Neuroserpin, a crucial regulator for axogenesis, synaptic modelling and cell-cell interactions in the pathophysiology of neurological disease.

Neuroserpin is an axonally secreted serpin that is involved in regulating plasminogen and its enzyme activators, such as tissue plasminogen activator (tPA). The protein has been increasingly shown to play key roles in neuronal development, plasticity, maturation and synaptic refinement. The proteinase inhibitor may function both independently and through tPA-dependent mechanisms. Herein, we discuss the recent evidence regarding the role of neuroserpin in healthy and diseased conditions and highlight the participation of the serpin in various cellular signalling pathways. Several polymorphisms and mutations have also been identified in the protein that may affect the serpin conformation, leading to polymer formation and its intracellular accumulation. The current understanding of the involvement of neuroserpin in Alzheimer's disease, cancer, glaucoma, stroke, neuropsychiatric disorders and familial encephalopathy with neuroserpin inclusion bodies (FENIB) is presented. To truly understand the detrimental consequences of neuroserpin dysfunction and the effective therapeutic targeting of this molecule in pathological conditions, a cross-disciplinary understanding of neuroserpin alterations and its cellular signaling networks is essential.

Cerebrospinal fluid neurofilament light chain differentiates primary psychiatric disorders from rapidly progressive, Alzheimer's disease and frontotemporal disorders in clinical settings.

INTRODUCTION: Many patients with cognitive and neuropsychiatric symptoms face diagnostic delay and misdiagnosis. We investigated whether cerebrospinal fluid (CSF) neurofilament light (NfL) and total-tau (t-tau) could assist in the clinical scenario of differentiating neurodegenerative (ND) from psychiatric disorders (PSY), and rapidly progressive disorders. METHODS: Biomarkers were examined in patients from specialist services (ND and PSY) and a national Creutzfeldt-Jakob registry (Creutzfeldt-Jakob disease [CJD] and rapidly progressive dementias/atypically rapid variants of common ND, RapidND). RESULTS: A total of 498 participants were included: 197 ND, 67 PSY, 161 CJD, 48 RapidND, and 20 controls. NfL was elevated in ND compared to PSY and controls, with highest levels in CJD and RapidND. NfL distinguished ND from PSY with 95%/78% positive/negative predictive value, 92%/87% sensitivity/specificity, 91% accuracy. NfL outperformed t-tau in most real-life clinical diagnostic dilemma scenarios, except distinguishing CJD from RapidND. DISCUSSION: We demonstrated strong generalizable evidence for the diagnostic utility of CSF NfL in differentiating ND from psychiatric disorders, with high accuracy.

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.

A pilot study of the utility of cerebrospinal fluid neurofilament light chain in differentiating neurodegenerative from psychiatric disorders: A 'C-reactive protein' for psychiatrists and neurologists?

OBJECTIVE: Neurofilament light has shown promise as a biomarker for diagnosis, staging and prognosis in a wide range of neurological and neurodegenerative disorders. This study explored the utility of cerebrospinal fluid neurofilament light in distinguishing primary psychiatric disorders from neurodegenerative and neurological disorders, a common diagnostic dilemma for psychiatrists and neurologists. METHODS: This cross-sectional retrospective pilot study assessed cerebrospinal fluid neurofilament light on patients referred to a tertiary neuropsychiatry service from 2009 to 2017 for diagnostic assessment of neuropsychiatric and neurocognitive symptoms, where a neurodegenerative disorder was a differential diagnosis, who received lumbar punctures as part of a comprehensive workup. The most recent gold-standard clinical consensus diagnosis was categorised into psychiatric disorder or neurodegenerative or neurological disorder. Data from healthy controls were available for comparison. Data extraction and diagnostic categorisation was blinded to neurofilament light results. RESULTS: A total of 129 participants were included: 77 neurodegenerative or neurological disorder (mean age 57 years, including Alzheimer's dementia, frontotemporal dementia), 31 psychiatric disorder (mean age 51 years, including schizophrenia, major depressive disorder) and 21 healthy controls (mean age 66 years). Neurofilament light was significantly higher in neurodegenerative or neurological disorder (M = 3560 pg/mL, 95% confidence intervals = [2918, 4601]) compared to psychiatric disorder (M = 949 pg/mL, 95% confidence intervals = [830, 1108]) and controls (M = 1036 pg/mL, 95% confidence intervals = [908, 1165]). Neurofilament light distinguished neurodegenerative or neurological disorder from psychiatric disorder with an area under the curve of 0.94 (95% confidence intervals = [0.89, 0.98]); a cut-off of 1332 pg/mL was associated with 87% sensitivity and 90% specificity. CONCLUSION: Cerebrospinal fluid neurofilament light shows promise as a diagnostic test to assist with the often challenging diagnostic dilemma of distinguishing psychiatric disorders from neurodegenerative and neurological disorders. Further studies are warranted to replicate and expand on these findings, including on plasma neurofilament light.

Cerebrospinal Fluid Neurofilament Light Predicts Risk of Dementia Onset in Cognitively Healthy Individuals 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-ß [Aß]+, 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 < 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 > 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 (>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 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's 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, > 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 (Aß) load as measured by standardized uptake value ratio (SUVR, standardized ß = 0.22, P = .009) and predicted the change in brain Aß load (standardized ß = 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.

Comparative Analysis of Aducanumab, Zagotenemab and Pioglitazone as Targeted Treatment Strategies for Alzheimer's Disease.

Alzheimer's disease (AD) is the leading cause of dementia that has remained a major medical, sociocultural and economical challenge globally. Previously developed treatments like anticholinesterase inhibitors (AChEIs) and N-methyl-D-aspartate receptor (NMDAR) antagonists only provide short-term symptomatic improvement and do not prevent progression. Repeated setbacks and failures over the past 25 years in AD clinical trials have hindered efforts to develop effective AD treatments. Fortunately, Aducanumab, a specific anti-amyloid ß antibody, has shown promising clinical results and was recently approved by the Food and Drug Administration (FDA) through an accelerated approval pathway. This has raised hopes for AD patients; however post-approval trials are necessary to estimate the true scope of its clinical benefits. We have reviewed several AD clinical studies and summarized the experience to date with Aducanumab and two other potential AD drugs including Zagotenemab (an anti-tau antibody) and Pioglitazone (nuclear Peroxisome-Proliferator Activated Receptor γ (PPARγ) agonist). These have shown mixed results so far and the next few years will be critical to elucidate and interpret their broad long-term protective effects. A concerted effort is required to understand and strengthen the translation of pre-clinical findings from these drugs to routine clinical practice.

Decreased cerebrospinal fluid neuronal pentraxin receptor is associated with PET-Aß load and cerebrospinal fluid Aß in a pilot study of Alzheimer's disease.

Multifactorial pathological processes of Alzheimer's disease (AD) begin decades prior to clinical onset. Early identification of patients at risk of developing AD using biomarkers reflecting various aspects of pathogenesis is necessary for prevention and early intervention. Cortical ß-amyloid (Aß) burden assessed by positron emission tomography (PET) or cerebrospinal fluid (CSF) levels of Aß42 are validated biomarkers for early identification. Recently, alterations in levels of neuronal proteins, neuronal pentraxin receptor (NPTXR) and neurofilament light (NfL), in the CSF have emerged as promising AD biomarkers. However, their association with Aß deposition is not well understood. In this pilot study, we evaluate whether CSF NfL and NPTXR are associated with PET-Aß imaging and core CSF biomarkers (Aß42, T-tau, and P-tau). CSF samples were collected from a sub-cohort of participants from the Australian Imaging Biomarkers and Lifestyle study of aging (AIBL) and categorized as either PET-Aß positive (n = 15) or negative (n = 15). NPTXR was significantly lower in PET-Aß positive than negative individuals (p =  0.04), and correlated with Aß42 (rho = 0.69, p <  0.0001), T-tau (rho = 0.45, p =  0.01), and P-tau (rho = 0.51, p =  0.004). However, CSF NfL was not significantly different between PET-Aß positive and negative individuals and did not correlate with any of the core CSF biomarkers. Similar associations of NPTXR and the core CSF biomarkers persisted in the cognitively normal individuals. Together, NPTXR concentration in CSF may be more sensitive NfL to identify AD risk during the preclinical stage, warranting further investigation into its contribution to AD pathogenesis.

Cerebrospinal fluid neurofilament light concentration predicts brain atrophy and cognition in Alzheimer's disease.

INTRODUCTION: This study assessed the utility of cerebrospinal fluid (CSF) neurofilament light (NfL) in Alzheimer's 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 ß (Aß42) were significantly elevated in AD compared to healthy controls (HC; P < .001), and in mild cognitive impairment (MCI) compared to HC (P = .008 NfL; P < .001 NfL/Aß42). CSF NfL and NfL/Aß42 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/Aß42 predicted cortical amyloid load, brain atrophy, and cognition. DISCUSSION: CSF NfL is a biomarker of neurodegeneration, correlating with cognitive impairment and brain neuropathology.