Amyloid-related biomarkers and axonal damage proteins in parkinsonian syndromes

doi:10.1016/j.parkreldis.2011.08.012

Parkinsonism & Related Disorders

Volume 18, Issue 1, January 2012, Pages 69-72

https://doi.org/10.1016/j.parkreldis.2011.08.012 Get rights and content

Abstract

Background

Clinical differentiation between parkinsonian syndromes (PS) remains a challenge despite well-established clinical diagnostic criteria. Specific diagnostic biomarkers have yet to be identified, though in recent years, studies have been published on the aid of certain brain related proteins (BRP) in the diagnosing of PS. We investigated the levels of the light subunit of neurofilament triplet protein (NF-L), total tau and phosphorylated tau, amyloid-β_1-42, and the soluble α- and β-cleaved fragments of amyloid precursor proteins in a cohort of patients with various PS.

Methods

Seventy-one patients with different PS and cerebellar disorders were included consecutively over 21 months. CSF was collected at inclusion. Clinical follow-up was performed after 16 months (median; range: 9-30). Statistical comparison was performed after follow-up on 53 patients in four subgroups of PS: multiple system atrophy (MSA)(n = 10), progressive supranuclear palsy (PSP)(n = 10), dementia with Lewy bodies (DLB)(n = 11), and Parkinson’s disease (PD)(n = 22), using the non-parametric Kruskal–Wallis test.

Results

A statistically significant difference was found for NF-L (p < 0.0001, lowest values for PD), Aβ_1–42, (p = 0.002, lowest values for DLB), and sAPPα and sAPPβ (p = 0.03 and 0.02, lower values observed for DLB and MSA).

Conclusion

We demonstrate a potential role for sAPPα and sAPPβ in distinguishing between PS, a finding that needs to be confirmed in future studies of larger cohorts. There is a tendency towards low levels of Aβ_1–42 in DLB patients in our cohort. Further, our results support findings from previous studies, which indicate an ability to separate atypical PS from PD based on levels of NF-L.

Introduction

Clinical differentiation between parkinsonian syndromes (PS) remains a challenge despite well-established clinical diagnostic criteria, particularly in early disease stages. So far, no specific biomarkers have been established which unequivocally differentiate between the conditions. In recent years, however, studies have been published on the usefulness of measuring certain brain related proteins (BRP), which indicate on-going neurodegeneration, in the diagnostic work-up of patients with suspected PS [1].

Neurofilament triplet proteins are major cytoskeletal components of the neuronal axons functioning as maintainers of axonal calibre and integrity [2]. NF-L in particular has been shown to represent an unspecific but sensitive marker of axonal damage, being elevated in a range of neurological diseases and cerebral insults [3]. Previous studies have described the ability, on the basis of CSF- levels of NF-L, to distinguish between Parkinson’s disease (PD) and different atypical parkinsonian syndromes (APS). However, it has not been possible on the basis of NF-L alone to distinguish between the various subtypes of APS such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), or corticobasal degeneration (CBD)[1].

Another marker of axonal degeneration is the microtubule associated protein tau. In the tauopathies, PSP and CBD, the aggregation of tau is the neuropathological hallmark. The results for the tauopathies have been conflicting, but tau levels have generally been found normal in PD and elevated in MSA patients [1].

The neuronal transmembrane protein amyloid precursor protein (APP) is the precursor for the amyloid-β_1–42 (Aβ_1–42) and α-cleaved and β-cleaved soluble APP (sAPPα and sAPPβ) peptides. The role of Aβ_1–42 in Alzheimer’s Disease (AD) is well described [4]. Studies of CSF-Aβ_1–42 in PS have had conflicting results, and a clear discriminative value has not been demonstrated for the peptide regarding these disorders [1], but it has been shown to be decreased in dementia with Lewy bodies (DLB) [5]. SAPPα and sAPPβ have been found unchanged [6] or slightly elevated in AD patients compared to healthy controls or other types of dementia patients [7]. A high degree of correlation between sAPPα and sAPPβ has been observed. The potential role of these sAPP fragments in PS is unknown.

The purpose of this study was to measure CSF levels of the described BRPs in patients with PS, in various stages of disease, to determine their differentiating value. We hypothesised that there might be a diagnostically useful difference in the CSF levels of amyloid-related biomarkers and axonal damage proteins in different PS.

Section snippets

Patients

We included 71 patients. They were recruited from the outpatient Movement Disorders clinic at the Department of Neurology, Bispebjerg Hospital, and from the Memory Disorders Clinic, Department of Neurology, Rigshospitalet, Copenhagen University Hospitals.

Patients were included consecutively based on a working diagnosis of an APS (MSA, PSP, CBD, or DLB), according to clinical diagnostic criteria (in case of MSA and PSP: possible and probable) [8], [9], [10], or unspecified PS, i.e., parkinsonism

Results

Of the 71 patients included, the original working diagnosis was changed in 18 at follow up (see Table 1). Among seven patients initially diagnosed as possible MSA, one progressed to fulfill criteria for PSP, one was diagnosed with DLB, two with PD, one had atypical features but did not progress at a pace typical for MSA, and only a diagnosis of unspecified PS could be maintained; and finally two were determined to have vascular parkinsonism. Five patients initially considered possible PSP were

Discussion

We confirmed previous findings that concentrations of NF-L in cerebrospinal fluid from patients with APS differed from that of the PD group with a high degree of statistical certainty [1]. A higher level of NF-L in CSF from APS patients compared to PD patients probably reflects the substantially greater loss of neurons that occurs over a shorter period of time in the atypical disorders. NF-L levels in the DLB group appear to be at a level between PD and the other APS, perhaps reflecting the

Acknowledgements

The study was supported by the Danish Multiple System Atrophy Association through a grant from The A.P. Møller Foundation for the Advancement of Medical Science. Additional support was provided by grants from: The ANT-Foundation, Bispebjerg Hospital Research Foundation, Fonden af 2. juli 1984 til bekæmpelse af Parkinsons syge, Signe and Peter Gregersen’s Foundation, the Novo Nordisk Foundation, and the Velux Foundation. Bispebjerg Movement Disorders Biobank is supported by The John and Birthe

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Short communicationAmyloid-related biomarkers and axonal damage proteins in parkinsonian syndromes

Abstract

Background

Methods

Results

Conclusion

Introduction

Section snippets

Patients

Results

Discussion

Acknowledgements

Parkinsonism Relat Disord

Lancet Neurol

Neurofilament gene expression: a major determinant of axonal caliber

Proc Natl Acad Sci U S A

Patients with amyotrophic lateral sclerosis and other neurodegenerative diseases have increased levels of neurofilament protein in CSF

J Neurochem

Decreased CSF amyloid beta42 and normal tau levels in dementia with Lewy bodies

Neurology

Short communication
Amyloid-related biomarkers and axonal damage proteins in parkinsonian syndromes