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INTRODUCTION: Frontotemporal lobar degeneration (FTLD) encompasses behavioral variant frontotemporal dementia (bvFTD), progressive supranuclear palsy, corticobasal syndrome/degeneration, and primary progressive aphasias (PPAs). We cross-validated fluid biomarkers and neuroimaging. METHODS: Seven fluid biomarkers from cerebrospinal fluid and serum were related to atrophy in 428 participants including these FTLD subtypes, logopenic variant PPA (lvPPA), Alzheimer's disease (AD), and healthy subjects. Atrophy was assessed by structural magnetic resonance imaging and atlas-based volumetry. RESULTS: FTLD subtypes, lvPPA, and AD showed specific profiles for neurofilament light chain, phosphorylated heavy chain, tau, phospho-tau, amyloid beta1-42 from serum/cerebrospinal fluid, and brain atrophy. Neurofilaments related to regional atrophy in bvFTD, whereas progranulin was associated with atrophy in semantic variant PPA. Ubiquitin showed no effects. DISCUSSION: Results specify biomarker and atrophy patterns in FTLD and AD supporting differential diagnosis. They identify neurofilaments and progranulin in interaction with structural imaging as promising candidates for monitoring disease progression and therapy. HIGHLIGHTS: Study cross-validated neuroimaging and fluid biomarkers in dementia. Five kinds of frontotemporal lobar degeneration and two variants of Alzheimer's disease. Study identifies disease-specific fluid biomarker and atrophy profiles. Fluid biomarkers and atrophy interact in a disease-specific way. Neurofilaments and progranulin are proposed as biomarkers for diagnosis and therapy.
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Doença de Alzheimer , Atrofia , Biomarcadores , Encéfalo , Degeneração Lobar Frontotemporal , Imageamento por Ressonância Magnética , Proteínas de Neurofilamentos , Progranulinas , Proteínas tau , Humanos , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/sangue , Degeneração Lobar Frontotemporal/patologia , Masculino , Feminino , Atrofia/patologia , Idoso , Pessoa de Meia-Idade , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Proteínas de Neurofilamentos/sangue , Proteínas tau/líquido cefalorraquidiano , Encéfalo/patologia , Encéfalo/diagnóstico por imagem , Doença de Alzheimer/patologia , Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidianoRESUMO
OBJECTIVE: In this randomized controlled trial, we investigated the effectiveness, side effects and user satisfaction of the self-help smartphone app "MCT & More" among inpatients with a diagnosis of depression after their discharge from a psychiatric hospital over a period of 4 weeks. METHODS: A total of 159 inpatients were recruited in four German psychiatric hospitals three days before hospital discharge (intervention group: n = 79; treatment as usual: n = 80). Based on the vulnerability model (low self-esteem contributes to depression), self-esteem represented the primary outcome, quality of life and depressive symptoms the secondary outcomes. RESULTS: Intention-to-treat analyzes showed no statistical significance for the primary and secondary outcome parameters, except for the subscale self-competence in favor of the intervention group (with a small effect size of d = 0.35), in the context of an exploratory approach (post hoc). The more positive the attitude toward mobile-based interventions and the more positive the treatment expectations, the more frequently the app was used (r = .35, p = .008; r = .34, p = .009). CONCLUSION: Further symptom reduction could not be obtained. However, the results suggest that an effect on improvement in self-competence could be achieved by low-threshold aftercare programs. Future studies should include long-term assessments to examine the impact of mobile-based aftercare on relapse.Trial registration: DRKS00022559.
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Assistência ao Convalescente , Depressão , Humanos , Depressão/psicologia , Assistência ao Convalescente/métodos , Pacientes Internados , Qualidade de Vida/psicologiaRESUMO
INTRODUCTION: Dementia syndromes can be difficult to diagnose. We aimed at building a classifier for multiple dementia syndromes using magnetic resonance imaging (MRI). METHODS: Atlas-based volumetry was performed on T1-weighted MRI data of 426 patients and 51 controls from the multi-centric German Research Consortium of Frontotemporal Lobar Degeneration including patients with behavioral variant frontotemporal dementia, Alzheimer's disease, the three subtypes of primary progressive aphasia, i.e., semantic, logopenic and nonfluent-agrammatic variant, and the atypical parkinsonian syndromes progressive supranuclear palsy and corticobasal syndrome. Support vector machine classification was used to classify each patient group against controls (binary classification) and all seven diagnostic groups against each other in a multi-syndrome classifier (multiclass classification). RESULTS: The binary classification models reached high prediction accuracies between 71 and 95% with a chance level of 50%. Feature importance reflected disease-specific atrophy patterns. The multi-syndrome model reached accuracies of more than three times higher than chance level but was far from 100%. Multi-syndrome model performance was not homogenous across dementia syndromes, with better performance in syndromes characterized by regionally specific atrophy patterns. Whereas diseases generally could be classified vs controls more correctly with increasing severity and duration, differentiation between diseases was optimal in disease-specific windows of severity and duration. DISCUSSION: Results suggest that automated methods applied to MR imaging data can support physicians in diagnosis of dementia syndromes. It is particularly relevant for orphan diseases beside frequent syndromes such as Alzheimer's disease.
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Doença de Alzheimer , Demência Frontotemporal , Degeneração Lobar Frontotemporal , Humanos , Doença de Alzheimer/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Imageamento por Ressonância Magnética/métodos , Degeneração Lobar Frontotemporal/patologia , Demência Frontotemporal/diagnóstico por imagem , Demência Frontotemporal/patologia , Síndrome , Atrofia/diagnóstico por imagem , Atrofia/patologiaRESUMO
BACKGROUND: Recent data support beta-synuclein as a blood biomarker to study synaptic degeneration in Alzheimer's disease (AD). METHODS: We provide a detailed comparison of serum beta-synuclein immunoprecipitation - mass spectrometry (IP-MS) with the established blood markers phosphorylated tau 181 (p-tau181) (Simoa) and neurofilament light (NfL) (Ella) in the German FTLD consortium cohort (n = 374) and its relation to brain atrophy (magnetic resonance imaging) and cognitive scores. RESULTS: Serum beta-synuclein was increased in AD but not in frontotemporal lobar degeneration (FTLD) syndromes. Beta-synuclein correlated with atrophy in temporal brain structures and was associated with cognitive impairment. Serum p-tau181 showed the most specific changes in AD but the lowest correlation with structural alterations. NfL was elevated in all diseases and correlated with frontal and temporal brain atrophy. DISCUSSION: Serum beta-synuclein changes differ from those of NfL and p-tau181 and are strongly related to AD, most likely reflecting temporal synaptic degeneration. Beta-synuclein can complement the existing panel of blood markers, thereby providing information on synaptic alterations. HIGHLIGHTS: Blood beta-synuclein is increased in Alzheimer's disease (AD) but not in frontotemporal lobar degeneration (FTLD) syndromes. Blood beta-synuclein correlates with temporal brain atrophy in AD. Blood beta-synuclein correlates with cognitive impairment in AD. The pattern of blood beta-synuclein changes in the investigated diseases is different to phosphorylated tau 181 (p-tau181) and neurofilament light (NfL).
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Doença de Alzheimer , Demência Frontotemporal , Degeneração Lobar Frontotemporal , Humanos , Doença de Alzheimer/patologia , beta-Sinucleína , Proteínas tau , Degeneração Lobar Frontotemporal/patologia , Encéfalo/patologia , Biomarcadores , Atrofia/patologia , Peptídeos beta-AmiloidesRESUMO
Importance: The behavioral and cognitive symptoms of severe psychotic disorders overlap with those seen in dementia. However, shared brain alterations remain disputed, and their relevance for patients in at-risk disease stages has not been explored so far. Objective: To use machine learning to compare the expression of structural magnetic resonance imaging (MRI) patterns of behavioral-variant frontotemporal dementia (bvFTD), Alzheimer disease (AD), and schizophrenia; estimate predictability in patients with bvFTD and schizophrenia based on sociodemographic, clinical, and biological data; and examine prognostic value, genetic underpinnings, and progression in patients with clinical high-risk (CHR) states for psychosis or recent-onset depression (ROD). Design, Setting, and Participants: This study included 1870 individuals from 5 cohorts, including (1) patients with bvFTD (n = 108), established AD (n = 44), mild cognitive impairment or early-stage AD (n = 96), schizophrenia (n = 157), or major depression (n = 102) to derive and compare diagnostic patterns and (2) patients with CHR (n = 160) or ROD (n = 161) to test patterns' prognostic relevance and progression. Healthy individuals (n = 1042) were used for age-related and cohort-related data calibration. Data were collected from January 1996 to July 2019 and analyzed between April 2020 and April 2022. Main Outcomes and Measures: Case assignments based on diagnostic patterns; sociodemographic, clinical, and biological data; 2-year functional outcomes and genetic separability of patients with CHR and ROD with high vs low pattern expression; and pattern progression from baseline to follow-up MRI scans in patients with nonrecovery vs preserved recovery. Results: Of 1870 included patients, 902 (48.2%) were female, and the mean (SD) age was 38.0 (19.3) years. The bvFTD pattern comprising prefrontal, insular, and limbic volume reductions was more expressed in patients with schizophrenia (65 of 157 [41.2%]) and major depression (22 of 102 [21.6%]) than the temporo-limbic AD patterns (28 of 157 [17.8%] and 3 of 102 [2.9%], respectively). bvFTD expression was predicted by high body mass index, psychomotor slowing, affective disinhibition, and paranoid ideation (R2 = 0.11). The schizophrenia pattern was expressed in 92 of 108 patients (85.5%) with bvFTD and was linked to the C9orf72 variant, oligoclonal banding in the cerebrospinal fluid, cognitive impairment, and younger age (R2 = 0.29). bvFTD and schizophrenia pattern expressions forecasted 2-year psychosocial impairments in patients with CHR and were predicted by polygenic risk scores for frontotemporal dementia, AD, and schizophrenia. Findings were not associated with AD or accelerated brain aging. Finally, 1-year bvFTD/schizophrenia pattern progression distinguished patients with nonrecovery from those with preserved recovery. Conclusions and Relevance: Neurobiological links may exist between bvFTD and psychosis focusing on prefrontal and salience system alterations. Further transdiagnostic investigations are needed to identify shared pathophysiological processes underlying the neuroanatomical interface between the 2 disease spectra.
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Doença de Alzheimer , Demência Frontotemporal , Transtornos Psicóticos , Esquizofrenia , Adulto , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Feminino , Demência Frontotemporal/diagnóstico por imagem , Demência Frontotemporal/genética , Humanos , Aprendizado de Máquina , Imageamento por Ressonância Magnética/métodos , Masculino , Testes Neuropsicológicos , Transtornos Psicóticos/diagnóstico por imagem , Transtornos Psicóticos/genética , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/genéticaRESUMO
IMPORTANCE: The entry of artificial intelligence into medicine is pending. Several methods have been used for the predictions of structured neuroimaging data, yet nobody compared them in this context. OBJECTIVE: Multi-class prediction is key for building computational aid systems for differential diagnosis. We compared support vector machine, random forest, gradient boosting, and deep feed-forward neural networks for the classification of different neurodegenerative syndromes based on structural magnetic resonance imaging. DESIGN, SETTING, AND PARTICIPANTS: Atlas-based volumetry was performed on multi-centric T1-weighted MRI data from 940 subjects, i.e., 124 healthy controls and 816 patients with ten different neurodegenerative diseases, leading to a multi-diagnostic multi-class classification task with eleven different classes. INTERVENTIONS: N.A. MAIN OUTCOMES AND MEASURES: Cohen's kappa, accuracy, and F1-score to assess model performance. RESULTS: Overall, the neural network produced both the best performance measures and the most robust results. The smaller classes however were better classified by either the ensemble learning methods or the support vector machine, while performance measures for small classes were comparatively low, as expected. Diseases with regionally specific and pronounced atrophy patterns were generally better classified than diseases with widespread and rather weak atrophy. CONCLUSIONS AND RELEVANCE: Our study furthermore underlines the necessity of larger data sets but also calls for a careful consideration of different machine learning methods that can handle the type of data and the classification task best.
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Inteligência Artificial , Aprendizado de Máquina , Algoritmos , Atrofia , Humanos , SíndromeRESUMO
BACKGROUND: Primary progressive aphasia (PPA) may present with three distinct clinical sybtypes: semantic variant PPA (svPPA), nonfluent/agrammatic variant PPA (nfvPPA), and logopenic variant PPA (lvPPA). OBJECTIVE: The aim was to examine the utility of the German version of the Repeat and Point (R&P) Test for subtyping patients with PPA. METHOD: During the R&P Test, the examiner reads out aloud a noun and the participants are asked to repeat the word and subsequently point to the corresponding picture. Data from 204 patients (68 svPPA, 85 nfvPPA, and 51 lvPPA) and 33 healthy controls were analyzed. RESULTS: Controls completed both tasks with >90% accuracy. Patients with svPPA had high scores in repetition (mean=9.2±1.32) but low scores in pointing (mean=6±2.52). In contrast, patients with nfvPPA and lvPPA performed comparably in both tasks with lower scores in repetition (mean=7.4±2.7 for nfvPPA and 8.2±2.34 for lvPPA) but higher scores in pointing (mean=8.9±1.41 for nfvPPA and 8.6±1.62 for lvPPA). The R&P Test had high accuracy discriminating svPPA from nfvPPA (83% accuracy) and lvPPA (79% accuracy). However, there was low accuracy discriminating nfvPPA from lvPPA (<60%). CONCLUSION: The R&P Test helps to differentiate svPPA from 2 nonsemantic variants (nfvPPA and lvPPA). However, additional tests are required for the differentiation of nfvPPA and lvPPA.
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Afasia Primária Progressiva , Afasia Primária Progressiva não Fluente , Afasia Primária Progressiva/diagnóstico , Humanos , IdiomaRESUMO
ApoE4, the strongest genetic risk factor for Alzheimer's disease (AD), has been shown to be associated with both beta-amyloid (Aß) and tau pathology, with the strongest evidence for effects on Aß, while the association between ApoE4 and tau pathology remains inconsistent. This study aimed to investigate the associations between ApoE4 with CSF Aß42, total tau (t-tau), phospho-tau181 (p-tau), and with the progression of decline in a large cohort of MCI subjects, both progressors to AD and other dementias, as well as non-progressors. We analyzed associations of CSF Aß42, p-tau and t-tau with ApoE4 allele frequency cross-sectionally and longitudinally over 3 years of follow-up in 195 individuals with a diagnosis of MCI-stable, MCI-AD converters and MCI progressing to other dementias from the German Dementia Competence Network. In the total sample, ApoE4 carriers had lower concentrations of CSF Aß42, and increased concentrations of t-tau and p-tau compared to non-carriers in a gene dose-dependent manner. Comparisons of these associations stratified by MCI-progression groups showed a significant influence of ApoE4 carriership and diagnostic group on all CSF biomarker levels. The effect of ApoE4 was present in MCI-stable individuals but not in the other groups, with ApoE4 + carriers having decreased CSF Aß 42 levels, and increased concentration of t-tau and p-tau. Longitudinally, individuals with abnormal t-tau and Aß42 had a more rapid progression of cognitive and clinical decline, independently of ApoE4 genotype. Overall, our results contribute to an emerging framework in which ApoE4 involves mechanisms associated with both CSF amyloid-ß burden and tau aggregation at specific time points in AD pathogenesis.
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Doença de Alzheimer , Disfunção Cognitiva , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Apolipoproteína E4/genética , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico , Genótipo , Humanos , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidianoRESUMO
Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous disorder. To which extent genetic aberrations dictate clinical presentation remains elusive. We investigated the spectrum of genetic causes and assessed the genotype-driven differences in biomarker profiles, disease severity and clinical manifestation by recruiting 509 FTD patients from different centers of the German FTLD consortium where individuals were clinically assessed including biomarker analysis. Exome sequencing as well as C9orf72 repeat analysis were performed in all patients. These genetic analyses resulted in a diagnostic yield of 18.1%. Pathogenic variants in C9orf72 (n = 47), GRN (n = 26), MAPT (n = 11), TBK1 (n = 5), FUS (n = 1), TARDBP (n = 1), and CTSF (n = 1) were identified across all clinical subtypes of FTD. TBK1-associated FTD was frequent accounting for 5.4% of solved cases. Detection of a homozygous missense variant verified CTSF as an FTD gene. ABCA7 was identified as a candidate gene for monogenic FTD. The distribution of APOE alleles did not differ significantly between FTD patients and the average population. Male sex was weakly associated with clinical manifestation of the behavioral variant of FTD. Age of onset was lowest in MAPT patients. Further, high CSF neurofilament light chain levels were found to be related to GRN-associated FTD. Our study provides large-scale retrospective clinico-genetic data such as on disease manifestation and progression of FTD. These data will be relevant for counseling patients and their families.
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Demência Frontotemporal , Proteína C9orf72/genética , Demência Frontotemporal/genética , Genótipo , Humanos , Masculino , Mutação , Estudos Retrospectivos , Sequenciamento do Exoma , Proteínas tau/genéticaRESUMO
OBJECTIVE: Motor speech disorders (MSDs) are characteristic for nonfluent primary progressive aphasia (nfvPPA). In primary progressive aphasia (PPA) of the semantic (svPPA) and of the logopenic type (lvPPA), speech motor function is considered typically intact. However, knowledge on the prevalence of MSDs in svPPA and lvPPA is mainly based on studies with a priori knowledge of PPA syndrome diagnosis. This fully blinded retrospective study aims to provide data on the prevalence of all types of MSDs in a large sample of German-speaking patients with different subtypes of PPA. METHOD: Two raters, blinded for PPA subtype, independently evaluated connected speech samples for MSD syndrome and severity from 161 patients diagnosed with nfvPPA, svPPA or lvPPA in the database of the German Consortium of Frontotemporal Lobar Degeneration (FTLDc). In case of disagreement, a third experienced rater re-evaluated the speech samples, followed by a consensus procedure. Consensus was reached for 160 patients (74 nfvPPA, 49 svPPA, 37 lvPPA). MAIN RESULTS: Across all PPA syndromes, 43.8% of the patients showed MSDs. Patients with nfvPPA demonstrated the highest proportion of MSDs (62.2%), but MSDs were also identified in svPPA (26.5%) and lvPPA (29.7%), respectively. Overall, dysarthria was the most common class of MSDs, followed by apraxia of speech. In addition, we identified speech abnormalities presenting as "syllabic speech", "dysfluent speech", and "adynamic speech". DISCUSSION: Our study confirmed MSDs as frequently occurring in PPA. The study also confirmed MSDs to be most common in patients with nfvPPA. However, MSDs were also found in substantial proportions of patients with svPPA and lvPPA. Furthermore, our study identified speech motor deficits that have not received attention in previous studies on PPA. The results are discussed against the background of the existing literature on MSDs in PPA, including theoretical considerations of the neuroanatomical conditions described for each of the different subtypes of PPA.
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Afasia Primária Progressiva , Afasia Primária Progressiva não Fluente , Afasia Primária Progressiva/epidemiologia , Humanos , Afasia Primária Progressiva não Fluente/epidemiologia , Estudos Retrospectivos , Semântica , FalaRESUMO
INTRODUCTION: The term primary progressive aphasia (PPA) sums up the non-fluent (nfv), the semantic (sv), and the logopenic (lv) variant. Up to now, there is only limited data available concerning magnetic resonance imaging volumetry to monitor disease progression. METHODS: Structural brain imaging and an extensive assessment were applied at baseline and up to 4-year(s) follow-up in 269 participants. With automated atlas-based volumetry 56 brain regions were assessed. Atrophy progression served to calculate sample sizes for therapeutic trials. RESULTS: At baseline highest atrophy appeared in parts of the left frontal lobe for nfvPPA (-17%) and of the left temporal lobe for svPPA (-34%) and lvPPA (-24%). Severest progression within 1-year follow-up occurred in the basal ganglia in nfvPPA (-7%), in the hippocampus/amygdala in svPPA (-9%), and in (medial) temporal regions in lvPPA (-6%). CONCLUSION: PPA presents as a left-dominant, mostly gray matter sensitive disease with considerable atrophy at baseline that proceeds variant-specific.
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Afasia Primária Progressiva , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Idoso , Afasia Primária Progressiva/classificação , Afasia Primária Progressiva/patologia , Atrofia/patologia , Encéfalo/patologia , Progressão da Doença , Feminino , Lobo Frontal/patologia , Substância Cinzenta/patologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Lobo Temporal/patologiaRESUMO
INTRODUCTION: The behavioral variant of frontotemporal dementia (bvFTD) is a rare neurodegenerative disease. Reliable predictors of disease progression have not been sufficiently identified. We investigated multivariate magnetic resonance imaging (MRI) biomarker profiles for their predictive value of individual decline. METHODS: One hundred five bvFTD patients were recruited from the German frontotemporal lobar degeneration (FTLD) consortium study. After defining two groups ("fast progressors" vs. "slow progressors"), we investigated the predictive value of MR brain volumes for disease progression rates performing exhaustive screenings with multivariate classification models. RESULTS: We identified areas that predict disease progression rate within 1 year. Prediction measures revealed an overall accuracy of 80% across our 50 top classification models. Especially the pallidum, middle temporal gyrus, inferior frontal gyrus, cingulate gyrus, middle orbitofrontal gyrus, and insula occurred in these models. DISCUSSION: Based on the revealed marker combinations an individual prognosis seems to be feasible. This might be used in clinical studies on an individualized progression model.
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OBJECTIVE: Synaptic loss plays a major role in Alzheimer's disease (AD). However so far no neurochemical marker for synaptic loss has been introduced into clinical routine. By mass spectrometry beta-synuclein was established as a candidate marker. We now aimed to set up a novel ELISA for beta-synuclein for evaluation of its potential as a diagnostic and predictive marker for AD. METHODS: We analysed in total 393 patients from four specialised centres. The diagnostic groups comprised: AD (n=151), behavioural variant frontotemporal dementia (bvFTD, n=18), Parkinson syndrome (n=46), Creutzfeldt-Jakob disease (CJD, n=23), amyotrophic lateral sclerosis (ALS, n=29), disease control (n=66) and 60 non-neurodegenerative control patients. Results were compared with core AD biomarkers (total tau, phospho-tau and amyloid-ß peptide 1-42). Additionally, coexistence of beta-synuclein with vesicular glutamate transporter 1 (VGLUT1) was determined and beta-synuclein levels were quantified in brain homogenates. RESULTS: Beta-synuclein levels quantified with the newly established ELISA correlated strongly with antibody-free quantitative mass spectrometry data (r=0.92 (95% CI: 0.89 to 0.94), p<0.0001). Cerebrospinal fluid (CSF) beta-synuclein levels were increased in AD-mild cognitive impairment (p<0.0001), AD dementia (p<0.0001) and CJD (p<0.0001), but not in bvFTD, Parkinson syndrome or ALS. Furthermore, beta-synuclein was localised in VGLUT1-positive glutamatergic synapses, and its expression was significantly reduced in brain tissue from patients with AD (p<0.01). CONCLUSION: We successfully established a sensitive and robust ELISA for the measurement of brain-enriched beta-synuclein, which we could show is localised in glutamatergic synapses. We confirmed previous, mass spectrometry-based observations of increased beta-synuclein levels in CSF of patients with AD and CJD supporting its potential use as a marker of synaptic degeneration.
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Doença de Alzheimer , Esclerose Lateral Amiotrófica , Doença de Parkinson , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Humanos , Doença de Parkinson/líquido cefalorraquidiano , Doença de Parkinson/diagnóstico , Fragmentos de Peptídeos/líquido cefalorraquidiano , beta-Sinucleína , Proteínas tau/líquido cefalorraquidianoRESUMO
OBJECTIVES: The hexanucleotide repeat expansion in the C9orf72 gene is the most common mutation associated with amyotrophic lateral sclerosis (C9-ALS) and frontotemporal dementia (C9-FTD). Until now, it is unknown which factors define whether C9orf72 mutation carriers develop ALS or FTD. Our aim was to identify protein biomarker candidates in the cerebrospinal fluid (CSF) which differentiate between C9-ALS and C9-FTD and might be indicative for the outcome of the mutation. METHODS: We compared the CSF proteome of 16 C9-ALS and 8 C9-FTD patients and 11 asymptomatic C9orf72 mutation carriers (CAR) by isobaric tags for relative and absolute quantitation. Eleven biomarker candidates were selected from the pool of differentially regulated proteins for further validation by multiple reaction monitoring and single-molecule array in a larger cohort (n=156). RESULTS: In total, 2095 CSF proteins were identified and 236 proteins were significantly different in C9-ALS versus C9-FTD including neurofilament medium polypeptide (NEFM) and chitotriosidase-1 (CHIT1). Eight candidates were successfully validated including significantly increased ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1) levels in C9-ALS compared with C9-FTD and controls and decreased neuronal pentraxin receptor (NPTXR) levels in C9-FTD versus CAR. CONCLUSIONS: This study presents a deep proteomic CSF analysis of C9-ALS versus C9-FTD patients. As a proof of concept, we observed higher NEFM and CHIT1 CSF levels in C9-ALS. In addition, we also show clear upregulation of UCHL1 in C9-ALS and downregulation of NPTXR in C9-FTD. Significant differences in UCHL1 CSF levels may explain diverging ubiquitination and autophagy processes and NPTXR levels might reflect different synapses organisation processes.
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Esclerose Lateral Amiotrófica/líquido cefalorraquidiano , Proteína C9orf72/genética , Expansão das Repetições de DNA/genética , Demência Frontotemporal/líquido cefalorraquidiano , Adulto , Idoso , Esclerose Lateral Amiotrófica/genética , Biomarcadores/líquido cefalorraquidiano , Feminino , Demência Frontotemporal/genética , Hexosaminidases/líquido cefalorraquidiano , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Proteoma/análise , Imagem Individual de MoléculaRESUMO
Synaptic degeneration is a major hallmark of Alzheimer's disease (AD) and the best pathological correlate of cognitive dysfunction. Synaptic markers are therefore a highly desired read-out for patient diagnosis and possible follow-up in clinical trials. Several synaptic markers for AD are described in cerebrospinal fluid (CSF), but studies in blood have failed so far. Using quantitative mass spectrometry (IP-MS, MRM) we observed increased concentrations of the presynaptic protein beta-synuclein (ßSyn) in CSF and blood of AD patients (n = 64, p < 0.01) and confirmed this finding in two validation cohorts (AD: n = 40 and n = 49, controls: n = 44 and n = 25). ßSyn was already increased in patients with mild cognitive impairment (p < 0.01) and was also markedly increased in Creutzfeldt-Jakob disease (CJD; n = 25, p < 0.001) but not behavioral variant frontotemporal dementia (n = 16), dementia with Lewy bodies/Parkinson's disease dementia (n = 13), Parkinson's disease (n = 25), or amyotrophic lateral sclerosis (n = 30). The diagnostic sensitivity and specificity for CJD versus other neurodegenerative diseases was ≥96%. These findings suggest ßSyn as a candidate blood marker for synaptic degeneration that might be used in clinical AD trials and patient follow-up as part of the recently suggested ATN biomarker panel. It can also serve in the differential diagnosis of CJD.
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Doença de Alzheimer , Doença de Alzheimer/diagnóstico , Biomarcadores , Diagnóstico Diferencial , Humanos , Espectrometria de Massas , beta-Sinucleína , Proteínas tauRESUMO
The overlapping symptoms of behavioural variant frontotemporal dementia (bvFTD) and primary psychiatric disorders (such as depressive disorder, schizophrenia spectrum, and bipolar disorder) present a challenge for the differential diagnosis of bvFTD in middle and older-aged people. Neurofilaments are cytoskeletal proteins in the neurons, and several studies have reported elevated levels of neurofilament light chain (NfL) in cerebrospinal fluid of neurodegenerative as well as psychiatric disorders. The study aims to determine the utility of serum NfL levels as a biomarker to differentiate between bvFTD and psychiatric disorder. In our study, we investigated the levels of NfL in the serum of schizophrenia (nâ¯=â¯11), depression (nâ¯=â¯28), bipolar (nâ¯=â¯11), bvFTD (nâ¯=â¯20) patients and controls (nâ¯=â¯27) by single molecule array (Simoa) technology. The schizophrenia, depression and bipolar patients did not show significant changes in serum NfL levels in comparison to the control group (pâ¯>â¯0.99). The serum NfL levels were significantly elevated in bvFTD patients in comparison to the control cohort (pâ¯<â¯0.0001), depression (pâ¯<â¯0.0001), schizophrenia (pâ¯<â¯0.0002) and bipolar patients (pâ¯<â¯0.0083). We propose serum NfL as a biomarker to differentiate bvFTD from psychiatric disorders and to rule out neurodegeneration in the course of psychiatric disorders.
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Transtorno Bipolar/sangue , Transtorno Depressivo/sangue , Demência Frontotemporal/sangue , Demência Frontotemporal/diagnóstico , Filamentos Intermediários/metabolismo , Esquizofrenia/sangue , Adulto , Biomarcadores/sangue , Transtorno Bipolar/diagnóstico , Estudos de Coortes , Transtorno Depressivo/diagnóstico , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esquizofrenia/diagnósticoRESUMO
Alien limb phenomenon is a rare syndrome associated with a feeling of non-belonging and disowning toward one's limb. In contrast, anarchic limb phenomenon leads to involuntary but goal-directed movements. Alien/anarchic limb phenomena are frequent in corticobasal syndrome (CBS), an atypical parkinsonian syndrome characterized by rigidity, akinesia, dystonia, cortical sensory deficit, and apraxia. The structure-function relationship of alien/anarchic limb was investigated in multi-centric structural magnetic resonance imaging (MRI) data. Whole-group and single-subject comparisons were made in 25 CBS and eight CBS-alien/anarchic limb patients versus controls. Support vector machine was used to see if CBS with and without alien/anarchic limb could be distinguished by structural MRI patterns. Whole-group comparison of CBS versus controls revealed asymmetric frontotemporal atrophy. CBS with alien/anarchic limb syndrome versus controls showed frontoparietal atrophy including the supplementary motor area contralateral to the side of the affected limb. Exploratory analysis identified frontotemporal regions encompassing the pre-/and postcentral gyrus as compromised in CBS with alien limb syndrome. Classification of CBS patients yielded accuracies of 79%. CBS-alien/anarchic limb syndrome was differentiated from CBS patients with an accuracy of 81%. Predictive differences were found in the cingulate gyrus spreading to frontomedian cortex, postcentral gyrus, and temporoparietoocipital regions. We present the first MRI-based group analysis on CBS-alien/anarchic limb. Results pave the way for individual clinical syndrome prediction and allow understanding the underlying neurocognitive architecture.
Assuntos
Fenômeno do Membro Alienígena/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Transtornos Parkinsonianos/diagnóstico por imagem , Idoso , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-IdadeRESUMO
AIMS: Aim of this study was to associate concentration of naltrexone and its major active metabolite 6ß-naltrexol in blood with therapeutic outcome during treatment with naltrexone in subjects with alcohol dependence. Treatment with the µ-opiate receptor antagonist naltrexone has been shown to reduce craving for alcohol and alcohol intake in patients suffering from alcohol dependence. SHORT SUMMARY: This article shows the use of therapeutic drug monitoring in alcohol dependent patients, who are treated with naltrexone. The plasma concentrations of naltrexone and 6ß-naltrexol showed high inter-individual variability. They were predictive for treatment response, as they correlated significantly with the reduction of alcohol craving. METHODS: Naltrexone and 6ß-naltrexol were analysed by high performance liquid chromatography with column switching and spectrophotometric detection. Alcohol craving was assessed with the Obsessive-Compulsive Drinking Scale (OCDS). RESULTS AND CONCLUSIONS: The study included 43 patients who were treated with naltrexone with a dose of 50 mg/day. Blood was taken for drug analysis 8 h after the last dose of the day at Week 4, 8 and 12. The plasma concentrations of naltrexone and 6ß-naltrexol showed high inter-individual variability. They were predictive for treatment response, as they correlated significantly with the reduction of alcohol craving. Defining patients with OCDS reduction of 70% or higher as responders, the mean±SD concentration of naltrexone plus naltrexol was 22 ± 13 ng/ml compared to 15 ± 8 ng/ml in patients with score reductions of 1-69%. Further analyses indicated that concentrations of 17-50 ng/ml at 8 h and 7-20 ng/ml at 24 h after drug intake were required for treatment response. CONCLUSIONS: Since plasma concentration of naltrexone plus 6ß-naltrexol was found to be predictive for reduction of alcohol craving, it is concluded that therapeutic drug monitoring has the potential to enhance naltrexone's moderate therapeutic efficiency in patients with alcohol dependence.
Assuntos
Alcoolismo/sangue , Alcoolismo/tratamento farmacológico , Fissura/efeitos dos fármacos , Monitoramento de Medicamentos/métodos , Naltrexona/administração & dosagem , Naltrexona/sangue , Acamprosato/administração & dosagem , Acamprosato/sangue , Adulto , Dissuasores de Álcool/administração & dosagem , Dissuasores de Álcool/sangue , Fissura/fisiologia , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/administração & dosagem , Antagonistas de Entorpecentes/sangue , Valores de Referência , Resultado do TratamentoRESUMO
OBJECTIVE: To investigate the role of neuroinflammation in asymptomatic and symptomatic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) mutation carriers. METHODS: The neuroinflammatory markers chitotriosidase 1 (CHIT1), YKL-40 and glial fibrillary acidic protein (GFAP) were measured in cerebrospinal fluid (CSF) and blood samples from asymptomatic and symptomatic ALS/FTD mutation carriers, sporadic cases and controls by ELISA. RESULTS: CSF levels of CHIT1, YKL-40 and GFAP were unaffected in asymptomatic mutation carriers (n=16). CHIT1 and YKL-40 were increased in gALS (p<0.001, n=65) whereas GFAP was not affected. Patients with ALS carrying a CHIT1 polymorphism had lower CHIT1 concentrations in CSF (-80%) whereas this polymorphism had no influence on disease severity. In gFTD (n=23), increased YKL-40 and GFAP were observed (p<0.05), whereas CHIT1 was nearly not affected. The same profile as in gALS and gFTD was observed in sALS (n=64/70) and sFTD (n=20/26). CSF and blood concentrations correlated moderately (CHIT1, r=0.51) to weak (YKL-40, r=0.30, GFAP, r=0.39). Blood concentrations of these three markers were not significantly altered in any of the groups except CHIT1 in gALS of the Ulm cohort (p<0.05). CONCLUSION: Our data indicate that neuroinflammation is linked to the symptomatic phase of ALS/FTD and shows a similar pattern in sporadic and genetic cases. ALS and FTD are characterised by a different neuroinflammatory profile, which might be one driver of the diverse presentations of the ALS/FTD syndrome.