David Giannandrea

Cerebrospinal fluid Tau/α-synuclein ratio in Parkinson's disease and degenerative dementias.

Although alpha‐synuclein is the main constituent of Lewy bodies, cerebrospinal fluid determination on its own does not seem fundamental for the diagnosis of synucleinopathies. We evaluated whether the combination of classical biomarkers, Aβ1–42, total tau, phosphorylated tau, and α‐synuclein can improve discrimination of Parkinsons disease, dementia with Lewy bodies, Alzheimers disease, and frontotemporal dementia. Aβ1–42, total tau, phosphorylated tau, and α‐synuclein were measured in a series of patients with Parkinsons disease (n = 38), dementia with Lewy bodies (n = 32), Alzheimers disease (n = 48), frontotemporal dementia (n = 31), and age‐matched control patients with other neurological diseases (n = 32). Mean α‐synuclein levels in cerebrospinal fluid were significantly lower in the pathological groups than in cognitively healthy subjects. An inverse correlation of α‐synuclein with total tau (r = −0.196, P < .01) was observed. In the group of patients with Parkinsons disease, Aβ1–42, total tau, and phosphorylated tau values were similar to controls, whereas total tau/α‐synuclein and phosphorylated tau/α‐synuclein ratios showed the lowest values. Cerebrospinal fluid α‐synuclein alone did not provide relevant information for Parkinsons disease diagnosis, showing low specificity (area under the curve, 0.662; sensitivity, 94%; specificity, 25%). Instead, a better performance was obtained with the total tau/α‐syn ratio (area under the curve, 0.765; sensitivity, 89%; specificity, 61%). Combined determination of α‐synuclein and classical biomarkers in cerebrospinal fluid shows differential patterns in neurodegenerative disorders. In particular, total tau/α‐synuclein and phosphorylated tau/α‐synuclein ratios can contribute to the discrimination of Parkinsons disease.

Differential role of CSF alpha-synuclein species, tau, and Aβ42 in Parkinson's disease

There is a great interest in developing cerebrospinal fluid (CSF) biomarkers for diagnosis and prognosis of Parkinsons disease (PD). CSF alpha synuclein (α-syn) species, namely total and oligomeric α-syn (t-α-syn and o-α-syn), have shown to be of help for PD diagnosis. Preliminary evidences show that the combination of CSF t-α-syn and classical Alzheimers disease (AD) biomarkers—β-amyloid 1–42 (Aβ42), total tau (t-tau), phosphorylated tau (p-tau)—differentiate PD patients from controls, and that reduced levels of Aβ42 represent a predictive factor for development of cognitive deterioration in PD. In this prospective study carried out in 44 PD patients and 25 neurological controls we wanted to verify whether the combination of CSF α-synuclein species—t-α-syn and o-α-syn—and classical AD biomarkers may help in differentiating PD from neurological controls, and if these biomarkers may predict cognitive decline. The median of follow-up duration was 3 years (range: 2–6 years). Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were used for monitoring cognitive changes along time, being administered once a year. Oligo/total α-syn ratio (o/t-α-syn ratio) confirmed its diagnostic value, significantly contributing to the discrimination of PD from neurological controls. A greater diagnostic accuracy was reached when combining o/t-α-syn and Aβ42/tau ratios (Sens = 0.70, Spec = 0.84, AUC = 0.82; PPV = 0.89, NPV = 0.62, LR+ = 4.40, DOR = 12.52). Low CSF Aβ42 level was associated with a higher rate of MMSE and MoCA decline, confirming its role as independent predictive factor for cognitive decline in PD. None of the other biomarkers assessed (t-tau, p-tau, t-α-syn and o-α-syn) showed to have prognostic value. We conclude that combination of CSF o/t-α-syn and Aβ42/tau ratios improve the diagnostic accuracy of PD. PD patients showing low CSF Aβ42 levels at baseline are more prone to develop cognitive decline.

Performance of Aβ1-40, Aβ1-42, Total Tau, and Phosphorylated Tau as Predictors of Dementia in a Cohort of Patients with Mild Cognitive Impairment

Mild cognitive impairment (MCI) is a common condition in the elderly which may remain stable along time (MCI-MCI) or evolve into Alzheimers disease (MCI-AD) or other dementias. Cerebrospinal fluid (CSF) classical biomarkers, i.e., amyloid-β 1-42 (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) reflect the neuropathological changes taking place in AD brains, thus disclosing the disease in its prodromal phase. With the aim to evaluate the power of each biomarker and/or their combination in predicting AD progression, we have measured CSF Aβ1-40, Aβ1-42, t-tau, and p-tau in patients with AD, MCI-MCI, MCI-AD, and other neurological diseases without dementia (OND) followed up for four years. Aβ1-42 levels were significantly lower in AD and MCI-AD than in MCI-MCI. T-tau and p-tau levels were significantly increased in AD and MCI-AD versus OND and MCI-MCI. The Aβ1-42/Aβ1-40 ratio showed a significant decrease in AD and MCI-AD as compared to MCI-MCI. Both Aβ1-42/t-tau and Aβ1-42/p-tau ratios showed significantly decreased values in AD and MCI-AD with respect to OND and MCI-MCI. Aβ1-42/p-tau ratio was the best parameter for discriminating MCI-AD from MCI-MCI (sensitivity 81%, specificity 95%), being also correlated with the annual change rate in the Mini Mental State Examination annual change rate score (MMSE-ACR, rS = -0.71, p < 0.0001). Survival analysis showed that 81% of MCI with a low Aβ1-42/p-tau ratio (<1372) progressed to AD. The best model of logistic regression analysis retained Aβ1-42 and p-tau (sensitivity 75%, 95%CI: 70-80%; specificity 96%, 95%CI: 94-98%). We can conclude that Aβ1-42 and p-tau reliably predict conversion to AD in MCI patients.

CSF Levels of Heart Fatty Acid Binding Protein are Altered During Early Phases of Alzheimer's Disease

Heart fatty acid binding protein (HFABP) has been proposed as a putative marker for dementia disorders. To evaluate the value of this protein as an early marker of Alzheimers disease (AD), we analyzed HFABP level and the classical biomarkers amyloid-β (Aβ)1-42, total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI) followed up for four years (n=41), AD (n=32), and subjects with other neurological diseases without dementia (OND, n=25). HFABP levels were higher in AD patients and in MCI converting to AD (MCI-AD) with respect to OND and to cognitively stable MCI patients (MCI-MCI). The receiver operator characteristics analysis for HFABP alone showed a sensitivity of 87% and a specificity of 81% for AD versus OND (area under the curve, AUC=0.83); sensitivity and specificity were 46% and 94%, respectively, when comparing MCI-MCI versus MCI-AD. CSF HFABP levels showed a strong positive correlation with both t-tau and p-tau. Interestingly, the ratio between HFABP and Aβ1-42 improved the performance in distinguishing AD from OND (sensitivity: 90%; specificity 82%, AUC=0.89), and gave the best accuracy in discriminating MCI-AD from MCI-MCI (sensitivity: 80%; specificity 100%, AUC=0.90). Survival analysis by means of Kaplan-Meier curve showed a significantly higher proportion of MCI patients converting to AD in the group with higher values of HFABP/Aβ1-42 ratio (cut-off=0.7). A significant correlation between HFABP/Aβ1-42 ratio and MMSE annual decrease rate was also documented (p<0.0001). HFABP /Aβ1-42 ratio might be a useful predictor of conversion in MCI patients.

Diagnostic utility of cerebrospinal fluid α-synuclein in Parkinson's disease: A systematic review and meta-analysis

The accumulation of misfolded α‐synuclein aggregates is associated with PD. However, the diagnostic value of the α‐synuclein levels in CSF is still under investigation.

Diagnostic utility of CSF α-synuclein species in Parkinson's disease: protocol for a systematic review and meta-analysis

Introduction The diagnostic criteria currently used for Parkinsons disease (PD) are mainly based on clinical motor symptoms. For these reasons many biomarkers are under investigation to support the diagnosis at the early stage. The neuropathological hallmark of PD is represented by Lewy bodies (LBs), which are intracytoplasmic inclusions in substantia nigra neurons. The major component of LBs, α-synuclein (α-syn), has been implicated in the pathogenesis of PD and in other ‘synucleinopathies’ such as multisystem atrophy (MSA) and dementia with LBs (DLBs). Several studies have investigated this presynaptic protein as a potential biomarker of PD. The aim of our meta-analysis is to determine the ability of cerebrospinal fluid (CSF) concentrations of total α-syn, oligomeric α-syn and phosphorylated α-syn to discriminate patients with PD from healthy participants, non-degenerative neurological controls and patients suffering from parkinsonism and or synucleinopathies. Methods and analysis This systematic review protocol has been developed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses Protocol (PRISMA-P) 2015 statement and was registered on PROSPERO (CRD42016013217). We will search Cochrane Library, Web of Science, MEDLINE (via PubMed) and EMBASE from inception, using appropriate search strategies. Two independent reviewers will screen titles, abstracts and full-text articles, and will complete data abstraction. We will include studies that involved patients with PD, DLB, MSA, progressive supranuclear palsy, corticobasal disease and vascular PD, and in which at least one between total α-syn, oligomeric α-syn and phosphorylated α-syn was measured in CSF. To evaluate the risk of bias and applicability of primary diagnostic accuracy studies, we will use QUADAS-2. Ethics and dissemination Our study will not include confidential data, and no intervention will be involved, so ethical approval is not required. The results of the study will be reported in international peer-reviewed journals.

Intravenous thrombolysis in stroke after dabigatran reversal with idarucizumab: case series and systematic review

Idarucizumab can reverse the effect of the direct thrombin inhibitor dabigatran,1 a non-vitamin K oral anticoagulant (NOAC) available for primary and secondary prevention of cardioembolic stroke due to non-valvular atrial fibrillation. Ischaemic stroke may happen despite ongoing anticoagulation, a contraindication to intravenous thrombolysis (IVT).2 Thus, patients with ischaemic stroke while on dabigatran might be eligible for anticoagulation reversal with idarucizumab to allow IVT. Here, we report our case series and provide a systematic review to define outcomes of such treatment algorithm. Case series of patients undergoing IVT after dabigatran reversal was identified from our stroke registry (online supplementary file 1). Systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines3 and specified protocol (PROSPERO: http://www.crd.york.ac.uk/PROSPERO, registration no. CRD42017060274) (online supplementary file 2). Search strategy, performed on Cochrane Library, MEDLINE, EMBASE and PubMed, can be found in online supplementary file 1. ### Supplementary data [jnnp-2018-318658-supp1.pdf] ### Supplementary data [jnnp-2018-318658-supp2.pdf] ### Data extraction and outcome assessment All available data were collected (online supplementary file 1). According to National Institute of Health Stroke Scale (NIHSS) total score, stroke were divided into mild (1–4), moderate (5–15), moderate to severe (16–20) and severe (21–42 4). Unfavourable outcome was defined as an increase in NIHSS score or death. Additional outcomes included modified Rankin Scale (mRS) at follow-up, symptomatic intracerebral haemorrhage, systemic bleeding, allergic reactions to idarucizumab, recurrent stroke and venous thrombosis during post-acute phase. ### Statistical analysis Statistical analysis was performed with R software using …

Diagnostic utility of cerebrospinal fluid α-synuclein in Parkinson's disease: A systematic review and meta-analysis

The accumulation of misfolded α‐synuclein aggregates is associated with PD. However, the diagnostic value of the α‐synuclein levels in CSF is still under investigation.

Diagnostic utility of cerebrospinal fluid α-synuclein in Parkinson's disease: A systematic review and meta-analysis: CSF α-Synuclein for PD Diagnosis

The accumulation of misfolded α‐synuclein aggregates is associated with PD. However, the diagnostic value of the α‐synuclein levels in CSF is still under investigation.