Biomarkers.

Background: Glial fibrillary acidic protein (GFAP) is a marker of cerebral astrogliosis and occasionally elevated in patients with dementia. GFAP in cerebrospinal fluid (CSF), is routinely requested in referrals to neurochemistry laboratories; however, its ability to differentiate dementias and diagnostic capability is unclear. Our aim was to elucidate this, using two large datasets.

Costs of Care in Relation to Alzheimer's Disease Severity in Sweden: A National Registry-Based Cohort Study.

Background: The advancement of diagnostic and therapeutic interventions in early Alzheimer's disease (AD) has demanded the economic evaluation of such interventions. Resource utilization and cost estimates in early AD and, more specifically, the amyloid-positive population are still lacking. We aimed to provide cost estimates in AD in relation to disease severity and compare these with the control population.

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 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.

Cerebrospinal fluid biomarkers of axonal and synaptic degeneration in a population-based sample.

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.

Subtle Differences in Cognition in 70-Year-Olds with Elevated Cerebrospinal Fluid Neurofilament Light and Neurogranin: A H70 Cross-Sectional Study.

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.

Slowing gait speed precedes cognitive decline by several years.

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.

Sex differences in CSF biomarkers for neurodegeneration and blood-brain barrier integrity.

Introduction: As cerebrospinal fluid (CSF) neurofilament light protein (NfL) and the CSF/serum albumin ratio (Q) 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, Q, n = 39252, age 0 to 95). In the population-based study, Q and NfL were examined in relation to sex, cardiovascular risk factors, and cerebral white matter lesions (WMLs).

Diagnostic Value of Cerebrospinal Fluid Neurofilament Light Protein in Neurology: A Systematic Review and Meta-analysis.

Importance: Neurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date.

Objectives: To assess the associations of age, sex, and diagnosis with NfL in CSF (cNfL) and to evaluate its potential in discriminating clinically similar conditions.

Erlangen Score Predicts Cognitive and Neuroimaging Progression in Mild Cognitive Impairment Stage of Alzheimer's Disease.

Background: To alleviate the interpretation of the core Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers, amyloid β1-42 (Aβ42), 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 (n = 193), and assigned an ES between 0 and 4 based on their baseline CSF biomarker profile.

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.

Sample Preparation for Endopeptidomic Analysis in Human Cerebrospinal Fluid.

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.

Preclinical effects of APOE ε4 on cerebrospinal fluid Aβ42 concentrations.

Background: From earlier studies it is known that the APOE ε2/ε3/ε4 polymorphism modulates the concentrations of cerebrospinal fluid (CSF) beta-amyloid (Aβ42) 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 Aβ42 varies by age, to understand the association between APOE and the onset of preclinical AD.

Methods: APOE genotype and CSF Aβ42 concentration were determined in a cohort comprising 716 cognitively healthy individuals aged 17-99 from nine different clinical research centers.

A novel quantification-driven proteomic strategy identifies an endogenous peptide of pleiotrophin as a new biomarker of Alzheimer's disease.

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.

CSF/serum albumin ratio in dementias: a cross-sectional study on 1861 patients.

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.

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.

Expanding the cerebrospinal fluid endopeptidome.

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.

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-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.

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.

The cerebrospinal fluid biomarker profile in an HIV-infected subject with Alzheimer's disease.

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 Aβ42 and normal levels of CSF neurofilament light protein and sAPPα and sAPPβ, distinctly different from findings in HIV-associated dementia (HAD).

Cerebrospinal fluid tau and amyloid-β1-42 in patients with dementia.

Progressive cognitive decline in combination with a cerebrospinal fluid biomarker pattern of low levels of amyloid-β1-42 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.

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

Introduction: 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.

Methods: By cross-referencing a laboratory database with the Swedish Dementia Registry (SveDem), 2357 patients with data on CSF Aβ and tau biomarkers and a clinical diagnosis of AD with dementia were acquired.

CSF neurofilament light differs in neurodegenerative diseases and predicts severity and survival.

Objectives: We hypothesized that CSF neurofilament light (NFL) levels would be elevated in dementias with subcortical involvement, including vascular dementia (VaD), but less elevated in dementias primarily affecting gray matter structures, such as Alzheimer disease (AD), and that elevated CSF NFL would correlate with disease severity and shorter survival time irrespective of clinical diagnosis.

Methods: We included 3,356 individuals with dementia who had CSF NFL analyzed in our laboratory between 2005 and 2012. Clinical diagnoses and Mini-Mental State Examination (MMSE) scores were obtained from the Swedish Dementia Registry, and in selected cases (n = 478), date of death from the Swedish Mortality Registry.

CSF in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive brain amyloidosis that injures brain regions involved in memory consolidation and other cognitive functions. Neuropathologically, the disease is characterized by accumulation of a 42-amino acid protein called amyloid beta, and N-terminally truncated fragments thereof, in extracellular senile plaques together with intraneuronal inclusions of hyperphosphorylated tau protein in neurofibrillary tangles, and neuronal and axonal degeneration and loss. Clinical chemistry tests for these pathologies have been developed for use on cerebrospinal fluid samples.