an appropriate screening method for diagnostic testing and novel gene-finding approaches. We performed WES and C9orf72 repeat testing in 60 well-defined Austrian EOD patients. Seven patients (12%) carried likely disease-causing variants in monogenic genes, PSEN1, MAPT, APP, and GRN. Five patients (8%) were APOE4 homozygote carriers. Definite and possible risk variants were detected in the genes TREM2, SORL1, ABCA7 and TBK1. In an explorative approach, we cross-checked rare gene variants in our cohort with a curated neurodegeneration candidate gene list and identified DCTN1, MAPK8IP3, LRRK2, VPS13C and BACE1 as promising candidate genes. Conclusively, 12 cases (20%) carried variants relevant to patient counseling, comparable to previously reported studies, and can thus be considered genetically resolved. Reduced penetrance, oligogenic inheritance and not yet identified high-risk genes might explain the high number of unresolved cases. To address this issue, we provide complete genetic and phenotypic information (uploaded to the European Genome-phenome Archive), enabling other researchers to cross-check variants. Thereby, we hope to increase the chance of independently finding the same gene/variant-hit in other well-defined EOD patient cohorts, thus confirming new genetic risk variants or variant combinations.
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Enfermedad de Alzheimer , Humanos , Anciano , Enfermedad de Alzheimer/genética , Secretasas de la Proteína Precursora del Amiloide/genética , Predisposición Genética a la Enfermedad , Austria , Ácido Aspártico Endopeptidasas/genética , Pruebas Genéticas , Mutación , Proteínas Relacionadas con Receptor de LDL/genética , Proteínas de Transporte de Membrana/genéticaRESUMEN
OBJECTIVE: An association between odor and cognitive impairment has been shown in many studies. The objective of the present hospital-based, single-center retrospective study was to assess the impact of odor impairment on the mortality of patients with Alzheimer's disease (AD), subjective cognitive decline (SCD), and mild cognitive impairment (MCI). METHODS: Odor function was measured by Sniffin Sticks (Burghart Messtechnik, Holm, Germany) and the assessment of self-reported olfactory functioning and olfaction-related quality of life (ASOF) test. Cognitive performance was assessed by an extensive neuropsychological test battery, symptoms of depression were diagnosed with the Geriatric Depressive Scale (GDS). The influence of demographic factors such as gender, age, and education were examined. RESULTS: Although the univariate analyses and pairwise post hoc comparison showed significant differences for some of the olfactory performance tests/subtests, the multivariate models showed no association between olfactory test performance and mortality among patients with cognitive impairment. "Attention," a domain of the Neuropsychological Test Battery Vienna (NTBV), as well as depressive symptoms, gender, and age, showed a significant influence on the mortality of the patient group. CONCLUSION: Lower olfactory performance showed no impact on mortality. However, decreased cognitive function of "Attention" can be considered as an influential predictor for mortality.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Trastornos del Olfato , Humanos , Anciano , Olfato , Depresión/diagnóstico , Calidad de Vida , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/psicología , Estudios Retrospectivos , Trastornos del Olfato/diagnóstico , Cognición , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/psicología , Pruebas NeuropsicológicasRESUMEN
BACKGROUND AND PURPOSE: Dementia prevalence is increasing, with numbers projected to double by 2050. Risk factors for its development include age and cardiovascular comorbidities, which are found more often in patients with dementia and should be treated properly to improve outcomes. In this case-control study, we analysed a large population-based prescription database to explore the patterns of co-medication in patients with dementia. METHODS: Prescription claims covering >99% of the Austrian population from 2005 to 2016 were obtained. Patients who were treated with an approved antidementia drug (ADD) were included and co-medication exposure was recorded. A group of people not taking ADDs was matched for age, sex and follow-up duration as a control. RESULTS: We included 70,799 patients on ADDs who were exposed to a mean of 5.3 co-medications while control patients were treated with a total of 5.2 co-medications (p < 0.001). We found that patients on ADDs received less somatic (4.1 vs. 4.5) but more psychiatric medication (1.1 vs. 0.6; p < 0.001 for both). Patients on ADDs were less likely to be treated for pain, cardiovascular conditions or hyperlipidemia. More than 50% of patients on ADDs were treated with antidepressants or antipsychotics. Greater number of co-medications was associated with markers of more intensive antidementia treatment. CONCLUSION: Patients on ADDs received more medications overall but were less frequently treated for somatic conditions known to be more prevalent in this group. Together, our data suggest that management of comorbidities in dementia could be improved to optimize outcome and quality of life.
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Demencia , Calidad de Vida , Humanos , Estudios de Casos y Controles , Comorbilidad , Demencia/tratamiento farmacológico , AustriaRESUMEN
Multiple Sclerosis (MS) is a common immune-mediated disorder of the central nervous system that affects young adults and is characterized by demyelination and neurodegeneration. Recent studies have associated C9orf72 intermediate repeat expansions with MS. The objective of this study was to investigate whether C9orf72 repeat length is associated with MS or with a specific disease course in a monocentric Austrian MS cohort. Genotyping of 382 MS patients and 643 non-neurological controls for C9orf72 repeat expansions was performed. The study did not find a difference in the distribution of repeat numbers between controls and MS cases (median repeat units = 2; p = 0.39). Additionally, sub-analysis did not establish a link between intermediate repeats and MS (p = 0.23) and none of the patients with progressive disease course carried an intermediate allele (20-30 repeat units). Exploratory analysis for different cut-offs (of ≥7, ≥17, and ≥24) did not reveal any significant differences in allele frequencies between MS and controls. However, the study did identify a progressive MS patient with a pathogenic C9orf72 expansion and probable co-existing behavioral variant frontotemporal dementia (bvFTD) in a retrospective chart review. In conclusion, this study did not find evidence supporting an association between C9orf72 repeat length and MS or a specific disease course in the Austrian MS cohort. However, the identification of a progressive MS patient with a pathogenic C9orf72 expansion and probable co-existing with FTD highlights the complexity and challenges involved in recognizing distinct neurodegenerative diseases that may co-occur in MS patients.
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Proteína C9orf72 , Esclerosis Múltiple , Humanos , Esclerosis Amiotrófica Lateral/genética , Austria , Proteína C9orf72/genética , Demencia Frontotemporal/genética , Esclerosis Múltiple/genética , Esclerosis Múltiple Crónica Progresiva/genética , Estudios RetrospectivosRESUMEN
BACKGROUND: C9orf72 repeat expansions have been observed in a wide variety of neurodegenerative disorders. The cut-off between normal and pathogenic alleles is not well established as repeat sizing methods are often semi-quantitative. However, intermediate alleles might influence disease prevalence and phenotype, as seen for other repeat expansion disorders. We aimed to further delineate the prevalence of small, intermediate and expanded C9orf72 alleles and elucidate their potential influence on the disease phenotype. METHODS: DNA derived from patients (n = 1804) and healthy individuals (n = 643) was obtained from multiple collectives in Austria. Genotyping was performed using a two-step PCR assay followed by Southern blotting. RESULTS: 3.4% of clinically diagnosed frontotemporal dementia (FTD; n = 5/147) cases and 0.8% of clinically diagnosed Alzheimer's disease (AD; n = 5/602) cases were carriers of a pathological C9orf72 repeat expansion. A significantly earlier disease onset was detected in expansion carriers compared to non-carriers in the FTD and AD cohorts (median 50 years, range 39-64 vs. median 64 years, range 36-92, p = 0.018 and median 63 years, range 54-71 vs. median 74 years, range 45-92, p = 0.006, respectively). C9orf72 intermediate alleles were significantly associated with cerebellar symptoms (p = 0.0004) and sensory deficits in the dementia cohort (p = 0.01). CONCLUSIONS: C9orf72 repeat expansion carriers showed earlier disease onset compared to non-carriers with clinical diagnosis of FTD and AD. Furthermore, C9orf72 intermediate repeats might modify the phenotypic expression in dementia.
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Esclerosis Amiotrófica Lateral , Demencia Frontotemporal , Humanos , Expansión de las Repeticiones de ADN/genética , Proteína C9orf72/genética , Demencia Frontotemporal/genética , Demencia Frontotemporal/patología , Proteínas/genética , Fenotipo , Esclerosis Amiotrófica Lateral/genéticaRESUMEN
BACKGROUND: Assistive technologies have the potential to facilitate everyday life of people with dementia and their families. Close collaboration with affected people and interdisciplinary research are essential to understand and address the needs of prospective users. In this study, we present the results of the evaluation of such an assistive system prototype. AIMS: Challenges from the patient and caregiver side, technical and design problems and acceptance and usability with regard to our special target group were evaluated. METHODS: MEMENTO, a system of two e-ink tablets and a smartwatch, was tested in the domestic environment of dementia patients. Thirty participants from Italy, Spain and Austria took part in a 3-month field trial and compared the MEMENTO system to traditional strategies in everyday life. Quantitative and qualitative data were collected and frequency of use of the system was monitored. RESULTS: There were no significant changes in quantitative measurements, such as activities of daily living and caregiver burden over the duration of the 3-month field trial. More frequent usage was significantly correlated with positive attitude towards technology (r = 0.723, p < 0.05), but not with age. The design of the system was positively emphasized, reducing fear of the technology on the one hand and stigmatization on the other. CONCLUSION: We show that a positive attitude towards technology is the essential variable for successful implementation of such systems, regardless of age. Participants showed great interest in digital solutions and agreed that technological systems will help in maintaining independency of persons with cognitive dysfunction in the future.
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Demencia , Dispositivos de Autoayuda , Actividades Cotidianas , Cuidadores/psicología , Humanos , Estudios ProspectivosRESUMEN
Background and Objectives: The neurofilament light chain (NfL) is a biomarker for neuro-axonal injury in various acute and chronic neurological disorders, including Alzheimer's disease (AD). We here investigated the cross-sectional and longitudinal associations between baseline serum NfL (sNfL) levels and cognitive, behavioural as well as MR volumetric findings in the Prospective Dementia Registry Austria (PRODEM-Austria). Materials and Methods: All participants were clinically diagnosed with AD according to NINCDS-ADRDA criteria and underwent a detailed clinical assessment, cognitive testing (including the Mini Mental State Examination (MMSE) and the Consortium to Establish a Registry for Alzheimer's Disease (CERAD)), the neuropsychiatric inventory (NPI) and laboratory evaluation. A total of 237 patients were included in the study. Follow-up examinations were done at 6 months, 1 year and 2 years with 93.3% of patients undergoing at least one follow-up. We quantified sNfL by a single molecule array (Simoa). In a subgroup of 125 subjects, brain imaging data (1.5 or 3T MRI, with 1 mm isotropic resolution) were available. Brain volumetry was assessed using the FreeSurfer image analysis suite (v6.0). Results: Higher sNfL concentrations were associated with worse performance in cognitive tests at baseline, including CERAD (B = −10.084, SE = 2.999, p < 0.001) and MMSE (B = −3.014, SE = 1.293, p = 0.021). The sNfL levels also correlated with the presence of neuropsychiatric symptoms (NPI total score: r = 0.138, p = 0.041) and with smaller volumes of the temporal lobe (B = −0.012, SE = 0.003, p = 0.001), the hippocampus (B = −0.001, SE = 0.000201, p = 0.013), the entorhinal (B = −0.000308, SE = 0.000124, p = 0.014), and the parahippocampal cortex (B = −0.000316, SE = 0.000113, p = 0.006). The sNfL values predicted more pronounced cognitive decline over the mean follow-up period of 22 months, but there were no significant associations with respect to change in neuropsychiatric symptoms and brain volumetric measures. Conclusions: the sNfL levels relate to cognitive, behavioural, and imaging hallmarks of AD and predicts short term cognitive decline.
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Enfermedad de Alzheimer , Enfermedad de Alzheimer/diagnóstico por imagen , Austria/epidemiología , Estudios Transversales , Humanos , Estudios Prospectivos , Sistema de RegistrosRESUMEN
BACKGROUND: The C9orf72 hexanucleotide expansion mutation is the most common cause of genetic frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS) and combined FTD-ALS. Its underlying neuropathology combines TDP-43 pathology and dipeptide repeat protein (DPR) deposits and may also associate with other neurodegeneration-associated protein aggregates. Herein we present a unique combination of C9orf72 mutation with sporadic Creutzfeldt-Jakob disease (CJD) in a 74-year-old patient with rapidly progressive dementia. METHODS: Detailed neuropathological examination including immunohistochemistry for several proteinopathies. Genetic analysis was conducted by repeat primed polymerase chain reaction (PCR). Furthermore, we analyzed additional C9orf72 mutation carriers for prion-protein (PrP) deposits in brain tissue and screened the cerebellar cortex of other CJD cases for p62/DPR neuronal inclusions to assess the frequency of combined pathologies. RESULTS: Postmortem brain examination of a patient with a rapidly progressive neurological deterioration of 8 months' duration confirmed the diagnosis of CJD. She harbored valine homozygosity at PRNP codon 129. In addition, a frontotemporal lobar degeneration (FTLD)-pattern with TDP-43 protein aggregates and p62+/C9RANT+ positive inclusions along with a high degree of Alzheimer-related pathology (A3B3C3) were identified. The suspected C9orf72 expansion mutation was confirmed by repeat-primed PCR. Screening of 13 C9orf72 cases showed no pathological PrP aggregates and screening of 100 CJD cases revealed no other C9orf72 expansion mutation carriers. CONCLUSION: A combination of a C9orf72 expansion mutation-related FTLD with sporadic CJD in the same patient is rare. While the rarity of both diseases makes this concurrence most likely to be coincidental, questions regarding a potential link between these two neurodegenerative pathologies deserve further studies.
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Esclerosis Amiotrófica Lateral , Síndrome de Creutzfeldt-Jakob , Demencia Frontotemporal , Degeneración Lobar Frontotemporal , Anciano , Esclerosis Amiotrófica Lateral/genética , Proteína C9orf72/genética , Síndrome de Creutzfeldt-Jakob/genética , Expansión de las Repeticiones de ADN/genética , Proteínas de Unión al ADN/genética , Femenino , Demencia Frontotemporal/genética , Degeneración Lobar Frontotemporal/genética , Humanos , MutaciónRESUMEN
OBJECTIVES: Evidence-based treatment of dementia includes pharmacological and non-pharmacological methods of which psycho-social interventions are an important component, commonly administered by occupational therapists. The aim of this study was to investigate the utilization of occupational therapy (OT) services and its association with survival in people taking dementia-specific medication in a population-based Austrian dataset compared to a two times as large control group without dementia-specific medication. METHODS/DESIGN: A retrospective study with a 13-year observation period (2003-2016) was conducted on real-world data. Two stratifications were done and we used descriptive statistics, Chi-squared/Fisher's Exact Tests and survival analyses including three Cox models. RESULTS: Data from 286,553 participants were analysed. Only 4.5% (n = 12,950) received OT services. In the dementia-medication group (n = 111,033), participants who received OT services (3.6%; n = 4032) had significantly more comorbidities (4.7%) compared to those without OT (3.5%; p < 0.001) and were also more likely to be male (4 vs. 3.5%; p < 0.001). While persons taking dementia-specific medication showed a slightly reduced survival with OT (p < 0.001) compared to those without, the result in the control group without dementia-specific medication showed a slightly better result of the participants who received OT (p < 0.001). The reduced survival in the dementia-medication group with OT is likely to be related to the higher number of comorbidities in this group. CONCLUSION: People receiving dementia-specific medication were more likely to receive OT if they had additional comorbidities, however our analysis showed that utilization of OT services in Austria was very low indicating an overall insufficient accessibility of OT services for patients who needed it.
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Demencia , Terapia Ocupacional , Austria , Demencia/tratamiento farmacológico , Femenino , Humanos , Masculino , Estudios RetrospectivosRESUMEN
BACKGROUND: The genetic architecture of non-acquired focal epilepsies (NAFEs) becomes increasingly unravelled using genome-wide sequencing datasets. However, it remains to be determined how this emerging knowledge can be translated into a diagnostic setting. To bridge this gap, we assessed the diagnostic outcomes of exome sequencing (ES) in NAFE. METHODS: 112 deeply phenotyped patients with NAFE were included in the study. Diagnostic ES was performed, followed by a screen to detect variants of uncertain significance (VUSs) in 15 well-established focal epilepsy genes. Explorative gene prioritisation was used to identify possible novel candidate aetiologies with so far limited evidence for NAFE. RESULTS: ES identified pathogenic or likely pathogenic (ie, diagnostic) variants in 13/112 patients (12%) in the genes DEPDC5, NPRL3, GABRG2, SCN1A, PCDH19 and STX1B. Two pathogenic variants were microdeletions involving NPRL3 and PCDH19. Nine of the 13 diagnostic variants (69%) were found in genes of the GATOR1 complex, a potentially druggable target involved in the mammalian target of rapamycin (mTOR) signalling pathway. In addition, 17 VUSs in focal epilepsy genes and 6 rare variants in candidate genes (MTOR, KCNA2, RBFOX1 and SCN3A) were detected. Five patients with reported variants had double hits in different genes, suggesting a possible (oligogenic) role of multiple rare variants. CONCLUSION: This study underscores the molecular heterogeneity of NAFE with GATOR1 complex genes representing the by far most relevant genetic aetiology known to date. Although the diagnostic yield is lower compared with severe early-onset epilepsies, the high rate of VUSs and candidate variants suggests a further increase in future years.
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Epilepsias Parciales/genética , Proteínas Activadoras de GTPasa/genética , Predisposición Genética a la Enfermedad , Adolescente , Adulto , Anciano , Niño , Preescolar , Epilepsias Parciales/diagnóstico , Epilepsias Parciales/patología , Exoma/genética , Femenino , Variación Genética/genética , Humanos , Lactante , Masculino , Persona de Mediana Edad , Complejos Multiproteicos/genética , Mutación/genética , Fenotipo , Proteínas Represoras/genética , Transducción de Señal/genética , Secuenciación del Exoma , Adulto JovenRESUMEN
Alzheimer's disease (AD) is the leading cause of neurodegeneration in the elderly and is clinically characterized by slowly progressing cognitive decline, which most commonly affects episodic memory function. This eventually leads to difficulties in activities of daily living. Biomarker studies show that the underlying pathology of AD begins 20 years before clinical symptoms. This results in the need to define specific targets and preclinical stages in order to address the problems of this disease at an earlier point in time. Genetic studies are indispensable for gaining insight into the etiology of neurodegenerative diseases and can play a major role in the early definition of the individual disease risk. This review provides an overview of the currently known genetic features of AD.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Actividades Cotidianas , Anciano , Enfermedad de Alzheimer/genética , Biomarcadores , Disfunción Cognitiva/genética , Progresión de la Enfermedad , HumanosRESUMEN
We characterize a consanguineous Egyptian family with an autosomal recessively inherited familial cortical myoclonic tremor and epilepsy. We used multipoint linkage analysis to map the causative mutation to a 12.7 megabase interval within 1q31.3-q32.2 with a log of odds score of 3.6. For further investigation of the linked region in an efficient and unbiased manner, we performed exome sequencing. Within the suspected region we identified a homozygous single base pair deletion (c.503_503delG) leading to a frameshift in the coding region of the sixth exon of CNTN2 alias TAG-1 (p.Trp168fs), which segregated in the respective family. Many studies point towards an important role of the CNTN2 product contactin 2 in neuronal excitability. Contactin 2, a glycosylphosphatidylinositol-anchored neuronal membrane protein, and another transmembrane protein called contactin associated protein-like 2 (CNTNAP2 alias CASPR2) are together necessary to maintain voltage-gated potassium channels at the juxtaparanodal region. CNTN2 knockout mice were previously reported to suffer from spontaneous seizures and mutations in the CNTNAP2 gene have been described to cause epilepsy in humans. To further delineate the role of CNTN2 in patients with epilepsy, we sequenced the coding exons in 189 Caucasian patients with epilepsy. No recessive mutation was detected and heterozygote carriers of rare CNTN2 variants do not seem to be predisposed to epilepsy. Given the severity of the mutation and the proposed function of the gene, we consider this mutation as the most likely cause for cortical myoclonic tremor and epilepsy in this family.
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Contactina 2/genética , Epilepsias Mioclónicas/genética , Mutación del Sistema de Lectura/genética , Adulto , Consanguinidad , Egipto , Epilepsias Mioclónicas/diagnóstico , Epilepsias Mioclónicas/fisiopatología , Exoma/genética , Femenino , Ligamiento Genético , Humanos , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Proteínas del Tejido Nervioso/genética , Linaje , Temblor/diagnóstico , Temblor/genética , Temblor/fisiopatología , Adulto JovenRESUMEN
Epilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandating the search for better understanding and treatment. The cause of mesial temporal lobe epilepsy with hippocampal sclerosis is unknown, but there is an association with childhood febrile seizures. Several rarer epilepsies featuring febrile seizures are caused by mutations in SCN1A, which encodes a brain-expressed sodium channel subunit targeted by many anti-epileptic drugs. We undertook a genome-wide association study in 1018 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 7552 control subjects, with validation in an independent sample set comprising 959 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 3591 control subjects. To dissect out variants related to a history of febrile seizures, we tested cases with mesial temporal lobe epilepsy with hippocampal sclerosis with (overall n = 757) and without (overall n = 803) a history of febrile seizures. Meta-analysis revealed a genome-wide significant association for mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures at the sodium channel gene cluster on chromosome 2q24.3 [rs7587026, within an intron of the SCN1A gene, P = 3.36 × 10(-9), odds ratio (A) = 1.42, 95% confidence interval: 1.26-1.59]. In a cohort of 172 individuals with febrile seizures, who did not develop epilepsy during prospective follow-up to age 13 years, and 6456 controls, no association was found for rs7587026 and febrile seizures. These findings suggest SCN1A involvement in a common epilepsy syndrome, give new direction to biological understanding of mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures, and open avenues for investigation of prognostic factors and possible prevention of epilepsy in some children with febrile seizures.
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Epilepsia del Lóbulo Temporal/genética , Mutación/genética , Canal de Sodio Activado por Voltaje NAV1.1/genética , Esclerosis/genética , Convulsiones Febriles/genética , Epilepsia del Lóbulo Temporal/etiología , Estudio de Asociación del Genoma Completo/métodos , Hipocampo/patología , Humanos , Estudios Prospectivos , Convulsiones Febriles/diagnóstico , Lóbulo Temporal/patologíaRESUMEN
Alzheimer's disease (AD) imposes a major burden on affected individuals, their caregivers and health-care systems alike. Though quite many risk factors for disease progression have been identified, there is a lack of prospective studies investigating the interplay and predictive value of a wide variety of patient variables associated with cognitive deterioration (defined as key feature of AD progression). Study participants were patients with probable and possible AD, that were assessed at four time points over a period of two years (T1-T4). The main results were threefold: (i) over time, significant changes were observed regarding patients' cognitive functioning, activities of daily living and caregiver load (but not depression, pain, neuropsychiatric symptoms); (ii) intercorrelations between caregiver load and patients' cognitive and functional variables were high, correlation patterns remaining rather stable across time; (iii) cognitive functioning at T4 was best predicted by patients' age, sex, atrial fibrillation and activities of daily living at T1; and (iv) across all four assessment points, cognitive functioning was best predicted by time (i.e., disease duration), age, sex, activities of daily living and depression. Overall, even in early stages of AD and during a short two-year period, functional changes were significant and tightly intertwined with caregiver load, thus stressing the need to consider caregiver load when diagnosing and treating patients with AD. A novel and clinically relevant finding is that even in early stages of AD, cognitive deterioration was best predicted by a combination of patients' demographic, somatic and functional variables.
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Actividades Cotidianas , Enfermedad de Alzheimer , Cuidadores , Progresión de la Enfermedad , Humanos , Enfermedad de Alzheimer/fisiopatología , Enfermedad de Alzheimer/psicología , Masculino , Femenino , Anciano , Estudios Prospectivos , Cuidadores/psicología , Anciano de 80 o más Años , Cognición/fisiología , Sistema de Registros , Disfunción Cognitiva/fisiopatología , Pruebas Neuropsicológicas , Persona de Mediana Edad , Depresión , Factores de RiesgoRESUMEN
OBJECTIVE: In light of clinical trials and disease-modifying therapies, an early identification of patients at-risk of developing Alzheimer's disease (AD) is crucial. Blood-based biomarkers have shown promising results regarding the in vivo detection of the earliest neuropathological changes in AD. Herein, we investigated the ability of plasma p-tau181 to act as a prescreening marker for amyloid positivity in a heterogeneous memory clinic-based cohort. METHODS: In this retrospective cross-sectional study, we included a total of 115 patients along the clinical AD continuum (mild cognitive impairment [MCI] due to AD, n = 62, probable AD dementia, n = 53). Based on their biomarker status, they were stratified into an amyloid-positive (Aß+, n = 88) or amyloid-negative cohort (Aß-, n = 27). Plasma and CSF p-tau181 concentrations were quantified using an ultrasensitive single-molecule array (SIMOA©). Furthermore, age- and sex-adjusted receiver operating characteristic (ROC) curves were calculated and the area under the curve (AUC) of each model was compared using DeLong's test for correlated AUC curves. RESULTS: The median (interquartile range [IQR]) concentration of plasma p-tau181 was significantly higher in Aß+ patients (3.6 pg/mL [2.5-4.6]), compared with Aß- patients (1.7 pg/mL [1.2-1.9], p < 0.001). Regarding the distinction between Aß+ and Aß- patients and the prediction of amyloid positivity, a high diagnostic accuracy for plasma p-tau181 with an AUC of 0.89 (95% CI = 0.82-0.95) was calculated. Adding the risk factors, age and APOE4, to the model did not significantly improve its performance. INTERPRETATION: Our findings demonstrate that plasma p-tau181 could be a noninvasive and feasible prescreening marker for amyloid positivity in a heterogeneous clinical AD cohort and therefore help in identifying those who would benefit from more invasive assessment of amyloid pathology.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Biomarcadores , Disfunción Cognitiva , Proteínas tau , Humanos , Proteínas tau/sangre , Proteínas tau/líquido cefalorraquídeo , Masculino , Femenino , Anciano , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/diagnóstico , Disfunción Cognitiva/sangre , Disfunción Cognitiva/diagnóstico , Biomarcadores/sangre , Estudios Transversales , Estudios Retrospectivos , Persona de Mediana Edad , Péptidos beta-Amiloides/sangre , Anciano de 80 o más Años , Estudios de CohortesRESUMEN
OBJECTIVE: Mutations in the gene encoding for optineurin (OPTN) have been reported in the context of different neurodegenerative diseases including the amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) spectrum. Based on single case reports, neuropathological data in OPTN mutation carriers have revealed transactive response DNA-binding protein 43 kDa (TDP-43) pathology, in addition to accumulations of tau and alpha-synuclein. Herein, we present two siblings from a consanguineous family with a homozygous frameshift mutation in the OPTN gene and different clinical presentations. METHODS: Both affected siblings underwent (i) clinical, (ii) neurophysiological, (iii) neuropsychological, (iv) radiological, and (v) laboratory examinations, and (vi) whole-exome sequencing (WES). Postmortem histopathological examination was conducted in the index patient, who deceased at the age of 41. RESULTS: The index patient developed rapidly progressing clinical features of upper and lower motor neuron dysfunction as well as apathy and cognitive deterioration at the age of 41. Autopsy revealed an ALS-FTLD pattern associated with prominent neuronal and oligodendroglial TDP-43 pathology, and an atypical limbic 4-repeat tau pathology reminiscent of argyrophilic grain disease. The brother of the index patient exhibited behavioral changes and mnestic deficits at the age of 38 and was diagnosed with behavioral FTD 5 years later, without any evidence of motor neuron dysfunction. WES revealed a homozygous frameshift mutation in the OPTN gene in both siblings (NM_001008212.2: c.1078_1079del; p.Lys360ValfsTer18). INTERPRETATION: OPTN mutations can be associated with extensive TDP-43 pathology and limbic-predominant tauopathy and present with a heterogeneous clinical phenotype within the ALS-FTD spectrum within the same family.
Asunto(s)
Esclerosis Amiotrófica Lateral , Proteínas de Ciclo Celular , Demencia Frontotemporal , Proteínas de Transporte de Membrana , Humanos , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Esclerosis Amiotrófica Lateral/fisiopatología , Esclerosis Amiotrófica Lateral/diagnóstico , Proteínas de Transporte de Membrana/genética , Proteínas de Ciclo Celular/genética , Demencia Frontotemporal/genética , Demencia Frontotemporal/patología , Demencia Frontotemporal/fisiopatología , Masculino , Adulto , Femenino , Linaje , Factor de Transcripción TFIIIA/genética , Hermanos , Mutación del Sistema de Lectura , HomocigotoRESUMEN
BACKGROUND: Cognitive impairment is prevalent in patients with heart failure with reduced ejection fraction (HFrEF), affecting self-care and outcomes. Novel blood-based biomarkers have emerged as potential diagnostic tools for neurodegeneration. OBJECTIVES: This study aimed to assess neurodegeneration in HFrEF by measuring neurofilament light chain (NfL), total tau (t-tau), amyloid beta 40 (Aß40), and amyloid beta 42 (Aß42) in a large, well-characterized cohort. METHODS: The study included 470 patients with HFrEF from a biobank-linked prospective registry at the Medical University of Vienna. High-sensitivity single-molecule assays were used for measurement. Unplanned heart failure (HF) hospitalization and all-cause death were recorded as outcome parameters. RESULTS: All markers, but not the Aß42:Aß40 ratio, correlated with HF severity, ie, N-terminal pro-B-type natriuretic peptide and NYHA functional class, and comorbidity burden and were significantly associated with all-cause death and HF hospitalization (crude HR: all-cause death: NfL: 4.44 [95% CI: 3.02-6.53], t-tau: 5.04 [95% CI: 2.97-8.58], Aß40: 3.90 [95% CI: 2.27-6.72], and Aß42: 5.14 [95% CI: 2.84-9.32]; HF hospitalization: NfL: 2.48 [95% CI: 1.60-3.85], t-tau: 3.44 [95% CI: 1.95-6.04], Aß40: 3.13 [95% CI: 1.84-5.34], and Aß42: 3.48 [95% CI: 1.93-6.27]; P < 0.001 for all). These associations remained statistically significant after multivariate adjustment including N-terminal pro-B-type natriuretic peptide. The discriminatory accuracy of NfL in predicting all-cause mortality was comparable to the well-established risk marker N-terminal pro-B-type natriuretic peptide (C-index: 0.70 vs 0.72; P = 0.225), whereas the C-indices of t-tau, Aß40, Aß42, and the Aß42:Aß40 ratio were significantly lower (P < 0.05 for all). CONCLUSIONS: Neurodegeneration is directly interwoven with the progression of HF. Biomarkers of neurodegeneration, particularly NfL, may help identify patients potentially profiting from a comprehensive neurological work-up. Further research is necessary to test whether early diagnosis or optimized HFrEF treatment can preserve cognitive function.