VGF and neuroserpin are neurosecretory proteins involved in the pathophysiology of neurodegenerative diseases. We aimed to evaluate their cerebrospinal fluid (CSF) concentrations in patients with ...Alzheimer's disease (AD) and Lewy body disease (LBD).
We measured CSF VGF AQEE peptide and neuroserpin levels in 108 LBD patients, 76 AD patients and 37 controls, and tested their associations with clinical scores and CSF AD markers.
We found decreased CSF levels of VGF AQEE in patients with LBD and dementia compared to controls (p = 0.016) and patients with AD-dementia (p = 0.011), but with significant influence of age and sex distribution. Moreover, we observed, on the one hand, a significant associations between lower VGF AQEE and neuroserpin levels and poorer cognitive performance (i.e., lower Mini-Mental State Examination scores). On the other hand, higher levels of CSF tau proteins, especially pTau181, were significantly associated with higher concentrations of VGF AQEE and neuroserpin. Indeed, LBD patients with AD-like CSF profiles, especially T+ profiles, had higher levels of VGF AQEE and neuroserpin compared to controls and LBD/T- cases.
CSF VGF AQEE and neuroserpin may show a complex relationship with cognitive decline when the levels are reduced, and with AD pathology when levels are increased. They may represent novel markers of neurosecretory impairment in neurodegenerative disorders.
•VGF and neuroserpin are neurosecretory proteins involved in different pathophysiological settings but their role in neurodeneration is poorly explored•reduced CSF VGF and neuroserpin levels were associated with the risk of dementia in both Lewy body disease (LBD) and Alzheimer's disease (AD)•CSF VGF and neuroserpin concentrations were increased in LBD with AD copathology
Rapidly progressive dementia (RPD) is an umbrella term referring to several conditions causing a rapid neurological deterioration associated with cognitive decline and short disease duration. They ...comprise Creutzfeldt-Jakob disease (CJD), the archetypal RPD, rapidly progressive variants of the most common neurodegenerative dementias (NDs), and potentially treatable conditions such as infectious or autoimmune encephalitis and cerebrovascular disease. Given the significant clinical and, sometimes, neuroradiological overlap between these different disorders, biofluid markers also contribute significantly to the differential diagnosis. Among them, the neurofilament light chain protein (NfL) has attracted growing attention in recent years as a biofluid marker of neurodegeneration due to its sensitivity to axonal damage and the reliability of its measurement in both cerebrospinal fluid (CSF) and blood. Here, we summarize current knowledge regarding biological and clinical implications of NfL evaluation in biofluids across RPDs, emphasizing CJD, and other prion diseases. In the latter, NfL demonstrated a good diagnostic and prognostic accuracy and a potential value as a marker of proximity to clinical onset in pre-symptomatic
mutation carriers. Similarly, in Alzheimer's disease and other NDs, higher NfL concentrations seem to predict a faster disease progression. While increasing evidence indicates a potential clinical value of NfL in monitoring cerebrovascular disease, the association between NfL and prediction of outcome and/or disease activity in autoimmune encephalitis and infectious diseases has only been investigated in few cohorts and deserves confirmatory studies. In the era of precision medicine and evolving therapeutic options, CSF and blood NfL might aid the diagnostic and prognostic assessment of RPDs and the stratification and management of patients according to disease progression in clinical trials.
Objective
Comprehensively describe the phenotypic spectrum of sporadic fatal insomnia (sFI) to facilitate diagnosis and management of this rare and peculiar prion disorder.
Methods
A survey among ...major prion disease reference centers in Europe identified 13 patients diagnosed with sFI in the past 20 years. We undertook a detailed analysis of clinical and histopathological features and the results of diagnostic investigations.
Results
Mean age at onset was 43 years, and mean disease duration 30 months. Early clinical findings included psychiatric, sleep, and oculomotor disturbances, followed by cognitive decline and postural instability. In all tested patients, video‐polysomnography demonstrated a severe reduction of total sleep time and/or a disorganized sleep. Cerebrospinal fluid (CSF) levels of proteins 14‐3‐3 and t‐tau were unrevealing, the concentration of neurofilament light protein (NfL) was more consistently increased, and the real‐time quaking‐induced conversion assay (RT‐QuIC) revealed a positive prion seeding activity in 60% of cases. Electroencephalography and magnetic resonance imaging showed nonspecific findings, whereas fluorodeoxyglucose positron emission tomography (FDG‐PET) demonstrated a profound bilateral thalamic hypometabolism in 71% of cases. Molecular analyses revealed PrPSc type 2 and methionine homozygosity at PRNP codon 129 in all cases.
Interpretation
sFI is a disease of young or middle‐aged adults, which is difficult to reconcile with the hypothesis of a spontaneous etiology related to stochastic, age‐related PrP misfolding. The combination of psychiatric and/or sleep‐related symptoms with oculomotor abnormalities represents an early peculiar clinical feature of sFI to be valued in the differential diagnosis. Video‐polysomnography, FDG‐PET, and especially CSF prion RT‐QuIC and NfL constitute the most promising supportive diagnostic tests in vivo. Ann Neurol 2018;84:347–360
The differential diagnosis of Creutzfeldt-Jakob disease (CJD) from other, sometimes treatable, neurological disorders is challenging, owing to the wide phenotypic heterogeneity of the disease. ...Real-time quaking-induced prion conversion (RT-QuIC) is a novel ultrasensitive in vitro assay, which, at variance with surrogate neurodegenerative biomarker assays, specifically targets the pathological prion protein (PrP
Sc
). In the studies conducted to date in CJD, cerebrospinal fluid (CSF) RT-QuIC showed good diagnostic sensitivity (82–96%) and virtually full specificity. In the present study, we investigated the diagnostic value of both prion RT-QuIC and surrogate protein markers in a large patient population with suspected CJD and then evaluated the influence on CSF findings of the CJD type, and the associated amyloid-β (Aβ) and tau neuropathology. RT-QuIC showed an overall diagnostic sensitivity of 82.1% and a specificity of 99.4%. However, sensitivity was lower in CJD types linked to abnormal prion protein (PrP
Sc
) type 2 (VV2, MV2K and MM2C) than in typical CJD (MM1). Among surrogate proteins markers (14-3-3, total (t)-tau, and t-tau/phosphorylated (p)-tau ratio) t-tau performed best in terms of both specificity and sensitivity for all sCJD types. Sporadic CJD VV2 and MV2K types demonstrated higher CSF levels of p-tau when compared to other sCJD types and this positively correlated with the amount of tiny tau deposits in brain areas showing spongiform change. CJD patients showed moderately reduced median Aβ42 CSF levels, with 38% of cases having significantly decreased protein levels in the absence of Aβ brain deposits. Our results: (1) support the use of both RT-QuIC and t-tau assays as first line laboratory investigations for the clinical diagnosis of CJD; (2) demonstrate a secondary tauopathy in CJD subtypes VV2 and MV2K, correlating with increased p-tau levels in the CSF and (3) provide novel insight into the issue of the accuracy of CSF p-tau and Aβ42 as markers of brain tauopathy and β-amyloidosis.
Despite the critical importance of pathologically confirmed samples for biomarker validation, only a few studies have correlated CSF A
42 values in vivo with postmortem Alzheimer's disease (AD) ...pathology, while none evaluated the CSF A
42/A
40 ratio. We compared CSF A
42 and A
42/A
40 ratio as biomarkers predicting AD neuropathological changes in patients with a short interval between lumbar puncture and death.
We measured CSF A
40 and A
42 and assessed AD pathology in 211 subjects with rapidly progressive dementia (RPD) and a definite postmortem diagnosis of Creutzfeldt-Jakob disease (
= 159), AD (
= 12), dementia with Lewy bodies (DLB,
= 4), AD/DLB mixed pathologies (
= 5), and various other pathologies (
= 31).
The score reflecting the severity of A
pathology showed a better correlation with ln(A
42/A
40) (
= 0.506,
= -0.713,
< 0.001) than with ln(A
42) (
= 0.206,
= -0.458,
< 0.001), which was confirmed after adjusting for covariates. A
42/A
40 ratio showed significantly higher accuracy than A
42 in the distinction between cases with or without AD pathology (AUC 0.818 ± 0.028 vs. 0.643 ± 0.039), especially in patients with A
42 levels ≤495 pg/mL (AUC 0.888 ± 0.032 vs. 0.518 ± 0.064). Using a cut-off value of 0.810, the analysis of A
42/A
40 ratio yielded 87.0% sensitivity, 88.2% specificity in the distinction between cases with an intermediate-high level of AD pathology and those with low level or no AD pathology.
The present data support the use of CSF A
42/A
40 ratio as a biomarker of AD pathophysiology and noninvasive screener for A
pathology burden, and its introduction in the research diagnostic criteria for AD.
Prion real-time quaking-induced conversion (RT-QuIC) is emerging as the most potent assay for the in vivo diagnosis of Creutzfeldt–Jakob disease (CJD), but its full application, especially as a ...screening test, is limited by suboptimal substrate availability, reagent costs, and incomplete assay standardization. Therefore, the search for the most informative cerebrospinal fluid (CSF) surrogate biomarker is still of primary importance. We compared the diagnostic accuracy of CSF protein 14-3-3, measured with both western blot (WB) and enzyme-linked immunosorbent assay (ELISA), total (t)-tau and neurofilament light chain protein (NfL) alone or in combination with RT-QuIC in 212 subjects with rapidly progressive dementia in which we reached a highly probable clinical diagnosis at follow-up or a definite neuropathological diagnosis. T-tau performed best as surrogate CSF biomarker for the diagnosis of CJD (91.3% sensitivity and 78.9% specificity). The 14-3-3 ELISA assay demonstrated a slightly higher diagnostic value compared to the WB analysis (76.9% vs. 72.2%), but both methods performed worse than the t-tau assay. NfL was the most sensitive biomarker for all sCJD subtypes (> 95%), including those with low values of t-tau or 14-3-3, but showed the lowest specificity (43.1%). When ELISA-based biomarkers were adopted as screening tests followed by RT-QuIC, t-tau correctly excluded a higher number of non-CJD cases compared to NfL and 14-3-3 ELISA. Our study showed that among the CSF surrogate biomarkers of potential application for the clinical diagnosis of CJD, t-tau performs best either alone or as screening test followed by RT-QuIC as a second-level confirmatory test.
β-synuclein (β-syn) is a presynaptic protein, whose cerebrospinal fluid (CSF) levels are increased in patients with Alzheimer's diseases (AD) showing mild cognitive impairment (MCI) and dementia ...(dem). Here, we aimed to investigate CSF β-syn in subjects at different AD stages, including preclinical AD (pre-AD), and to compare its behaviour with another synaptic biomarker, α-synuclein (α-syn), and two biomarkers of neuro-axonal damage, namely neurofilament light chain protein (NfL) and total tau protein (t-tau).
We measured β-syn, α-syn, t-tau and NfL in CSF of 75 patients with AD (pre-AD n=17, MCI-AD n=28, dem-AD n=30) and 35 controls (subjective memory complaints, SMC-Ctrl n=13, non-degenerative neurological disorders, Dis-Ctrl n=22).
CSF β-syn, α-syn, t-tau were significantly elevated in pre-AD patients compared with controls (p<0.0001, p=0.02 and p=0.0001, respectively), while NfL only increased in dem-AD (p=0.001). Pre-AD cases showed lower t-tau concentrations than MCI-AD (p=0.04) and dem-AD (p=0.01). CSF β-syn had the best diagnostic performance for the discrimination of pre-AD subjects from all controls (area under the curve, AUC=0.97) and from SMC-Ctrl subjects (AUC=0.99).
CSF β-syn increases in the whole AD continuum since the preclinical stage and represents a promising biomarker of synaptic damage in AD.
PDF
