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Neuroflaments in the diagnosis omotor neuron diseases: a
prospective study
Petra Steinacker, Emily Feneberg et al.
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Introduction
Motorneuron diseases are a group ofneurodegenerative disorders,
the most common formof which is AS.
!t is characterised by degeneration of the upper andlower motor
neurons.
AS has a median survival of " years from symptom
onset.
Around #$ of those initially diagnosed as ASultimately turned
out to have a di%erent disease.
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&y the time the patients ful'l the El Escorial criteriafor
clinically de'nite AS they are usually in theadvanced stage of
disease
(alidated neurochemical biomarkers thatdistinguish early between
AS and its di%erentialdiagnoses are lacking.
Early disease diagnosis through the use ofbiomarkers may aid in
correct clinical managementof patients and possibly delay time to
ventilator.
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Aim
)o determine the *SF biomarkers to di%erentiateM+ from its
mimics.
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Neuroflaments-+F are the /0 nm intermediate'laments found in
neurons.
)hey are a ma1or component of the neuronal
cytoskeleton
isorgani2ed neuro'laments can provokedegeneration and death of
neurons-Apoptosis
An interference of a3onal transport by disorgani2edneuro'laments
has been proposed as one possiblemechanism of neuro'lament4induced
pathology
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!t is a monocentric prospective study
Study Place5 epartment of +eurology, 6niversityof
6lm,7ermany
Study Period5 May 80/0 to 9une 80/:
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MATERIAL/METHODS
Participants and clinicalcharacterisation
Ethical Clearance: Patients provided written informed consent
for
the study
)he study was approved by the ethics committeeof the 6niversity
of 6lm
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A total of :;; participating patients were seen ina prospective
manner.
All patients who consulted the epartment of+eurology -inpatients
and outpatients were
asked to participate in this study. Patients were then followed
up every ?0@* until analysis.
*ommercially available E!SA kits were used for+f and p+f and for
)au and p)au.
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Calculations and statistics
9MP4SAS4software.
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RESULTS
)here was no age di%erence between the M+group and the control
groups.
)he concentrations of +f and p+f weresigni'cantly higher in the
*SF obtained frompatients with M+ -pB0.000/
)he concentrations of )au and p)au in the *SFwere signi'cantly
higher in A patients than in allpatients with non4A diagnoses taken
together.-pB0.000/.
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)here was no signi'cant di%erence between AS,PS and genetically
de'ned AS for all biomarkers-+f5 pC0.0D;, p+f5 pC0.0;D )au5
pC0.?8D, p)au5pC0.#
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Alication o! cut"o#s !or $!Land $!H
An +f concentration above 8800 pgGm yieldedthe optimal
discrimination between M+ and M+mimics4
sensitivity 4 ##$ -*! #/$ to ?8$
Speci'city4 ??$ -*! #D$ to D:$
PP( 4 D;$ -*! D/$ to D?$,
+P(4 ;
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For p+f, the best diagnostic performance wasachieved at a cut4o%
of ;
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igher progression rates -timebetween onset and sampling
-inmonths divided by reduction in AS4
FHS4H were associated with higher+f concentrations in M+
+o correlation could be found
between biomarker levels and FA4*S)values of MH!
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%alse ositi&e cases
// patients had 'i(' &alues !or $!L )*++,, (/mL- and $!H
)*., (/mL-
Myopathy -nC8
*!P-nC"
P+P -nC8
&enign fasciculation
Encephalitis
Hadiculopathy
Myositis
$!H only
&enign fasciculation
MyositisEndocrine myopathy
*hronic pain
Spinocerebellar ata3ia
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DISCUSSIO$
*SF levels of +f and p+f are elevated in M+,thus enabling a
sensitive and speci'cdiscrimination of M+ vs M+ Mimics
!n particular, a high positive predictive valuecould be found
for these biomarkers =ualifyingthem as con'rmation markers for
suspected M+.
+egative results for these markers do not ruleout M+
diagnosis.
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+f levels were associated with M+ diseaseprogression and disease
duration, and potentially=ualify as prognostic markers
Hecently, data on the predictive validity of
increased +f levels in the blood of patients withAS was
published.
+f serum or plasma levels measured with
anelectrochemiluminescence assay -as yet not
purchasable strongly correlated with *SF levels )he +f E!SAs
used in this study were not suitable
for measurement of serum samples due to higherdetection
limits
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!n contrast to recent observations on a much smallercohort of
patients with AS -nC;/,": p)au and )auconcentrations did not show a
speci'c pro'le in this
large cohort and were only elevated in patients with
A. )he highest concentrations of +f are found in large
myelinated a3ons and these are presumably shed intothe
e3tracellular space and *SF following neuroa3onal
damage.
*onse=uently, the e3tent of neuroa3onal damageshould be reIected
by elevated +f concentrations andthere should be a correlation of
+f with the disease
state
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!n conclusion, it suggested that +fmeasurements are included in
the diagnosticwork4up of patients with AS,
+fs correlate with M+ progression and theapplicability of +f as
prognostic marker in clinicalroutine should be investigated
further.
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Comments
)he therapeutic implications of the earlydiagnosis needs to be
studied
)he pathogenic role of these biomarkerabnormalities need to be
studied
