It can be hard to tell one parkinsonian disorder from another based on clinical tests alone. Though their underlying pathologies differ, these degenerative brain disorders all affect movement, and at early stages they resemble one another. Parkinson’s disease (PD) looks like multiple system atrophy (MSA), which is similar to progressive supranuclear palsy (PSP). In addition, about three-quarters of patients with PD will go on to develop dementia (PDD). Could biomarkers help differentiate these diseases and predict who will decline cognitively? Scientists led by Lars Forsgren, Umeå University, Sweden, report a combination of useful candidates in the cerebrospinal fluid (CSF) that may help. One biomarker in particular, neurofilament light chain (NFL), a neuronal cytoskeleton protein, best distinguished PSP from PD. In helping predict which patients with PD would become demented, NFL joined two other proteins: Aβ42 and heart fatty acid–binding protein (HFABP), which helps carry fatty acids to the mitochondria for oxidization. All in all, the results propose useful diagnostic biomarkers for these diseases and may offer clues to their pathophysiology.
“This is a very important study,” John Growdon, Massachusetts General Hospital, Boston, told Alzforum. “There’s been no reliable blood or spinal-fluid test for parkinsonian disorders until now.”
First author David Bäckström and colleagues collected CSF samples from 30 older healthy controls and 128 non-demented patients newly diagnosed with parkinsonism—99 with PD, 11 with MSA, and 12 with PSP. PD diagnosis was based on the U.K. Parkinson’s Disease Society Brain Bank’s criteria, and PSP or MSA diagnoses were based on the respective international criteria (Litvan et al., 1996; Gilman et al., 1999). For longitudinal data, the researchers took a second CSF sample one year later from 72 patients—57 with PD, six with MSA, and nine with PSP. Using ELISA, the researchers measured levels of Aβ42, α-synuclein, NFL, total tau, tau phosphorylated at threonine 181 (ptau181), and HFABP. All 128 patients took follow-up clinical tests, including the Modified Hoehn and Yahr Scale for PD staging, the Mini-Mental State Examination, and motor assessments, each year for five to nine years. The PD patients also underwent screening for mild cognitive impairment or dementia every few years (Litvan et al., 2012; Emre et al., 2007).
Which CSF biomarkers helped in differential diagnosis? The authors found that NFL best distinguished PSP from PD. While baseline levels were moderately elevated in PD relative to controls—about 1,100 ng/L vs. 880 ng/L—average levels in PSP were higher still (2,020 ng/L) and identified PSP with 75 percent sensitivity and 83 percent specificity. After a year, NFL levels stayed steady in PD but rose almost 30 percent in PSP. A cutoff of 2,916 ng/L or higher detected PSP with a sensitivity of 89 percent and a specificity of 93 percent. This result fits with previous cross-sectional data suggesting elevated NFL in the CSF of patients with atypical forms of parkinsonism, including PSP (Holmberg et al., 1998). More NFL might reflect a higher degree of neurodegeneration in PSP relative to PD, the authors wrote. No single biomarker or combination separated MSA from PD. In addition, total tau, p-tau181, and HFABP looked similar between groups.
What about forecasting decline? During the five to nine years of follow-up, 35 percent of the PD patients developed dementia. These people typically had more than 1,100 ng/L of NFL, more than 500 ng/L of HFABP, and less than 626 ng/L of Aβ42. A combined ratio (NFL + HFABP: Aβ42) exceeding 2.1 predicted that a PD patient was 11.8 times more likely to develop dementia, with a 90 percent sensitivity and 71 percent specificity.
Finding less Aβ42 in the CSF supports the idea that Aβ pathology plays a role in PDD, the authors wrote, although they noted that the biomarker is not specific for the disorder. Neither is NFL, as it is elevated in other neurodegenerative disorders such as frontotemporal dementia and amyotrophic lateral sclerosis (Sjögren et al., 2000; Lu et al., 2015). The involvement of HFABP may link PDD to mitochondrial issues, they added.
Growdon was surprised at PD patients’ brisk rate of conversion to dementia during follow-up, and suggested some must have had cognitive impairments short of dementia at baseline. However, he said the proportion of converters underscored the risk of cognitive decline in this disease. “To be able to predict with some certainty who’s on the path to dementia and who’s not is a very important finding,” he told Alzforum. If these results can be reproduced, it could mean that Aβ-lowering therapeutics for Alzheimer’s disease (AD) will be applicable to the PDD group. It would be useful to compare these biomarkers in other disorders that might also cause diagnostic confusion, such as AD and dementia with Lewy bodies, he said.—Gwyneth Dickey Zakaib
- Litvan I, Agid Y, Calne D, Campbell G, Dubois B, Duvoisin RC, Goetz CG, Golbe LI, Grafman J, Growdon JH, Hallett M, Jankovic J, Quinn NP, Tolosa E, Zee DS. Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology. 1996 Jul;47(1):1-9. PubMed.
- Gilman S, Low PA, Quinn N, Albanese A, Ben-Shlomo Y, Fowler CJ, Kaufmann H, Klockgether T, Lang AE, Lantos PL, Litvan I, Mathias CJ, Oliver E, Robertson D, Schatz I, Wenning GK. Consensus statement on the diagnosis of multiple system atrophy. J Neurol Sci. 1999 Feb 1;163(1):94-8. PubMed.
- Litvan I, Goldman JG, Tröster AI, Schmand BA, Weintraub D, Petersen RC, Mollenhauer B, Adler CH, Marder K, Williams-Gray CH, Aarsland D, Kulisevsky J, Rodriguez-Oroz MC, Burn DJ, Barker RA, Emre M. Diagnostic criteria for mild cognitive impairment in Parkinson's disease: Movement Disorder Society Task Force guidelines. Mov Disord. 2012 Mar;27(3):349-56. Epub 2012 Jan 24 PubMed.
- Emre M, Aarsland D, Brown R, Burn DJ, Duyckaerts C, Mizuno Y, Broe GA, Cummings J, Dickson DW, Gauthier S, Goldman J, Goetz C, Korczyn A, Lees A, Levy R, Litvan I, McKeith I, Olanow W, Poewe W, Quinn N, Sampaio C, Tolosa E, Dubois B. Clinical diagnostic criteria for dementia associated with Parkinson's disease. Mov Disord. 2007 Sep 15;22(12):1689-707; quiz 1837. PubMed.
- Holmberg B, Rosengren L, Karlsson JE, Johnels B. Increased cerebrospinal fluid levels of neurofilament protein in progressive supranuclear palsy and multiple-system atrophy compared with Parkinson's disease. Mov Disord. 1998 Jan;13(1):70-7. PubMed.
- Sjögren M, Rosengren L, Minthon L, Davidsson P, Blennow K, Wallin A. Cytoskeleton proteins in CSF distinguish frontotemporal dementia from AD. Neurology. 2000 May 23;54(10):1960-4. PubMed.
- Lu CH, Macdonald-Wallis C, Gray E, Pearce N, Petzold A, Norgren N, Giovannoni G, Fratta P, Sidle K, Fish M, Orrell R, Howard R, Talbot K, Greensmith L, Kuhle J, Turner MR, Malaspina A. Neurofilament light chain: A prognostic biomarker in amyotrophic lateral sclerosis. Neurology. 2015 Jun 2;84(22):2247-57. Epub 2015 May 1 PubMed.
- Williams DR, Litvan I. Parkinsonian syndromes. Continuum (Minneap Minn). 2013 Oct;19(5 Movement Disorders):1189-212. PubMed.
- Svenningsson P, Westman E, Ballard C, Aarsland D. Cognitive impairment in patients with Parkinson's disease: diagnosis, biomarkers, and treatment. Lancet Neurol. 2012 Aug;11(8):697-707. PubMed.
- Hall S, Öhrfelt A, Constantinescu R, Andreasson U, Surova Y, Bostrom F, Nilsson C, Håkan W, Decraemer H, Någga K, Minthon L, Londos E, Vanmechelen E, Holmberg B, Zetterberg H, Blennow K, Hansson O. Accuracy of a panel of 5 cerebrospinal fluid biomarkers in the differential diagnosis of patients with dementia and/or parkinsonian disorders. Arch Neurol. 2012 Nov;69(11):1445-52. PubMed.
- Kang JH, Irwin DJ, Chen-Plotkin AS, Siderowf A, Caspell C, Coffey CS, Waligórska T, Taylor P, Pan S, Frasier M, Marek K, Kieburtz K, Jennings D, Simuni T, Tanner CM, Singleton A, Toga AW, Chowdhury S, Mollenhauer B, Trojanowski JQ, Shaw LM, . Association of Cerebrospinal Fluid β-Amyloid 1-42, T-tau, P-tau181, and α-Synuclein Levels With Clinical Features of Drug-Naive Patients With Early Parkinson Disease. JAMA Neurol. 2013 Aug 26; PubMed.
- Alves G, Brønnick K, Aarsland D, Blennow K, Zetterberg H, Ballard C, Kurz MW, Andreasson U, Tysnes OB, Larsen JP, Mulugeta E. CSF amyloid-beta and tau proteins, and cognitive performance, in early and untreated Parkinson's disease: the Norwegian ParkWest study. J Neurol Neurosurg Psychiatry. 2010 Oct;81(10):1080-6. Epub 2010 Jun 14 PubMed.
- Form and Function: What Makes α-Synuclein Toxic?
- Deep Brain Stimulation: It’s All About the Rhythm
- Neurodegenerative Proteins in the Skin Could be Diagnostic
- Biomarker Progress? Picking the New, Better Measuring the Old
- Does PET Tracer Reveal Severity of Parkinson's?
- Prodromal Initiative to Identify Biomarkers for Parkinson’s
- Bäckström DC, Eriksson Domellöf M, Linder J, Olsson B, Öhrfelt A, Trupp M, Zetterberg H, Blennow K, Forsgren L. Cerebrospinal Fluid Patterns and the Risk of Future Dementia in Early, Incident Parkinson Disease. JAMA Neurol. 2015 Oct;72(10):1175-82. PubMed.