Robertson, Neil

Wynford-Thomas, Ray

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Ray Wynford-Thomas

Neil P. Robertson

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Journal of Neurology

The role of skin biopsy in differentiating idiopathic Parkinson’s disease from other types of parkinsonism

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Online Research @ Cardiff

JOURNAL CLUBThe role of skin biopsy in differentiating idiopathic Parkinson’sdisease from other types of parkinsonismRay Wynford-Thomas1 • Neil P. Robertson1Published online: 17 November 2015 The Author(s) 2015. This article is published with open access at Springerlink.comIntroductionParkinson’s disease is one of the most common neurode-generative disorders with a worldwide distribution. It hasvariable and complex phenotype with motor and non-motormanifestations, causes considerable psychosocial morbid-ity and consumes significant health care resources.Changing population demographics, and in particular, anageing population in western societies is likely to result ingradually increasing prevalence. Despite significantadvances in the understanding of disease pathology, thediagnosis of idiopathic Parkinson’s disease (IPD) remainslargely clinical, with discriminatory investigations such asIoflupane (123I)-labelled single-photon emission computedtomography (DaTSCAN) being used only in the minorityof patients. However, postmortem studies have historicallydemonstrated the fallibility of relying on clinical phenotypeand in differentiating IPD from ‘Parkinson’s plus’ condi-tions such as multiple system atrophy (MSA). An in vivoaccessible peripheral biomarker for IPD and MSA would,therefore, be of great value to direct therapy and moreaccurate patient counselling.The three papers discussed below assess the value of oneof the most promising of the available candidatebiomarkers in this context; phosphorylated alpha-synuclein(p-a-Syn) which has recently been identified within dermalnerve fibres in IPD. In the first paper, the authors examinethe utility of p-a-Syn as a biomarker for diagnosis of IPD,the second looks at p-a-Syn as a biomarker for MSA andthe third at using p-a-Syn to differentiate IPD from MSA.Skin nerve alpha-synuclein deposits: a biomarkerfor idiopathic Parkinson’s diseaseThis paper focuses on two hypotheses: whether p-a-Syndeposits in skin nerve fibres represent a useful biomarkerfor IPD and whether there is a link between these depositsand the underlying pathogenesis of peripheral neuropathyassociated with IPD. The latter is based on experimentaldata showing that an accumulation of p-a-Syn depositsleads to neuron death. Twenty-one patients with well-characterised IPD (20 of whom had the diagnosis supportedby cardiac uptake of [123I]-metaiodobenzylguanidine), 20patients with parkinsonism (PAR) of different pathogenesisassumed not to have p-a-Syn deposits (vascular parkin-sonism 10, tauopathies 6, parkin mutations 4) and 30 age-matched healthy controls were recruited for the study.Three-millimetre punch biopsies of skin nerve fibreswere taken at a proximal site (cervical C8 paravertebralarea) and distal sites (thigh and distal leg). A second biopsywas also taken to assess variability of p-a-Syn expressionfrom all areas in IPD patients, but only at the cervical areain the two other groups. No p-a-Syn deposits were iden-tified in skin samples taken from the control or PARgroups. In contrast, when both skin samples were consid-ered from the cervical area in the IPD group all patientswere positive for p-a-Syn deposits. However, samples fromthigh and distal leg sites in IPD patients were positive inonly 52 and 24 %, respectively.In the IPD group, p-a-Syn deposits showed a significantindirect correlation with leg epidermal innervation.Deposits were not correlated with age, disease duration, or& Neil P. Robertsonrobertsonnp@cardiff.ac.uk1 Department of Neurology, Institute of PsychologicalMedicine and Clinical Neuroscience, Cardiff University,Cardiff, UK123J Neurol (2015) 262:2793–2795DOI 10.1007/s00415-015-7974-2Unified Parkinson’s Disease Rating Scale (UPDRS) score.The authors conclude that p-a-Syn deposits in proximalskin nerve fibres are a sensitive biomarker for the diagnosisof IPD and can help differentiate between other forms ofparkinsonism. As a result of variable local expression, thehighest sensitivity (100 %) was achieved by analysing twocervical skin samples. The authors also concluded thatneuritic synuclein inclusions were correlated with a smallfibre neuropathy, suggesting a possible direct role of p-a-Syn in peripheral nerve damage.Comment. The use of skin biopsy in the diagnosis of IPDis an intriguing prospect. It is easily performed and mini-mally invasive with few adverse effects. This study pro-vides some compelling evidence for use of skin biopsy inthe diagnosis of IPD, although clearly larger studies wouldbe of value in validating its use in clinical practice. Themean disease duration in the IPD group was 13 years, but itmay be interesting to explore this biomarker in early orpreclinical disease which may have significant implicationsfor guiding earlier therapeutic interventions. However, theinsights provided into pathophysiology remain limitedsince p-a-Syn deposits did not appear to correlate withdisease duration or sub-phenotype.Donadio V et al. (2014) Neurology 82:1362–1369.Distinctive distribution of phospho-alpha-synuclein in dermal nerves in multiple systematrophyMSA also remains a largely clinical diagnosis with supportfrom autonomic function tests and neuroradiology. Patho-logically MSA is characterised by detection of a-Syndeposits in oligodendrocytes and neurons. In this study,Doppler et al. explore whether p-a-Syn deposits in dermalnerve fibres can be used as a biomarker in MSA andwhether this could differentiate MSA from tauopathies andIPD. Twelve patients with probable MSA according to theGilman criteria (6 where MSA was supported by neu-roimaging and a further 6 without MRI support), 15patients with presumed tauopathies (based on the criteria ofArmstrong et al.), 30 patients with IPD (based on the UKBrain Bank criteria) and 39 healthy controls wereexamined.Five-millimetre punch skin biopsies were taken fromthe back (Th12) and distal and proximal leg. Serialsections were undertaken to determine sensitivity andone in ten sections were double stained. p-a-Syn withindermal nerve fibres was detected in 8/12 patients with aclinical diagnosis of MSA. No p-a-Syn immunoreactivenerve fibres were identified in patients with presumedtauopathies or normal controls (p\ 0.05). The sensi-tivity of skin biopsies stained positively for p-a-Syn inMSA was 67 % and specificity for a diagnosis of MSAversus tauopathies/controls was 100 %. In the IPDgroup, p-a-Syn was detected in 20 out of 30 patients,resulting in a sensitivity of 67 %. Double-staining serialsections of all p-a-Syn-negative patients identified onefurther patient with MSA and two more patients withIPD, increasing sensitivity to 75 and 73 %,respectively.In MSA patients, p-a-Syn was predominantly depositedin somatosensory fibres of the subepidermal plexus, incontrast to IPD where autonomic fibres were predomi-nantly affected. In the IPD group, proximal biopsy sitesshowed the highest detection rate, raising the possibility ofantidromic spreading of p-a-Syn from ganglia to sensorynerve findings. The authors conclude that detection of p-a-Syn in cutaneous nerve fibres may support the diagnosis ofa ‘synucleinopathy’ in contrast to tauopathies. They alsosuggest that p-a-Syn in somatosensory fibres is associatedwith MSA-parkinsonism, whereas autonomic fibres areinvolved in IPD.Comment. This study advocates the use of skin biopsy indistinguishing IPD from MSA and other forms of parkin-sonism. No attempt was made to correlate p-a-Syn depo-sition to disease severity or duration. Once again, a largerstudy would be of value in validating these results anddeveloping wider datasets before its use can be supportedin clinical practice. Mean disease duration varied consid-erably between clinical groups (MSA 4.9 years; IPD12.4 years; tauopathies 3.6 years) and future studies mayconsider matching for both age and diseased duration.Doppler MD et al. (2015) Mov Disord 30(12):1688–1692.Phosphorylated alpha-synuclein in skin nervefibres differentiates Parkinson’s diseasefrom multiple system atrophyZange et al. addressed the hypothesis that p-a-Syn can bedetected in skin sympathetic nerve fibres in Parkinson’sdisease, but not MSA. This study included 10 patients withIPD (according to the UK Parkinson’s Disease SocietyBrain Bank criteria) and 10 patients with MSA (accordingto Gilman criteria). Clinical classification was furthersupported by nuclear imaging and autonomic reflexscreening. Six patients with an essential tremor served ascontrols.Three-millimetre punch biopsies were taken from theforearm of the clinically more affected side. p-a-Syndeposits were detected in nerve fibres innervating skinautonomic structures in a-Syn-dependent neurodegenera-tive disorders and p-a-Syn deposition was limited toParkinson’s disease. However, dermal nerve fibres of MSAand control patients were devoid of p-a-Syn. The authors2794 J Neurol (2015) 262:2793–2795123conclude that as their study did not show involvement ofpostganglionic sympathetic skin nerve fibres in MSA (witha clinical duration up to 7 years), testing sympathetic skinnerve fibres for p-a-Syn deposits is of value in differenti-ating Parkinson’s disease from MSA. However, they sug-gest that further studies of a variety of disease durations arenecessary to verify this. Their data support the finding ofdermal denervation in Parkinson’s disease, occurringindependently of age and correlating with the extent ofintra-axonal p-a-Syn deposition.Comment. This study supports the use of skin biopsy todifferentiate IPD from MSA, specifically looking at auto-nomic skin nerve fibres. However, perhaps the most rele-vant conclusion that can be drawn is that autonomic skinfibre biopsies can be used to differentiate IPD from ‘notIPD’. The Parkinson’s disease patients in this study had amean disease duration of 5.85 years, compared to4.10 years for the MSA patients which are relatively wellmatched, although mean age of the cohorts differed byalmost 10 years. As in the previous two papers, this studyalso supports the relationship of dermal denervation to p-a-Syn deposition. It would clearly be of value to obtainlonger term follow-up data on these cohorts includingpathology if available, to verify diagnosis and pathologicalconclusions.Zange et al. (2015) Brain 138:2310–2321.Open Access This article is distributed under the terms of theCreative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,distribution, and reproduction in any medium, provided you giveappropriate credit to the original author(s) and the source, provide alink to the Creative Commons license, and indicate if changes weremade.J Neurol (2015) 262:2793–2795 2795123

The role of skin biopsy in differentiating idiopathic Parkinson's disease from other types of parkinsonism

JOURNAL CLUB
The role of skin biopsy in differentiating idiopathic Parkinson’s
disease from other types of parkinsonism
Ray Wynford-Thomas1 • Neil P. Robertson1
Published online: 17 November 2015
 The Author(s) 2015. This article is published with open access at Springerlink.com
Introduction
Parkinson’s disease is one of the most common neurode-
generative disorders with a worldwide distribution. It has
variable and complex phenotype with motor and non-motor
manifestations, causes considerable psychosocial morbid-
ity and consumes significant health care resources.
Changing population demographics, and in particular, an
ageing population in western societies is likely to result in
gradually increasing prevalence. Despite significant
advances in the understanding of disease pathology, the
diagnosis of idiopathic Parkinson’s disease (IPD) remains
largely clinical, with discriminatory investigations such as
Ioflupane (123I)-labelled single-photon emission computed
tomography (DaTSCAN) being used only in the minority
of patients. However, postmortem studies have historically
demonstrated the fallibility of relying on clinical phenotype
and in differentiating IPD from ‘Parkinson’s plus’ condi-
tions such as multiple system atrophy (MSA). An in vivo
accessible peripheral biomarker for IPD and MSA would,
therefore, be of great value to direct therapy and more
accurate patient counselling.
The three papers discussed below assess the value of one
of the most promising of the available candidate
biomarkers in this context; phosphorylated alpha-synuclein
(p-a-Syn) which has recently been identified within dermal
nerve fibres in IPD. In the first paper, the authors examine
the utility of p-a-Syn as a biomarker for diagnosis of IPD,
the second looks at p-a-Syn as a biomarker for MSA and
the third at using p-a-Syn to differentiate IPD from MSA.
Skin nerve alpha-synuclein deposits: a biomarker
for idiopathic Parkinson’s disease
This paper focuses on two hypotheses: whether p-a-Syn
deposits in skin nerve fibres represent a useful biomarker
for IPD and whether there is a link between these deposits
and the underlying pathogenesis of peripheral neuropathy
associated with IPD. The latter is based on experimental
data showing that an accumulation of p-a-Syn deposits
leads to neuron death. Twenty-one patients with well-
characterised IPD (20 of whom had the diagnosis supported
by cardiac uptake of [123I]-metaiodobenzylguanidine), 20
patients with parkinsonism (PAR) of different pathogenesis
assumed not to have p-a-Syn deposits (vascular parkin-
sonism 10, tauopathies 6, parkin mutations 4) and 30 age-
matched healthy controls were recruited for the study.
Three-millimetre punch biopsies of skin nerve fibres
were taken at a proximal site (cervical C8 paravertebral
area) and distal sites (thigh and distal leg). A second biopsy
was also taken to assess variability of p-a-Syn expression
from all areas in IPD patients, but only at the cervical area
in the two other groups. No p-a-Syn deposits were iden-
tified in skin samples taken from the control or PAR
groups. In contrast, when both skin samples were consid-
ered from the cervical area in the IPD group all patients
were positive for p-a-Syn deposits. However, samples from
thigh and distal leg sites in IPD patients were positive in
only 52 and 24 %, respectively.
In the IPD group, p-a-Syn deposits showed a significant
indirect correlation with leg epidermal innervation.
Deposits were not correlated with age, disease duration, or
& Neil P. Robertson
robertsonnp@cardiff.ac.uk
1 Department of Neurology, Institute of Psychological
Medicine and Clinical Neuroscience, Cardiff University,
Cardiff, UK
123
J Neurol (2015) 262:2793–2795
DOI 10.1007/s00415-015-7974-2
Unified Parkinson’s Disease Rating Scale (UPDRS) score.
The authors conclude that p-a-Syn deposits in proximal
skin nerve fibres are a sensitive biomarker for the diagnosis
of IPD and can help differentiate between other forms of
parkinsonism. As a result of variable local expression, the
highest sensitivity (100 %) was achieved by analysing two
cervical skin samples. The authors also concluded that
neuritic synuclein inclusions were correlated with a small
fibre neuropathy, suggesting a possible direct role of p-a-
Syn in peripheral nerve damage.
Comment. The use of skin biopsy in the diagnosis of IPD
is an intriguing prospect. It is easily performed and mini-
mally invasive with few adverse effects. This study pro-
vides some compelling evidence for use of skin biopsy in
the diagnosis of IPD, although clearly larger studies would
be of value in validating its use in clinical practice. The
mean disease duration in the IPD group was 13 years, but it
may be interesting to explore this biomarker in early or
preclinical disease which may have significant implications
for guiding earlier therapeutic interventions. However, the
insights provided into pathophysiology remain limited
since p-a-Syn deposits did not appear to correlate with
disease duration or sub-phenotype.
Donadio V et al. (2014) Neurology 82:1362–1369.
Distinctive distribution of phospho-alpha-
synuclein in dermal nerves in multiple system
atrophy
MSA also remains a largely clinical diagnosis with support
from autonomic function tests and neuroradiology. Patho-
logically MSA is characterised by detection of a-Syn
deposits in oligodendrocytes and neurons. In this study,
Doppler et al. explore whether p-a-Syn deposits in dermal
nerve fibres can be used as a biomarker in MSA and
whether this could differentiate MSA from tauopathies and
IPD. Twelve patients with probable MSA according to the
Gilman criteria (6 where MSA was supported by neu-
roimaging and a further 6 without MRI support), 15
patients with presumed tauopathies (based on the criteria of
Armstrong et al.), 30 patients with IPD (based on the UK
Brain Bank criteria) and 39 healthy controls were
examined.
Five-millimetre punch skin biopsies were taken from
the back (Th12) and distal and proximal leg. Serial
sections were undertaken to determine sensitivity and
one in ten sections were double stained. p-a-Syn within
dermal nerve fibres was detected in 8/12 patients with a
clinical diagnosis of MSA. No p-a-Syn immunoreactive
nerve fibres were identified in patients with presumed
tauopathies or normal controls (p\ 0.05). The sensi-
tivity of skin biopsies stained positively for p-a-Syn in
MSA was 67 % and specificity for a diagnosis of MSA
versus tauopathies/controls was 100 %. In the IPD
group, p-a-Syn was detected in 20 out of 30 patients,
resulting in a sensitivity of 67 %. Double-staining serial
sections of all p-a-Syn-negative patients identified one
further patient with MSA and two more patients with
IPD, increasing sensitivity to 75 and 73 %,
respectively.
In MSA patients, p-a-Syn was predominantly deposited
in somatosensory fibres of the subepidermal plexus, in
contrast to IPD where autonomic fibres were predomi-
nantly affected. In the IPD group, proximal biopsy sites
showed the highest detection rate, raising the possibility of
antidromic spreading of p-a-Syn from ganglia to sensory
nerve findings. The authors conclude that detection of p-a-
Syn in cutaneous nerve fibres may support the diagnosis of
a ‘synucleinopathy’ in contrast to tauopathies. They also
suggest that p-a-Syn in somatosensory fibres is associated
with MSA-parkinsonism, whereas autonomic fibres are
involved in IPD.
Comment. This study advocates the use of skin biopsy in
distinguishing IPD from MSA and other forms of parkin-
sonism. No attempt was made to correlate p-a-Syn depo-
sition to disease severity or duration. Once again, a larger
study would be of value in validating these results and
developing wider datasets before its use can be supported
in clinical practice. Mean disease duration varied consid-
erably between clinical groups (MSA 4.9 years; IPD
12.4 years; tauopathies 3.6 years) and future studies may
consider matching for both age and diseased duration.
Doppler MD et al. (2015) Mov Disord 30(12):1688–1692.
Phosphorylated alpha-synuclein in skin nerve
fibres differentiates Parkinson’s disease
from multiple system atrophy
Zange et al. addressed the hypothesis that p-a-Syn can be
detected in skin sympathetic nerve fibres in Parkinson’s
disease, but not MSA. This study included 10 patients with
IPD (according to the UK Parkinson’s Disease Society
Brain Bank criteria) and 10 patients with MSA (according
to Gilman criteria). Clinical classification was further
supported by nuclear imaging and autonomic reflex
screening. Six patients with an essential tremor served as
controls.
Three-millimetre punch biopsies were taken from the
forearm of the clinically more affected side. p-a-Syn
deposits were detected in nerve fibres innervating skin
autonomic structures in a-Syn-dependent neurodegenera-
tive disorders and p-a-Syn deposition was limited to
Parkinson’s disease. However, dermal nerve fibres of MSA
and control patients were devoid of p-a-Syn. The authors
2794 J Neurol (2015) 262:2793–2795
123
conclude that as their study did not show involvement of
postganglionic sympathetic skin nerve fibres in MSA (with
a clinical duration up to 7 years), testing sympathetic skin
nerve fibres for p-a-Syn deposits is of value in differenti-
ating Parkinson’s disease from MSA. However, they sug-
gest that further studies of a variety of disease durations are
necessary to verify this. Their data support the finding of
dermal denervation in Parkinson’s disease, occurring
independently of age and correlating with the extent of
intra-axonal p-a-Syn deposition.
Comment. This study supports the use of skin biopsy to
differentiate IPD from MSA, specifically looking at auto-
nomic skin nerve fibres. However, perhaps the most rele-
vant conclusion that can be drawn is that autonomic skin
fibre biopsies can be used to differentiate IPD from ‘not
IPD’. The Parkinson’s disease patients in this study had a
mean disease duration of 5.85 years, compared to
4.10 years for the MSA patients which are relatively well
matched, although mean age of the cohorts differed by
almost 10 years. As in the previous two papers, this study
also supports the relationship of dermal denervation to p-a-
Syn deposition. It would clearly be of value to obtain
longer term follow-up data on these cohorts including
pathology if available, to verify diagnosis and pathological
conclusions.
Zange et al. (2015) Brain 138:2310–2321.
Open Access This article is distributed under the terms of the
Creative Commons Attribution 4.0 International License (http://crea
tivecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided you give
appropriate credit to the original author(s) and the source, provide a
link to the Creative Commons license, and indicate if changes were
made.
J Neurol (2015) 262:2793–2795 2795
123


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The role of skin biopsy in differentiating idiopathic Parkinson's disease from other types of parkinsonism

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