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INTRODUCTION: In this longitudinal study, we aimed to examine if slowing gait speed preceded cognitive decline and correlated with brain amyloidosis. METHODS: The sample (n = 287) was derived from the Gothenburg H70 Birth Cohort Studies, with follow-ups between 2000 and 2015. Gait speed was measured by indoor walk, and cognition using the Clinical Dementia Rating (CDR) score. All participants had CDR = 0 at baseline. Some participants had data on cerebrospinal fluid (CSF) amyloid beta (Aß)1-42 concentrations at the 2009 examination. RESULTS: Gait speed for participants who worsened in CDR score during follow-up was slower at most examinations. Baseline gait speed could significantly predict CDR change from baseline to follow-up. Subjects with pathological CSF Aß1- 42 concentrations at the 2009 visit had lost more gait speed compared to previous examinations. DISCUSSION: Our results indicate that gait speed decline precedes cognitive decline, is linked to Alzheimer's pathology, and might be used for early detection of increased risk for dementia development.
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Doença de Alzheimer , Disfunção Cognitiva , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico , Humanos , Estudos Longitudinais , Fragmentos de Peptídeos/líquido cefalorraquidiano , Velocidade de CaminhadaRESUMO
BACKGROUND: The objective of this study was to develop a method for directly analysing osteochondral samples straight out of the operating room without cell culturing, thereby enabling identification of potential peptide biomarkers to better understand the mechanisms involved in the development of osteoarthritis and pain. MATERIAL AND METHODS: Osteochondral plugs from wounded and macroscopically nonwounded zones of the femur condyle were collected from six patients with manifest osteoarthritis (OA) undergoing total knee arthroplasty (TKA). The samples were demineralized and supernatant was collected and isotopically marked with Tandem Mass Tag (TMT) labelling and analysed using liquid chromatography coupled with tandem mass spectrometry LC-MS/MS. RESULTS: Using peptidomics, 6292 endogenous peptides were identified. Five hundred sixty-six peptides (8 identified endogenous peptides) differed significantly (P-value 0.10) from wounded zones compared to nonwounded zones. CONCLUSION: This pilot study shows promising results for enabling peptidomic analysis of cartilage and bone straight out of the operating room. With further refinement, peptidomics can potentially become a diagnostic tool for OA, and improve the knowledge of disease progression and genesis of pain.
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Cartilagem/química , Fêmur/química , Osteoartrite do Joelho/metabolismo , Peptídeos/análise , Biomarcadores/análise , Cromatografia Líquida , Humanos , Projetos Piloto , Manejo de Espécimes , Espectrometria de Massas em TandemRESUMO
INTRODUCTION: The ε4 allele of the apolipoprotein E (APOE) gene is a prominent risk factor for Alzheimer's disease (AD), but its implication in other dementias is less well studied. METHODS: We used a data set on 2858 subjects (1098 AD, 260 vascular dementia [VaD], 145 mixed AD and VaD, 90 other dementia diagnoses, and 1265 controls) to examine the association of APOE polymorphisms with clinical dementia diagnoses, biomarker profiles, and longevity. RESULTS: The ε4 allele was associated with reduced longevity as ε4 versus ε3 homozygotes lived on average 2.6 years shorter (P = .006). In AD, ε4 carriers lived 1.0 years shorter than noncarriers (P = .028). The ε4 allele was more prevalent in AD, mixed AD and VaD, and VaD patients compared to controls, but not in other dementia disorders. DISCUSSION: The APOE ε4 allele is influential in AD but might also be of importance in VaD and in mixed AD and VaD, diseases in which concomitant AD pathology is common.
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Doença de Alzheimer/genética , Apolipoproteínas E/genética , Demência Vascular/genética , Longevidade/genética , Idoso , Alelos , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
Biomarkers of neurodegenerative disorders are needed to assist in diagnosis, to monitor disease progression and therapeutic interventions, and to provide insight into disease mechanisms. One route to identify such biomarkers is by proteomic and peptidomic analysis of cerebrospinal fluid (CSF). In the current study, we performed an in-depth analysis of the human CSF endopeptidome to establish an inventory that may serve as a basis for future targeted biomarker studies. High-pH RP HPLC was employed for off-line sample prefractionation followed by low-pH nano-LC-MS analysis. Different software programs and scoring algorithms for peptide identification were employed and compared. A total of 18 031 endogenous peptides were identified at a FDR of 1%, increasing the number of known endogenous CSF peptides 10-fold compared to previous studies. The peptides were derived from 2 053 proteins of which more than 60 have been linked to neurodegeneration. Notably, among the findings were six peptides derived from microtubule-associated protein tau, three of which span the diagnostically interesting threonine-181 (Tau-F isoform). Also, 213 peptides from amyloid precursor protein were identified, 58 of which were partially or completely within the sequence of amyloid ß 1-40/42, as well as 109 peptides from apolipoprotein E, spanning sequences that discriminate between the E2/E3/E4 isoforms of the protein.
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Proteínas do Líquido Cefalorraquidiano/análise , Peptídeos/líquido cefalorraquidiano , Proteômica/métodos , Biomarcadores/líquido cefalorraquidiano , Cromatografia Líquida/métodos , Humanos , Espectrometria de Massas/métodos , Doenças Neurodegenerativas/líquido cefalorraquidiano , SoftwareRESUMO
Synaptic dysfunction is linked to cognitive symptoms in Alzheimer's disease. Thus, measurement of synapse proteins in cerebrospinal fluid may be useful biomarkers to monitor synaptic degeneration. Cerebrospinal fluid levels of the postsynaptic protein neurogranin are increased in Alzheimer's disease, including in the predementia stage of the disease. Here, we tested the performance of cerebrospinal fluid neurogranin to predict cognitive decline and brain injury in the Alzheimer's Disease Neuroimaging Initiative study. An in-house immunoassay was used to analyse neurogranin in cerebrospinal fluid samples from a cohort of patients who at recruitment were diagnosed as having Alzheimer's disease with dementia (n = 95) or mild cognitive impairment (n = 173), as well as in cognitively normal subjects (n = 110). Patients with mild cognitive impairment were grouped into those that remained cognitively stable for at least 2 years (stable mild cognitive impairment) and those who progressed to Alzheimer's disease dementia during follow-up (progressive mild cognitive impairment). Correlations were tested between baseline cerebrospinal fluid neurogranin levels and baseline and longitudinal cognitive impairment, brain atrophy and glucose metabolism within each diagnostic group. Cerebrospinal fluid neurogranin was increased in patients with Alzheimer's disease dementia (P < 0.001), progressive mild cognitive impairment (P < 0.001) and stable mild cognitive impairment (P < 0.05) compared with controls, and in Alzheimer's disease dementia (P < 0.01) and progressive mild cognitive impairment (P < 0.05) compared with stable mild cognitive impairment. In the mild cognitive impairment group, high baseline cerebrospinal fluid neurogranin levels predicted cognitive decline as reflected by decreased Mini-Mental State Examination (P < 0.001) and increased Alzheimer's Disease Assessment Scale-cognitive subscale (P < 0.001) scores at clinical follow-up. In addition, high baseline cerebrospinal fluid neurogranin levels in the mild cognitive impairment group correlated with longitudinal reductions in cortical glucose metabolism (P < 0.001) and hippocampal volume (P < 0.001) at clinical follow-up. Furthermore, within the progressive mild cognitive impairment group, elevated cerebrospinal fluid neurogranin levels were associated with accelerated deterioration in Alzheimer's Disease Assessment Scale-cognitive subscale (ß = 0.0017, P = 0.01). These data demonstrate that cerebrospinal fluid neurogranin is increased already at the early clinical stage of Alzheimer's disease and predicts cognitive deterioration and disease-associated changes in metabolic and structural biomarkers over time.
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Doença de Alzheimer/líquido cefalorraquidiano , Córtex Cerebral/patologia , Cognição , Disfunção Cognitiva/líquido cefalorraquidiano , Hipocampo/patologia , Neurogranina/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Córtex Cerebral/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/patologia , Disfunção Cognitiva/psicologia , Progressão da Doença , Feminino , Hipocampo/diagnóstico por imagem , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Tamanho do Órgão , Tomografia por Emissão de Pósitrons , PrognósticoRESUMO
Progressive cognitive decline in combination with a cerebrospinal fluid biomarker pattern of low levels of amyloid-ß1-42 and high levels of total tau and phosphorylated tau is typical of Alzheimer's disease. However, several neurodegenerative disorders may overlap with Alzheimer's disease both in regards to clinical symptoms and neuropathology. In a uniquely large cohort of dementia patients, we examined the associations of cerebrospinal fluid biomarkers for Alzheimer's disease molecular pathology with clinical dementia diagnoses and disease severity. We cross-referenced the Swedish Dementia Registry with the clinical laboratory database at the Sahlgrenska University Hospital. The final data set consisted of 5676 unique subjects with a clinical dementia diagnosis and a complete set of measurements for cerebrospinal fluid amyloid-ß1-42, total tau and phosphorylated tau. In cluster analysis, disregarding clinical diagnosis, the optimal natural separation of this data set was into two clusters, with the majority of patients with early onset Alzheimer's disease (75%) and late onset Alzheimer's disease (73%) assigned to one cluster and the patients with vascular dementia (91%), frontotemporal dementia (94%), Parkinson's disease dementia (94%) and dementia with Lewy bodies (87%) to the other cluster. Frontotemporal dementia had the highest cerebrospinal fluid levels of amyloid-ß1-42 and the lowest levels of total tau and phosphorylated tau. The highest levels of total tau and phosphorylated tau and the lowest levels of amyloid-ß1-42 and amyloid-ß1-42:phosphorylated tau ratios were found in Alzheimer's disease. Low amyloid-ß1-42, high total tau and high phosphorylated tau correlated with low Mini-Mental State Examination scores in Alzheimer's disease. In Parkinson's disease dementia and vascular dementia low cerebrospinal fluid amyloid-ß1-42 was associated with low Mini-Mental State Examination score. In the vascular dementia, frontotemporal dementia, dementia with Lewy bodies and Parkinson's disease dementia groups 53%, 34%, 67% and 53% of the subjects, respectively had abnormal amyloid-ß1-42 levels, 41%, 41%, 28% and 28% had abnormal total tau levels, and 29%, 28%, 25% and 19% had abnormal phosphorylated tau levels. Cerebrospinal fluid biomarkers were strongly associated with specific clinical dementia diagnoses with Alzheimer's disease and frontotemporal dementia showing the greatest difference in biomarker levels. In addition, cerebrospinal fluid amyloid-ß1-42, total tau, phosphorylated tau and the amyloid-ß1-42:phosphorylated tau ratio all correlated with poor cognitive performance in Alzheimer's disease, as did cerebrospinal fluid amyloid-ß1-42 in Parkinson's disease dementia and vascular dementia. The results support the use of cerebrospinal fluid biomarkers to differentiate between dementias in clinical practice, and to estimate disease severity.
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Peptídeos beta-Amiloides/líquido cefalorraquidiano , Demência/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Idoso , Análise de Variância , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Entrevista Psiquiátrica Padronizada , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença , SuéciaRESUMO
It is a challenge to differentiate between HIV-associated neurocognitive disorders (HAND) and other types of neurocognitive disease in the ageing HIV-infected population. Here we describe a 63 year old HIV-infected woman who had a history, neuropsychological test result, and PET examination consistent with characteristic Alzheimer's disease (AD). The cerebrospinal fluid (CSF) biomarker profile was analogous to the profile typically found in AD in HIV-negative patients with increased t-tau and p-tau, a decreased level of Aß42 and normal levels of CSF neurofilament light protein and sAPPα and sAPPß, distinctly different from findings in HIV-associated dementia (HAD). Assessment of CSF biomarkers may be a valuable tool for clinicians to distinguish between HAD and AD.
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INTRODUCTION: New research guidelines for the diagnosis of Alzheimer's disease (AD) include biomarker evidence of amyloid-ß (Aß) and tau pathology. The aim of this study was to investigate what proportion of AD patients diagnosed in clinical routine in Sweden that had an AD-indicative cerebrospinal fluid (CSF) biomarker profile. METHODS: By cross-referencing a laboratory database with the Swedish Dementia Registry (SveDem), 2357 patients with data on CSF Aß and tau biomarkers and a clinical diagnosis of AD with dementia were acquired. RESULTS: Altogether, 77.2% had pathologic Aß42 and total tau or phosphorylated tau in CSF. These results were stable across age groups. Female sex and low mini-mental state examination score increased the likelihood of pathologic biomarkers. DISCUSSION: About a quarter of clinically diagnosed AD patients did not have an AD-indicative CSF biomarker profile. This discrepancy may partly reflect incorrect (false positive) clinical diagnosis or a lack in sensitivity of the biomarker assays.
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Doença de Alzheimer/líquido cefalorraquidiano , Benchmarking/métodos , Biomarcadores/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fosforilação , Sistema de Registros , Fatores Sexuais , Suécia , Proteínas tau/líquido cefalorraquidianoRESUMO
OBJECTIVES: To determine the prevalence of individuals with Alzheimer disease (AD) eligible for treatment with the recently FDA-approved lecanemab based on data from a population-based sample of 70-year-olds and extrapolate an estimation of individuals eligible in Europe and the United States. METHODS: Participants from the Gothenburg H70 Birth Cohort Study with clinical data, CSF-amyloid beta 42, and brain MRI analysis were evaluated for eligibility to receive lecanemab treatment according to FDA-approved recommendations, noting factors requiring special consideration. Results were used to extrapolate the number of eligible individuals in Europe and the United States using public demographic data. RESULTS: Thirty (10.3%) of 290 participants met the indication for treatment of whom 18 (6.2%) were eligible and did not present factors requiring special consideration. Our estimate that 6.2% of all 70-year-olds in the full cohort are eligible for treatment extrapolates to an approximation that around 5.9 million Europeans and 2.2 million US residents could be eligible. DISCUSSION: Information on proportion of individuals eligible for AD treatment with lecanemab in the general public is limited. We provide information on 70-year-olds in Sweden and extrapolate these data to Europe and the United States. This study opens for larger studies on this proportion and implementation of lecanemab treatment.
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Doença de Alzheimer , Peptídeos beta-Amiloides , Anticorpos Monoclonais Humanizados , Humanos , Estados Unidos , Estudos de Coortes , Vida Independente , Doença de Alzheimer/epidemiologiaRESUMO
BACKGROUND: Neurofilament light (NfL) and neurogranin (Ng) are promising candidate AD biomarkers, reflecting axonal and synaptic damage, respectively. Since there is a need to understand the synaptic and axonal damage in preclinical Alzheimer's disease (AD), we aimed to determine the cerebrospinal fluid (CSF) levels of NfL and Ng in cognitively unimpaired elderly from the Gothenburg H70 Birth Cohort Studies classified according to the amyloid/tau/neurodegeneration (A/T/N) system. METHODS: The sample consisted of 258 cognitively unimpaired older adults (age 70, 129 women and 129 men) from the Gothenburg Birth Cohort Studies. We compared CSF NfL and Ng concentrations in A/T/N groups using Student's T-test and ANCOVA. RESULTS: CSF NfL concentration was higher in the A-T-N+ group (p=0.001) and the A-T+N+ group (p=0.006) compared with A-T-N-. CSF Ng concentration was higher in the A-T-N+, A-T+N+, A+T-N+, and A+T+N+ groups (p<0.0001) compared with A-T-N-. We found no difference in NfL or Ng concentration in A+ compared with A- (disregarding T- and N- status), whereas those with N+ had higher concentrations of NfL and Ng compared with N- (p<0.0001) (disregarding A- and T- status). CONCLUSIONS: CSF NfL and Ng concentrations are increased in cognitively normal older adults with biomarker evidence of tau pathology and neurodegeneration.
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Doença de Alzheimer , Idoso , Masculino , Humanos , Feminino , Proteínas Amiloidogênicas , Axônios , Biomarcadores , Correlação de Dados , NeurograninaRESUMO
BACKGROUND: Most research on cerebrospinal fluid (CSF) neurofilament light protein (NfL) as a marker for neurodegeneration and neurogranin (Ng) for synaptic dysfunction has largely focused on clinical cohorts rather than population-based samples. OBJECTIVE: We hypothesized that increased CSF levels of NfL and Ng are associated with subtle cognitive deficits in cognitively unimpaired (CU) older adults. METHODS: The sample was derived from the Gothenburg H70 Birth Cohort Studies and comprised 258 CU 70-year-olds, with a Clinical Dementia Rating score of zero. All participants underwent extensive cognitive testing. CSF levels of NfL and Ng, as well as amyloid ß1 - 42, total tau, and phosphorylated tau, were measured. RESULTS: Participants with high CSF NfL performed worse in one memory-based test (Immediate recall, pâ=â0.013) and a language test (FAS, pâ=â0.016). Individuals with high CSF Ng performed worse on the memory-based test Supra Span (pâ=â0.035). When stratified according to CSF tau and Aß42 concentrations, participants with high NfL and increased tau performed worse on a memory test than participants normal tau concentrations (Delayed recall, pâ=â0.003). In participants with high NfL, those with pathologic Aß42 concentrations performed worse on the Delayed recall memory (pâ=â0.044). In the high Ng group, participants with pathological Aß42 concentrations had lower MMSE scores (pâ=â0.027). However, in regression analysis we found no linear correlations between CSF NfL or CSF Ng in relation to cognitive tests when controlled for important co-variates. CONCLUSION: Markers of neurodegeneration and synaptic pathology might be associated with subtle signs of cognitive decline in a population-based sample of 70-year-olds.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Idoso , Doença de Alzheimer/patologia , Neurogranina/líquido cefalorraquidiano , Estudos Transversais , Proteínas tau/líquido cefalorraquidiano , Filamentos Intermediários , Biomarcadores/líquido cefalorraquidiano , Cognição , Disfunção Cognitiva/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Proteínas de Neurofilamentos/líquido cefalorraquidianoRESUMO
BACKGROUND AND OBJECTIVES: Studies associate chronic kidney disease (CKD) with neurodegeneration. This study investigated the relationship between kidney function, blood, CSF, and structural brain MRI markers of neurodegeneration in a sample including individuals with and without CKD. METHODS: Participants from the Gothenburg H70 Birth Cohort Study, with data on plasma neurofilament light (P-NfL), estimated glomerular filtration rate (eGFR), and structural brain MRI were included. Participants were invited to also have the CSF collected. The primary endpoint of this study was to determine any association between CKD and P-NfL. Secondary endpoints included cross-sectional associations between CKD, eGFR, and CSF-derived and MRI-derived markers of neurodegeneration and Alzheimer disease (AD) pathology (MRI: cortical thickness, hippocampal volume, lateral ventricle volume, and white matter lesion volume; CSF: ß-amyloid (Aß) 42, Aß42/40, Aß42/p-tau, t-tau, p-tau, and NfL). Participants with P-NfL and eGFR at baseline were re-examined on eGFR, 5.5 (5.3-6.1) years (median; IQR) after the first visit, and the predictive value of P-NfL levels on incident CKD was estimated longitudinally, using a Cox proportional hazards model. RESULTS: We included 744 participants, 668 without CKD (age 71 [70-71] years, 50% males) and 76 with CKD (age 71 [70-71] years, 39% males). Biomarkers from the CSF were analyzed in 313 participants. A total of 558 individuals returned for a re-examination of eGFR (75% response rate, age 76 [76; 77] years, 48% males, 76 new cases of CKD). Participants with CKD had higher P-NfL levels than those with normal kidney function (median; 18.8 vs 14.1 pg/mL, p < 0.001), while MRI and CSF markers were similar between the groups. P-NfL was independently associated with CKD after adjustment for confounding variables, including hypertension and diabetes (OR; 3.231, p < 0.001), in a logistic regression model. eGFR and CSF Aß 42/40: R = 0.23, p = 0.004 correlated in participants with Aß42 pathology. P-NfL levels in the highest quartile were associated with incident CKD at follow-up (HR; 2.39 [1.21: 4.72]). DISCUSSION: In a community-based cohort of 70-year olds, P-NfL was associated with both prevalent and incident CKD, while CSF and/or imaging measures did not differ by CKD status. Participants with CKD and dementia presented similar levels of P-NfL.
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Doença de Alzheimer , Proteínas de Neurofilamentos , Masculino , Humanos , Idoso , Feminino , Estudos de Coortes , Estudos Transversais , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides , Biomarcadores , Proteínas tauRESUMO
INTRODUCTION: As cerebrospinal fluid (CSF) neurofilament light protein (NfL) and the CSF/serum albumin ratio (QAlb) are used in the clinical routine, the impact of demographic factors on these biomarkers is important to understand. METHODS: Participants were derived from two Swedish samples: the population-based H70 Study (n = 308, age 70) and a clinical routine cohort (CSF NfL, n = 8995, QAlb, n = 39252, age 0 to 95). In the population-based study, QAlb and NfL were examined in relation to sex, cardiovascular risk factors, and cerebral white matter lesions (WMLs). In the clinical cohort, QAlb and NfL sex differences were tested in relation to age. RESULTS: Men had higher QAlb and NfL concentrations and had higher QAlb and NfL concentrations from adolescence throughout life. NfL was not related to WML, but QAlb correlated positively with WMLs. DISCUSSION: The CSF NfL sex difference could not be explained by vascular pathology. Future studies should consider using different reference limits for men and women.
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BACKGROUND: To alleviate the interpretation of the core Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers, amyloid ß1-42 (Aß42), total tau (T-tau), and phosphorylated tau (P-tau), the Erlangen Score (ES) interpretation algorithm has been proposed. OBJECTIVE: In this study, we aim to assess the predictive properties of the ES algorithm on cognitive and neuroimaging outcomes in mild cognitive impairment (MCI). METHODS: All MCI subjects with an available baseline CSF sample from ADNI-1 were included (nâ=â193), and assigned an ES between 0 and 4 based on their baseline CSF biomarker profile. Structural magnetic resonance imaging brain scans and MMSE and ADAS-Cog scores were collected at up to 7 times in follow-up examinations. RESULTS: We observed strong and significant correlations between the ES at baseline and neuroimaging and cognitive results with patients with neurochemically probable AD (ESâ=â4) progressing significantly (p≤0.01) faster than those with a neurochemically improbable AD (ESâ=â0 or 1), and the subjects with neurochemically possible AD (ESâ=â2 or 3) in-between these two groups. CONCLUSION: This study further demonstrates the utility of the ES algorithm as a as a tool in predicting cognitive and imaging progression in MCI patients.
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Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico por imagem , Testes de Estado Mental e Demência , Neuroimagem/tendências , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/psicologia , Estudos de Coortes , Progressão da Doença , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética/tendências , Masculino , Testes de Estado Mental e Demência/normas , Pessoa de Meia-Idade , Neuroimagem/normas , Fragmentos de Peptídeos/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons/tendências , Valor Preditivo dos Testes , Proteínas tau/líquido cefalorraquidianoRESUMO
OBJECTIVE: To aid diagnostics, patient stratification and studies seeking to find treatments for the related diseases motor neuron disease (MND) and frontotemporal dementia (FTD), there is a need to establish a way to assess disease severity and the amount of ongoing neurodegeneration. Previous studies have suggested that cerebrospinal fluid (CSF) neurofilament light (NFL) may serve this purpose. METHODS: We cross-referenced the Swedish mortality registry with the laboratory database at Sahlgrenska University Hospital to produce a dataset of CSF NFL concentrations and mortality information for 715 MND patients, 87 FTD patients, and 107 healthy controls. Biomarker concentrations were analysed in relation to recorded cause of death and time of death. RESULTS: MND patients had significantly higher CSF NFL concentrations than FTD patients. Both groups had significantly higher concentrations than the healthy controls (mean 709% increase in MND and 307% increase in FTD). Higher concentrations of CSF NFL were associated with shorter survival in both MND and FTD. CONCLUSIONS: The results of this study strengthen the notion of CSF NFL as a useful tool for determining disease intensity in MND and FTD patients. Further studies in patient cohorts with clinically subtyped and genetically classified diagnoses are needed.
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Demência Frontotemporal/líquido cefalorraquidiano , Demência Frontotemporal/mortalidade , Doença dos Neurônios Motores/líquido cefalorraquidiano , Doença dos Neurônios Motores/mortalidade , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/líquido cefalorraquidiano , Estudos de Coortes , Feminino , Demência Frontotemporal/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Doença dos Neurônios Motores/diagnóstico , Valor Preditivo dos Testes , Sistema de Registros , Taxa de Sobrevida/tendências , Suécia/epidemiologiaRESUMO
This protocol describes a method developed to identify endogenous peptides in human cerebrospinal fluid (CSF). For this purpose, a previously developed method based on molecular weight cut-off (MWCO) filtration and mass spectrometric analysis was combined with an offline high-pH reverse phase HPLC pre-fractionation step. Secretion into CSF is the main pathway for removal of molecules shed by cells of the central nervous system. Thus, many processes in the central nervous system are reflected in the CSF, rendering it a valuable diagnostic fluid. CSF has a complex composition, containing proteins that span a concentration range of 8 - 9 orders of magnitude. Besides proteins, previous studies have also demonstrated the presence of a large number of endogenous peptides. While less extensively studied than proteins, these may also hold potential interest as biomarkers. Endogenous peptides were separated from the CSF protein content through MWCO filtration. By removing a majority of the protein content from the sample, it is possible to increase the sample volume studied and thereby also the total amount of the endogenous peptides. The complexity of the filtrated peptide mixture was addressed by including a reverse phase (RP) HPLC pre-fractionation step at alkaline pH prior to LC-MS analysis. The fractionation was combined with a simple concatenation scheme where 60 fractions were pooled into 12, analysis time consumption could thereby be reduced while still largely avoiding co-elution. Automated peptide identification was performed by using three different peptide/protein identification software programs and subsequently combining the results. The different programs were complementary rather than comparable with less than 15% of the identifications overlapped between the three.
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Líquido Cefalorraquidiano/química , Cromatografia Líquida/métodos , Peptidomiméticos/líquido cefalorraquidiano , Espectrometria de Massas em Tandem/métodos , Líquido Cefalorraquidiano/citologia , HumanosRESUMO
A connection between dementias and blood-brain barrier (BBB) dysfunction has been suggested, but previous studies have yielded conflicting results. We examined cerebrospinal fluid (CSF)/serum albumin ratio in a large cohort of patients diagnosed with Alzheimer's disease (AD, early onset [EAD, n = 130], late onset AD [LAD, n = 666]), vascular dementia (VaD, n = 255), mixed AD and VaD (MIX, n = 362), Lewy body dementia (DLB, n = 50), frontotemporal dementia (FTD, n = 56), Parkinson's disease dementia (PDD, n = 23), other dementias (other, n = 48), and dementia not otherwise specified (NOS, n = 271). We compared CSF/serum albumin ratio to 2 healthy control groups (n = 292, n = 20), between dementia diagnoses, and tested biomarker associations. Patients in DLB, LAD, VaD, MIX, other, and NOS groups had higher CSF/serum albumin ratio than controls. CSF/serum albumin ratio correlated with CSF neurofilament light in LAD, MIX, VaD, and other groups but not with AD biomarkers. Our data show that BBB leakage is common in dementias. The lack of association between CSF/serum albumin ratio and AD biomarkers suggests that BBB dysfunction is not inherent to AD but might represent concomitant cerebrovascular pathology.
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Demência/diagnóstico , Albumina Sérica , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Barreira Hematoencefálica/fisiopatologia , Estudos de Coortes , Estudos Transversais , Demência/fisiopatologia , Feminino , Humanos , Filamentos Intermediários , Masculino , Pessoa de Meia-IdadeRESUMO
We present a new, quantification-driven proteomic approach to identifying biomarkers. In contrast to the identification-driven approach, limited in scope to peptides that are identified by database searching in the first step, all MS data are considered to select biomarker candidates. The endopeptidome of cerebrospinal fluid from 40 Alzheimer's disease (AD) patients, 40 subjects with mild cognitive impairment, and 40 controls with subjective cognitive decline was analyzed using multiplex isobaric labeling. Spectral clustering was used to match MS/MS spectra. The top biomarker candidate cluster (215% higher in AD compared to controls, area under ROC curve = 0.96) was identified as a fragment of pleiotrophin located near the protein's C-terminus. Analysis of another cohort (n = 60 over four clinical groups) verified that the biomarker was increased in AD patients while no change in controls, Parkinson's disease or progressive supranuclear palsy was observed. The identification of the novel biomarker pleiotrophin 151-166 demonstrates that our quantification-driven proteomic approach is a promising method for biomarker discovery, which may be universally applicable in clinical proteomics.
Assuntos
Doença de Alzheimer/metabolismo , Proteínas de Transporte/metabolismo , Citocinas/metabolismo , Peptídeos/metabolismo , Proteoma , Proteômica , Biomarcadores , Proteínas de Transporte/química , Citocinas/química , Feminino , Humanos , Masculino , Proteômica/métodos , Curva ROC , Reprodutibilidade dos TestesRESUMO
BACKGROUND: From earlier studies it is known that the APOE ε2/ε3/ε4 polymorphism modulates the concentrations of cerebrospinal fluid (CSF) beta-amyloid1-42 (Aß42) in patients with cognitive decline due to Alzheimer's disease (AD), as well as in cognitively healthy controls. Here, in a large cohort consisting solely of cognitively healthy individuals, we aimed to evaluate how the effect of APOE on CSF Aß42 varies by age, to understand the association between APOE and the onset of preclinical AD. METHODS: APOE genotype and CSF Aß42 concentration were determined in a cohort comprising 716 cognitively healthy individuals aged 17-99 from nine different clinical research centers. RESULTS: CSF concentrations of Aß42 were lower in APOE ε4 carriers than in noncarriers in a gene dose-dependent manner. The effect of APOE ε4 on CSF Aß42 was age dependent. The age at which CSF Aß42 concentrations started to decrease was estimated at 50 years in APOE ε4-negative individuals and 43 years in heterozygous APOE ε4 carriers. Homozygous APOE ε4 carriers showed a steady decline in CSF Aß42 concentrations with increasing age throughout the examined age span. CONCLUSIONS: People possessing the APOE ε4 allele start to show a decrease in CSF Aß42 concentration almost a decade before APOE ε4 noncarriers already in early middle age. Homozygous APOE ε4 carriers might deposit Aß42 throughout the examined age span. These results suggest that there is an APOE ε4-dependent period of early alterations in amyloid homeostasis, when amyloid slowly accumulates, that several years later, together with other downstream pathological events such as tau pathology, translates into cognitive decline.
Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Apolipoproteína E4/genética , Fragmentos de Peptídeos/líquido cefalorraquidiano , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/líquido cefalorraquidiano , Envelhecimento/genética , Biomarcadores/líquido cefalorraquidiano , Estudos de Coortes , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Sintomas Prodrômicos , Adulto JovemRESUMO
IMPORTANCE: The extent to which large-caliber axonal degeneration contributes to Alzheimer disease (AD) progression is unknown. Cerebrospinal fluid (CSF) neurofilament light (NFL) concentration is a general marker of damage to large-caliber myelinated axons. OBJECTIVE: To test whether CSF NFL concentration is associated with cognitive decline and imaging evidence of neurodegeneration and white matter change in AD. DESIGN, SETTING, AND PARTICIPANTS: A commercially available immunoassay was used to analyze CSF NFL concentration in a cohort of patients with AD (n = 95) or mild cognitive impairment (MCI) (n = 192) and in cognitively normal individuals (n = 110) from the Alzheimer's Disease Neuroimaging Initiative. The study dates were January 2005 to December 2007. The NFL analysis was performed in November 2014. MAIN OUTCOMES AND MEASURES: Correlation was investigated among baseline CSF NFL concentration and longitudinal cognitive impairment, white matter change, and regional brain atrophy within each diagnostic group. RESULTS: Cerebrospinal fluid NFL concentration (median [interquartile range]) was higher in the AD dementia group (1479 [1134-1842] pg/mL), stable MCI group (no progression to AD during follow-up; 1182 [923-1687] pg/mL), and progressive MCI group (MCI with progression to AD dementia during follow-up; 1336 [1061-1693] pg/mL) compared with control participants (1047 [809-1265] pg/mL) (P < .001 for all) and in the AD dementia group compared with the stable MCI group (P = .01). In the MCI group, a higher CSF NFL concentration was associated with faster brain atrophy over time as measured by changes in whole-brain volume (ß = -4177, P = .003), ventricular volume (ß = 1835, P < .001), and hippocampus volume (ß = -54.22, P < .001); faster disease progression as reflected by decreased Mini-Mental State Examination scores (ß = -1.077, P < .001) and increased Alzheimer Disease Assessment Scale cognitive subscale scores (ß = 2.30, P < .001); and faster white matter intensity change (ß = 598.7, P < .001). CONCLUSIONS AND RELEVANCE: Cerebrospinal fluid NFL concentration is increased by the early clinical stage of AD and is associated with cognitive deterioration and structural brain changes over time. This finding corroborates the contention that degeneration of large-caliber axons is an important feature of AD neurodegeneration.