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Alterations in proteostasis and ubiquitin-proteasome system have been involved in several neurological diseases, including neurodegenerative dementias (NDs) such as prion disease, Alzheimer’s disease (AD) and frontotemporal dementia (FTD). Accordingly, several studies reported increased levels of cerebrospinal fluid (CSF) free monoubiquitin in patients with AD and Creutzfeldt-Jakob disease (CJD). However, to date, no study investigated the biomarker profile and its association with the neuropathological correlates across the heterogeneous spectrum of prion disease subtypes. We analysed CSF free monoubiquitin in controls (n = 28) and in subjects with prion disease (n = 84), AD (n = 38), and FTD (n = 30) using a liquid chromatography−multiple reaction monitoring mass spectrometry. AD core biomarkers were also measured in the diagnostic groups. Moreover, we assessed by immunohistochemistry (IHC) the relative extent of brain ubiquitin deposits in sporadic (s)CJD subtypes. In prion disease and, to a lesser extent, in AD subjects CSF free monoubiquitin was significantly increased, whereas the biomarker values did not differ between FTD cases and controls. Regarding diagnostic accuracy, the biomarker yielded a good to optimal performance in the discrimination between prion disease and other groups and between AD and FTD. Among sCJD most prevalent molecular subtypes, we found significantly higher CSF ubiquitin values and more numerous brain ubiquitin deposits at IHC in sCJD with valine homozygosity and scrapie prion protein type 2 (VV2) than in the typical and most common sCJD subtype with methionine homozygosity (valine) and scrapie prion protein type 1 [MM(V)1]. Furthermore, CSF ubiquitin strongly correlated with total tau in NDs and showed an association with disease stage but not with survival in prion disease. CSF free monoubiquitin is differentially increased in prion disease subtypes and AD, reflecting several events associated with neurodegeneration, such as alterations in proteostasis, neuronal damage and neuroinflammation.

Additional file 1: Table S1. Classification of prion disease (definite and probable) cases. Table S2. AD core biomarker values in controls, AD and FTD groups. Table S3. Multivariate linear regression models for CSF biomarker comparisons among diagnostic groups. Figure S1. Glial marker levels in distinct sCJD genotypes. Table S4. CSF biomarkers of neurodegeneration in prion disease subtypes. Figure S2. CSF biomarkers of neurodegeneration in sCJD molecular subtypes and genotypes. Table S5. Multivariate linear regression models for CSF biomarker comparisons among sCJD strains and molecular subtypes. Table S6. Distribution of CHIT1 levels in FTD proteinopathies according to CHIT1 genotype. Table S7. CSF biomarkers of neurodegeneration in the FTD/FTLD spectrum. Figure S3. CSF NfL and p-tau/t-tau in distinct FTD clinical syndromes and molecular subtypes. Table S8. Multivariate linear regression models for CSF biomarker comparisons among FTLD molecular subtypes. Table S9. CSF biomarkers of neuroinflammation and neurodegeneration in FTD mutation carriers. Supplementary text. CSF biomarkers within the FTD/FTLD spectrum after stratification according to the center. Supplementary text. CSF biomarkers inter-correlations.

We describe the case of a man whose initial clinical presentation included sensorineural hearing loss and orthostatic hypotension. The patient was diagnosed with superficial siderosis associated with peripheral autonomic failure and tetraventricular hydrocephalus.

Diagnostic value of CSF biomarkers in the comparison between subjects with ND and control subjects. Table S2. Diagnostic value of CSF biomarkers in the differential diagnosis of prion disease, AD, and FTLD. Figure S1. ROC analysis of CSF biomarkers in the comparison between prion disease and AD. Figure S2. ROC analysis of CSF biomarkers in the comparison between atypical prion disease and other atypical/rapidly progressive NDs. Figure S3. ROC analysis of CSF biomarkers in the comparison between atypical prion disease and atypical/rapidly progressive AD. (DOCX 1967 kb)

Study ObjectivesTo measure the levels of five neurodegenerative biomarkers in the cerebrospinal fluid (CSF) of patients with narcolepsy type 1 (NT1) with variable disease duration.MethodsFollowing a standardized protocol of CSF collection and storage, we measured CSF total- and phosphorylated-tau, amyloid-beta 1–40 and 1–42, and neurofilament light chain (NfL) proteins in 30 nonneurological controls and 36 subjects with NT1, including 14 patients with recent disease onset (i.e. ≤12 months, short disease duration group).ResultsCSF levels of all biomarkers were similar in NT1 subjects and controls. The comparison between NT1 with short and long disease duration only revealed slightly higher levels of CSF amyloid-beta 1–40 in the former group (median 9,549.5, interquartile range [IQR] 7,064.2–11,525.0 vs. 6,870.0, IQR 5,133.7–9,951.2, p = 0.043). CSF storage time did not influence the levels of the tested biomarkers.ConclusionsThe measurement of CSF total-tau, phosphorylated-tau, amyloid-beta 1–40 and 1–42, and NfL proteins is not informative in NT1.

Cerebrospinal fluid (CSF) neurofilament light chain protein (NfL) and Alzheimer's disease (AD) core biomarker levels have been evaluated in cohorts of patients with frontotemporal dementia spectrum (FTD), but the distribution of values across the different clinical syndromes and underlying proteinopathies, and the relative diagnostic accuracy appear discordant among studies. We measured CSF NfL, total (t)-tau, phosphorylated (p)-tau, and amyloid-β (Aβ) 42 in healthy controls (n = 38) and subjects with a clinical, genetic, CSF biomarker-based, and/or neuropathological diagnosis of FTD (n = 141) or AD (n = 60). Sub-analyses were conducted in a proportion of subjects with definite and/or probable frontotemporal lobar degeneration with tau (FTLD-TAU) (n = 42) or TDP43 pathology (FTLD-TDP) (n = 36). Both FTD and AD groups showed significantly increased CSF NfL levels in comparison to controls (p < 0.001). CSF NfL levels were significantly higher in FTD patients than in AD (p < 0.001), reaching the highest values in amyotrophic lateral sclerosis associated with FTD. Patients with probable and definite FTLD-TDP had significantly higher NfL levels (p < 0.001) and lower p-tau/t-tau values (p < 0.001) in comparison with probable and definite FTLD-TAU cases. NfL showed good diagnostic accuracy in the distinction between FTD and controls (AUC 0.862±0.027) and yielded an accuracy (AUC 0.861±0.045) comparable to that of the p-tau/t-tau ratio (AUC 0.814±0.050), with 80.0% sensitivity and 81.0% specificity, in the discrimination between probable/definite FTLD-TAU and FTLD-TDP. Our data further validate CSF NfL as a surrogate biomarker of neurodegeneration and disease severity in patients with FTD spectrum. Moreover, they demonstrate a good diagnostic value for NfL and p-tau/t-tau ratio in the discrimination between FTLD-TAU and FTLD-TDP.

A 62-year-old man presented to the Emergency Department of Sant'Orsola-Malpighi University Hospital in Bologna, Italy, because of a rapidly progressive cognitive decline. He had recently come back to Italy after a 3-month journey in Brazil because relatives found him confused while speaking over the phone. Because of global slowing, disorientation, and confabulation, which developed over the previous 2 months, he underwent a brain MRI in Brazil, which showed cortical atrophy and multiple white matter lesions with no contrast enhancement. No further clinical information about the medical assessment in Brazil was available.

[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.

Background: To determine the prevalence of Idiopathic intracranial hypertension without papilledema (IIHWOP) testing revised diagnostic criteria by Friedman in refractory chronic headache (CH) patients. Methods: This is a prospective observational study. Each patient underwent ophthalmologic evaluation and Optical Coherence Tomography; brain magnetic resonance venography (MRV) and a lumbar puncture (LP) with opening pressure (OP) measurement. CSF withdrawal was performed in patients with CSF OP > 200 mmH20. IIHWOP was defined according Friedman's diagnostic criteria. Effect of CSF withdrawal was evaluated clinically in a 6-month follow-up and with a MRV study at 1 month. Results: Forty-five consecutive patients were enrolled. Five were excluded due to protocol violations. Analyses were conducted in 40 patients (32 F, 8 M; mean age 49.4 ± 10.8). None had papilledema. Nine patients (22.5%) had OP greater than 200 mmH2O, two of them above 250 mmH2O. Two (5%) had neuroimaging findings suggestive of elevated intracranial pressure. One of them (2.5%) met the newly proposed diagnostic criteria by Friedman for IIHWOP. After CSF withdrawal seven (77.8%) of the nine patients improved. No changes in neuroimaging findings were found. Conclusions: We found a low prevalence (2.5%) of IIHWOP in refractory CH patients according to current diagnostic criteria. In agreement with Friedman's criteria, our results confirm that a diagnosis of IIHWOP should be based on CSF OP and the combination of neuroradiological findings. However, where to set the CSF OP upper limit in IIHWOP needs further field testing. Although IIHWOP is a rare clinical condition, it should be considered and treated in refractory CH patients.

Background Neurofilament light chain protein (NfL) is a surrogate biomarker of neurodegeneration that has never been systematically tested, either alone or in combination with other biomarkers, in atypical/rapidly progressive neurodegenerative dementias (NDs). Methods Using validated, commercially available enzyme-linked immunosorbent assay kits, we measured cerebrospinal fluid (CSF) NfL, total tau (t-tau), phosphorylated tau, and β-amyloid 42 in subjects with a neuropathological or clinical diagnosis of prion disease (n = 141), Alzheimer’s disease (AD) (n = 73), dementia with Lewy bodies (DLB) (n = 35), or frontotemporal lobar degeneration (FTLD) (n = 44). Several cases with an atypical/rapidly progressive course were included in each group. We evaluated the diagnostic accuracy of every CSF biomarker and their combinations by ROC curve analyses. Results In each patient group CSF NfL showed higher levels than in control subjects, reaching the highest values in those with Creutzfeldt-Jakob disease (CJD). In the latter, NfL showed a divergent, subtype-specific correlation with t-tau, depending on the degree of subcortical involvement and disease duration. Most significantly, patients with classic sporadic CJD (sCJD) MM1 showed a significantly lower concentration of CSF NfL than those with sCJD MV2, despite the much higher t-tau levels and the more rapid clinical course. High NfL levels were also detected in most atypical CJD cases, showing a disease duration longer than 2 years and/or borderline/negative results in other CSF assays (e.g., 14-3-3, t-tau, and prion real-time quaking-induced conversion). Rapidly progressive/atypical cases showed higher NfL levels than typical patients in FTLD, but not in AD or DLB. NfL showed accuracy similar to that of t-tau in discriminating CJD from other NDs, but it had higher efficacy in differentiating atypical forms, especially in regard to Alzheimer’s disease. Conclusions The present data indicate that CSF NfL and t-tau levels reflect distinct pathophysiological mechanisms of neurodegeneration and support the clinical use of NfL as a fast screening biomarker for the differential diagnosis of atypical/rapidly progressive NDs. Electronic supplementary material The online version of this article (doi:10.1186/s13195-017-0331-1) contains supplementary material, which is available to authorized users.

According to recent studies, the determination of cerebrospinal fluid (CSF) total tau (t-tau)/phosphorylated tau (p-tau) ratio and total prion protein (t-PrP) levels significantly improves the accuracy of the diagnosis of Alzheimer's disease (AD) in atypical cases with clinical or laboratory features mimicking Creutzfeldt-Jakob disease (CJD). However, this has neither been validated nor tested in series including atypical CJD variants. Furthermore, the added diagnostic value of amyloid-β (Aβ)42 remains unclear. To address these issues, we measured t-PrP, 14-3-3, t-tau, p-tau, and Aβ42 CSF levels in 45 typical and 44 atypical/rapidly progressive AD patients, 54 typical and 54 atypical CJD patients, and 33 controls. CJD patients showed significantly lower CSF t-PrP levels than controls and AD patients. Furthermore, atypical CJD was associated with lower t-PrP levels in comparison to typical CJD. T-tau, 14-3-3, or t-PrP alone yielded, respectively, 80.6, 63.0, and 73.0% sensitivity and 75.3, 92.1, and 75% specificity in distinguishing AD from CJD. On receiver operating characteristic (ROC) curve analyses of biomarker combinations, the (t-tau×Aβ42)/(p-tau×t-PrP) ratio achieved the best accuracy, with 98.1% sensitivity and 97.7% specificity overall, and 96.2% sensitivity and 95.5% specificity for the "atypical" disease groups. Our results show that the combined analysis of CSF t-PrP, t-tau, p-tau, and Aβ42 is clinically useful in the differential diagnosis between CJD and AD. Furthermore, the finding of reduced CSF t-PrP levels in CJD patients suggest that, likewise Aβ42 in AD, CSF t-PrP levels reflect the extent of PrPc conversion into abnormal PrP (PrPSc) and the burden of PrPSc deposition in CJD.

Genetics is intricately involved in the etiology of neurodegenerative dementias. The incidence of monogenic dementia among all neurodegenerative forms is unknown due to the lack of systematic studies and of patient/clinician access to extensive diagnostic procedures. In this study, we conducted targeted sequencing in 246 clinically heterogeneous patients, mainly with early-onset and/or familial neurodegenerative dementia, using a custom-designed next-generation sequencing panel covering 27 genes known to harbor mutations that can cause different types of dementia, in addition to the detection of C9orf72 repeat expansions. Forty-nine patients (19.9%) carried known pathogenic or novel, likely pathogenic, variants, involving both common (presenilin 1, presenilin 2, C9orf72, and granulin) and rare (optineurin, serpin family I member 1 and protein kinase cyclic adenosine monophosphate (cAMP)-dependent type I regulatory subunit beta) dementia-associated genes. Our results support the use of an extended next-generation sequencing panels as a quick, accurate, and cost-effective method for diagnosis in clinical practice. This approach could have a significant impact on the proportion of tested patients, especially among those with an early disease onset.