Cerebrospinal fluid levels of fatty acid–binding protein 3 are associated with likelihood of amyloidopathy in cognitively healthy individuals

Introduction: Fatty acid–binding protein 3 (FABP3) is a biomarker of neuronal membrane disruption, associated with lipid dyshomeostasis—a notable Alzheimer\u27s disease (AD) pathophysiological change. We assessed the association of cerebrospinal fluid (CSF) FABP3 levels with brain amyloidosis and the likelihood/risk of developing amyloidopathy in cognitively healthy individuals. Methods: FABP3 levels were measured in CSF samples of cognitively healthy participants, \u3e 60 years of age (n = 142), from the Australian Imaging, Biomarkers & Lifestyle Flagship Study of Ageing (AIBL). Results: FABP3 levels were positively associated with baseline brain amyloid beta (Aβ) load as measured by standardized uptake value ratio (SUVR, standardized β = 0.22, P =.009) and predicted the change in brain Aβ load (standardized β = 0.32, P =.004). Higher levels of CSF FABP3 (above median) were associated with a likelihood of amyloidopathy (odds ratio [OR] 2.28, 95% confidence interval [CI] 1.12 to 4.65, P =.023). Discussion: These results support inclusion of CSF FABP3 as a biomarker in risk-prediction models of AD

Cerebrospinal fluid neurofilament light predicts risk of dementia onset in cognitively healthy iIndividuals and rate of cognitive decline in mild cognitive impairment: A prospective longitudinal study

Background: Biomarkers that are indicative of early biochemical aberrations are needed to predict the risk of dementia onset and progression in Alzheimer’s disease (AD). We assessed the utility of cerebrospinal fluid (CSF) neurofilament light (NfL) chain for screening preclinical AD, predicting dementia onset among cognitively healthy (CH) individuals, and the rate of cognitive decline amongst individuals with mild cognitive impairment (MCI). Methods: Neurofilament light levels were measured in CSF samples of participants (CH, n = 154 and MCI, n = 32) from the Australian Imaging, Biomarkers and Lifestyle study of ageing (AIBL). Cases of preclinical AD were identified using biomarker-guided classification (CH, amyloid-b [Ab]+, phosphorylated-tau [P-tau]+ and total-tau [T-tau]±; A+T+/N±). The prediction of dementia onset (questionable dementia) among CH participants was assessed as the risk of conversion from Clinical Dementia Rating [CDR = 0] to CDR ≥ 0.5 over 6 years. Mixed linear models were used to assess the utility of baseline CSF NfL levels for predicting the rate of cognitive decline among participants with MCI over 4.5 years. Results: Neurofilament light levels were significantly higher in preclinical AD participants (CH, A+T+/N±) as compared to A-T-N-(p \u3c 0.001). Baseline levels of CSF NfL were higher in CH participants who converted to CDR ≥ 0.5 over 6 years (p = 0.045) and the risk of conversion to CDR ≥ 0.5 was predicted (hazard ratio [HR] 1.60, CI 1.03–2.48, p = 0.038). CH participants with CSF NfL \u3e cut-off were at a higher risk of developing dementia (HR 4.77, CI 1.31–17.29, p = 0.018). Participants with MCI and with higher baseline levels of CSF NfL ( \u3e median) had a higher rate of decline in cognition over 4.5 years. Conclusion: An assessment of CSF NfL levels can help to predict dementia onset among CH vulnerable individuals and cognitive decline among those with MCI

Cerebrospinal fluid neurofilament light concentration predicts brain atrophy and cognition in Alzheimer\u27s disease

Introduction This study assessed the utility of cerebrospinal fluid (CSF) neurofilament light (NfL) in Alzheimer\u27s disease (AD) diagnosis, its association with amyloid and tau pathology, as well as its potential to predict brain atrophy, cognition, and amyloid accumulation. Methods CSF NfL concentration was measured in 221 participants from the Australian Imaging, Biomarkers & Lifestyle Flagship Study of Ageing (AIBL). Results CSF NfL levels as well as NfL/amyloid β (Aβ42) were significantly elevated in AD compared to healthy controls (HC; P \u3c .001), and in mild cognitive impairment (MCI) compared to HC (P = .008 NfL; P\u3c .001 NfL/Aβ42). CSF NfL and NfL/Aβ42 differentiated AD from HC with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.84 and 0.90, respectively. CSF NfL and NfL/Aβ42 predicted cortical amyloid load, brain atrophy, and cognition. Discussion CSF NfL is a biomarker of neurodegeneration, correlating with cognitive impairment and brain neuropathology

Utility of CSF biomarkers for the diagnosis, prognosis and assessment of cognitive decline in Alzheimer’s disease

Alzheimer’s disease (AD) is a slow and progressive neurodegenerative disorder.With new treatment strategies failing in clinical trials, there is a need to initiate a targeted treatment strategy, by administering the right medication, to the right individual, at the right stage. This concept of precision medicine not only requires diagnosis at the preclinical stage, but a thorough understanding of the stage-associated neuropathological changes that occur along the continuum of AD. Pathophysiological biomarkers indicative of neuropathological changes in the brain are needed to identify the preclinical stage of AD, as well as track the extent of cognitive deficit that occurs with the evolution of such changes. The current study was conducted to assess the diagnostic and prognostic potential of cerebrospinal fluid (CSF) biomarkers in AD, associated with neurodegeneration (neurofilament light chain protein, NfL; visinin-like protein-1, VILIP-1; fatty acid binding protein 3, FABP3), neuroinflammation (YKL-40) and synaptic dysfunction (neurogranin, growth-associated protein 43, GAP-43; synaptosomal-associated protein 25, SNAP-25; synaptotagmin-1). CSF samples of participants (n = 221) from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing were used in the study. The study participants were clinically classified as healthy controls (HC, n = 159), mild cognitive impairment (MCI, n = 34) and AD (n = 28). The study aimed to assess the diagnostic potential of CSF biomarkers, their preclinical diagnostic utility, prediction of disease onset and progression, association with central AD pathology, as well as their ability to predict baseline cognition, brain atrophy and amyloid accumulation. The CSF biomarkers NfL, VILIP-1, FABP3, YKL-40, neurogranin, GAP-43 and SNAP-25 distinguished AD participants from HC with a fairly high area under the receiver operating characteristic curve (AUC). CSF biomarkers of neurodegeneration (NfL and FABP3) predicted disease onset among HC who converted from Clinical Dementia Rating (CDR) 0 to CDR ≥ 0.5, over a follow-up period of 4.5 years. CSF biomarkers predicted disease progression among patients (MCI and AD), assessed through the annual change in cognitive scores in patients, divided into tertiles based on 33rd and 66th percentile of CSF measures. CSF levels of NfL significantly increase in the earlier stages of the disease, but not in the later stages, indicating that the brain reaches a stage of irreversible neurodegeneration in late AD, with not much further evolution. CSF biomarkers significantly correlated with core CSF biomarkers total tau (T-tau) and phosphorylated tau (P-tau); classified study participants according to the A/T/N classification (based on biomarker of amyloid deposition, A; tau pathology, T and neurodegeneration, N) and predicted baseline cognition and brain atrophy. All CSF biomarkers were weak predictors of baseline amyloid load, and did not distinguish amyloid positives from negatives with a high sensitivity. This makes it apparent that neurodegeneration, neuroinflammation and synaptic dysfunction, all run independent of amyloid pathology along the disease continuum, but amyloid beta (Aβ) accumulation does contribute to the disruption of spines or neuritis, and inflammatory response. These biomarkers and the pathologies they drive conglomerate at one stage or the other to constitute the AD neuropathology, and demonstrate an excellent diagnostic accuracy in combination. Neurodegeneration and neuroinflammation evolve in synchronisation at all stages, along the disease continuum. Neurodegeneration and synaptic dysfunction are synchronised as well, but not in an advanced stage of the disease continuum. These biomarkers give a clear picture of the pathological changes that occur along the disease continuum, and can be used as endpoint measures in clinical trials

Cerebrospinal fluid biomarkers for understanding multiple aspects of Alzheimer’s disease pathogenesis

Alzheimer’s disease (AD) is a multifactorial age-related brain disease. Numerous pathological events run forth in the brain leading to AD. There is an initial long, dormant phase before the clinical symptoms become evident. There is a need to diagnose the disease at the preclinical stage since therapeutic interventions are most likely to be effective if initiated early. Undoubtedly, the core cerebrospinal fluid (CSF) biomarkers have a good diagnostic accuracy and have been used in clinical trials as end point measures. However, looking into the multifactorial nature of AD and the overlapping pathology with other forms of dementia, it is important to integrate the core CSF biomarkers with a broader panel of other biomarkers reflecting different aspects of pathology. The review is focused upon a panel of biomarkers that relate to different aspects of AD pathology, as well as various studies that have evaluated their diagnostic potential. The panel includes markers of neurodegeneration: neurofilament light chain and visinin-like protein (VILIP-1); markers of amyloidogenesis and brain amyloidosis: apolipoproteins; markers of inflammation: YKL-40 and monocyte chemoattractant protein 1; marker of synaptic dysfunction: neurogranin. These markers can highlight on the state and stage-associated changes that occur in AD brain with disease progression. A combination of these biomarkers would not only aid in preclinical diagnosis, but would also help in identifying early brain changes during the onset of disease. Successful treatment strategies can be devised by understanding the contribution of these markers in different aspects of disease pathogenesis