Association of Chronic Kidney Disease With Plasma NfL and Other Biomarkers of Neurodegeneration: The H70 Birth Cohort Study in Gothenburg

BACKGROUND AND OBJECTIVES: Studies associate chronic kidney disease (CKD) with neurodegeneration. This study investigated the relation between kidney function, blood, cerebrospinal fluid (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 CSF collected. The primary endpoint of the present study was to determine any association between CKD and P-NfL. Secondary endpoints included cross-sectional associations between CKD, eGFR and cerebrospinal fluid (CSF)- and MRI-derived markers of neurodegeneration and Alzheimer's disease (AD) pathology (MRI: cortical thickness, hippocampal volume, lateral ventricle volume, white matter lesion volume; CSF: β-amyloid (Aβ) 42, Aβ42/40, Aβ42/p-tau, t-tau, p-tau, 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 cerebrospinal fluid (CSF) were analysed in 313 participants. 558 individuals returned for a re-examination of eGFR (75% response rate, age 76 (76; 77), 48% males, 76 new cases of CKD). Participants with CKD had higher P-NfL levels than those with normal kidney function (median; 18.8 versus 14.0 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 Aβ 42/40: R=0.23, p=0.004 correlated in participants with Aβ42 pathology. P-NfL levels in the highest quartile were associated with incident CKD at follow-up (HR; 2.08 (1.14: 4.50)). 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

Diagnostic performance of cerebrospinal fluid biomarkers in Creutzfeldt-Jakob disease Results from the Swedish mortality registry

Master thesis, Programme in Medicine. TITLE: Diagnostic performance of cerebrospinal fluid biomarkers in Creutzfeldt-Jakob disease Results from the Swedish mortality registry. AUTHOR: Tobias Skillbäck. Background: Distinguishing the invariably lethal prion disease Creutzfeldt-Jakob disease (CJD) from non-prion rapidly progressive dementias is important and sometimes difficult, and reliable tools for diagnosis are thus in great demand. Cerebrospinal fluid (CSF) levels of total tau (T-tau) and phosphorylated tau (P-tau) have been used to identify patients with CJD in small studies. Here, we wanted to validate the diagnostic performance of CSF T-tau, P-tau and the T-tau/P-tau-ratio by analyzing results from a large database of clinical routine samples, in combination with diagnosis information from the Swedish mortality registry. Methods: We cross-referenced the Swedish mortality registry with a dataset of CSF measurements of T-tau and P-tau performed in clinical routine at the Clinical Neurochemistry Laboratory of the Sahlgrenska University Hospital, serving most of Sweden. The dataset consisted of 9765 deceased subjects with CSF measures, including 93 with CJD, whereof 56% autopsy verified. Results: Patients who later died of CJD had elevated CSF T-tau and T-tau/P-tau ratio, but not CSF P-tau, compared to all other dementia patients and compared to patients who died of Alzheimer’s disease (AD). The previously defined biomarker profile had a specificity of 99.0%, a sensitivity of 78.5% and a positive likelihood ratio (LR+) of 79.9. When tested against common differential diagnoses, the sensitivity, specificity and LR+ of this profile was 78.5%, 99.6% and 196.6 in relation to AD, and 78.5%, 99.3% and 109.3 in relation to other dementias. In CJD subjects (n=30) with repeated measurements, but not in subjects with AD (n=242) or other dementias (n=258), T-tau and T-tau/P-tau ratios increased over time. Conclusion: In this clinical routine setting, the combination of increased T-tau levels and increased T-tau/P-tau ratios in CJD patients has a very high specificity against important differential diagnoses to CJD, and may serve as a clinically useful diagnostic test.Background: Distinguishing the invariably lethal prion disease Creutzfeldt-Jakob disease (CJD) from non-prion rapidly progressive dementias is important and sometimes difficult, and reliable tools for diagnosis are thus in great demand. Cerebrospinal fluid (CSF) levels of total tau (T-tau) and phosphorylated tau (P-tau) have been used to identify patients with CJD in small studies. Here, we wanted to validate the diagnostic performance of CSF T-tau, P-tau and the T-tau/P-tau-ratio by analyzing results from a large database of clinical routine samples, in combination with diagnosis information from the Swedish mortality registry. Methods: We cross-referenced the Swedish mortality registry with a dataset of CSF measurements of T-tau and P-tau performed in clinical routine at the Clinical Neurochemistry Laboratory of the Sahlgrenska University Hospital, serving most of Sweden. The dataset consisted of 9765 deceased subjects with CSF measures, including 93 with CJD, whereof 56% autopsy verified. Results: Patients who later died of CJD had elevated CSF T-tau and T-tau/P-tau ratio, but not CSF P-tau, compared to all other dementia patients and compared to patients who died of Alzheimer’s disease (AD). The previously defined biomarker profile had a specificity of 99.0%, a sensitivity of 78.5% and a positive likelihood ratio (LR+) of 79.9. When tested against common differential diagnoses, the sensitivity, specificity and LR+ of this profile was 78.5%, 99.6% and 196.6 in relation to AD, and 78.5%, 99.3% and 109.3 in relation to other dementias. In CJD subjects (n=30) with repeated measurements, but not in subjects with AD (n=242) or other dementias (n=258), T-tau and T-tau/P-tau ratios increased over time. Conclusion: In this clinical routine setting, the combination of increased T-tau levels and increased T-tau/P-tau ratios in CJD patients has a very high specificity against important differential diagnoses to CJD, and may serve as a clinically useful diagnostic test

Biochemical markers in dementia - Exploring Swedish registry data and the human proteome

Cerebrospinal fluid (CSF) biomarkers of neurodegenerative diseases have a wide scope of applications in diagnostics, prognosis assessment, disease staging, treatment evaluation and more. In this PhD project we aimed to expand the understanding of the properties of known CSF biomarkers of Alzheimer’s disease (AD) and other neurodegenerative diseases, including the most prevalent dementia disorders. In study I, we explored CSF concentrations of three hallmark biomarkers of AD (amyloid β 1-42 [Aβ1-42], total tau [T-tau] and phosphorylated tau [P-tau]) in samples collected in clinical routine from 5676 patients. We found that the most clear-cut AD-like biomarker pattern was found in patients diagnosed with AD, but that large proportions of patients with other dementia disorders also had an AD-like profile. However, this was less often seen in the frontotemporal dementia (FTD) group. In study II, we studied CSF concentrations of neurofilament light (NfL), a biomarker of general neurodegeneration, in 3356 patients with different dementia diagnoses. We found that CSF NfL is especially high in dementias with vascular engagement, but also in frontotemporal dementia. We also found that high CSF NfL concentrations are linked to short survival, which supports the notion that high CSF NfL indicates more aggressive disease processes. In study III, the biomarkers T-tau and P-tau were evaluated as biomarkers of Creutzfeldt-Jakob disease (CJD), a rare rapid neurodegenerative disease. We could conclude that the combination of increased T-tau levels and increased T-tau/P-tau ratios in patients with CJD has a very high specificity against important differential diagnoses to CJD. We further concluded that CJD patients exhibit rising T-tau concentrations as the disease progresses. In study IV, we developed a new strategy for analyzing data output from explorative mass spectrometry. We used a clustering algorithm to allow for higher efficiency and were able to prove the validity of this concept by identifying and validating a new biomarker of AD, a 16 amino acids long peptide from the protein pleiotrophin (PTN151-166). We concluded that quantification-driven proteomics aided by clustering is a viable way of hypothesis generation in biomarker discovery studies. We further concluded that PTN151-166 is a promising AD biomarker candidate that our data indicates to be AD specific and able to discriminate AD from other dementia pathologies at an early stage of disease. In conclusion, the results from the studies in this thesis demonstrate the diagnostic, prognostic and investigative properties of CSF biomarkers

Determining cut-points for Alzheimer's disease biomarkers: statistical issues, methods and challenges.

New proposed criteria for the clinical diagnosis of Alzheimer's disease increasingly incorporate biomarkers, most of which are normally measured on a continuous scale. Operationalizing such criteria thus requires continuous biomarkers to be dichotomized, which in turns requires the selection of a cut-point at which to dichotomize. In this article, we review the statistical principles underlying the choice of cut-points, describe some of the most commonly adopted statistical approaches used to estimate cut-points, highlight potential pitfalls in some of the approaches and characterize in what sense the estimated cut-point from each approach is optimal. We also emphasize that how a cut-point is selected must be made in reference to how the resulting dichotomized biomarker is to be used, and in particular what actions will follow from a positive or negative test result

Cerebrospinal fluid neurofilament light concentration in motor neuron disease and frontotemporal dementia predicts survival

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

Association of cerebrospinal fluid neurofilament light concentration with Alzheimer disease progression

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-calibermyelinated 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 immunoassaywas 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 Correlationwas 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

Cerebrospinal fluid neurogranin: relation to cognition and neurodegeneration in Alzheimer's disease.

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 (β = 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

Apolipoprotein E genotypes and longevity across dementia disorders

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

Benchmarking biomarker-based criteria for Alzheimer's disease: Data from the Swedish Dementia Registry, SveDem.

New research guidelines for the diagnosis of Alzheimer's disease (AD) include biomarker evidence of amyloid-β (Aβ) 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