Amyloid mis-metabolism in idiopathic normal pressure hydrocephalus
Hydrocephalus Research Unit, Institute of Neuroscience and Physiology, The
Sahlgrenska Academy, University of Gothenburg
Amyloid mis-metabolism in idiopathic normal pressure hydrocephalus
A. Jeppsson 0
C. Wikkelsø 0
Mats Tullberg 0
0 Hydrocephalus Research Unit, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg , 413 45 Gothenburg , Sweden
Background: Patients with idiopathic normal pressure hydrocephalus (iNPH) have reduced cerebrospinal fluid (CSF) concentrations of amyloid-β (Aβ) and α- and β-cleaved soluble forms of amyloid precursor protein (sAPPα and sAPPβ). The aims of this study were to examine if changes could also be seen in the CSF for secreted metabolites of APP-like protein 1 (APLP1) and to explore the prognostic value of amyloid-related CSF biomarkers, as well as markers of neuronal injury and astroglial activation, as regards to clinical outcome after shunt surgery. Methods: Twenty patients diagnosed with iNPH, 10 improved and 10 unchanged by shunt surgery, and 20 neurologically healthy controls were included. All patients were examined clinically prior to surgery and at 6-month followup after surgery using the iNPH scale. Lumbar puncture was performed pre-operatively. CSF samples were analyzed for neurofilament light (NFL), Aβ isoforms Aβ38, Aβ40 and Aβ42, sAPPα, sAPPβ, APLP1 β-derived peptides APL1β25, APL1β 27 and APL1β 28 and YKL40 by immunochemical methods. Results: The concentrations of all soluble forms of APP, all Aβ isoforms and APL1β28 were lower, whilst APL1β25 and APL1β27 were higher in the CSF of iNPH patients compared to controls. There was no difference in biomarker concentrations between patients who improved after surgery and those who remained unchanged. Conclusions: The reduced CSF concentrations of Aβ38, Aβ40, Aβ42, sAPPα and sAPPβ suggest that APP expression could be downregulated in iNPH. In contrast, APLP1 concentration in the CSF seems relatively unchanged. The increase of APL1β25 and APL1β27 in combination with a slight decreased APL1β28 could be caused by more available γ-secretase due to reduced availability of its primary substrate, APP. The data did not support the use of these markers as indicators of shunt responsiveness.
Neurodegeneration; Normal pressure hydrocephalus; Cerebrospinal fluid; Amyloid; NFL; YKL40; Prediction; APLP1
Idiopathic normal pressure hydrocephalus (iNPH) is
a condition with gait and balance disturbances,
cognitive decline and urinary incontinence in combination
with enlarged cerebral ventricles [1, 2]. Shunt treatment
improves more than 80 % of the patients . Without
surgery, the clinical course is progressive and a delay in
treatment means a loss of function that cannot be restored .
Being one of the few treatable neurodegenerative
conditions, an accurate diagnosis and identification of patients
who will benefit from shunt surgery is essential. The use
of CSF biomarkers for such purposes has been identified
as one of the priorities for hydrocephalus research .
Patients with iNPH exhibit suppressed CSF
concentrations of amyloid-β (Aβ) and the precursors soluble
amyloid precursor protein α-, and β- (sAPPα, sAPPβ), in
combination with elevated neurofilament light protein
(NFL) [6–9]. Hypothetically, this is thought to be due
to a downregulation of APP in the periventricular tissue
possibly caused by changed amyloid metabolism and/or
a reduced clearance of extracellular fluid into CSF
leading to lowered concentrations of APP-derived proteins in
Amyloid-like protein 1 (APLP1)-derived peptides are
processed by similar enzymatic pathways as APP and share
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related structural domains and functions [10–12]. APLP1 is
processed into short Aβ-like peptides (APL1β25, 1β27 and
1β28) . APLP1 is a substrate for the enzyme γ-secretase
and the ratio of APLP1-derived APL1β28 to total APL1β
is a surrogate marker for Aβ42 production in the
central nervous system [13, 14]. Recently, it was reported
that γ-secretase was higher in brain biopsies from iNPH
patients with amyloid plaques than in those without .
The aim of this study was to examine CSF
concentrations of APLP1-derived peptides in iNPH, especially if
the APL1β28 form was increased, and to explore the
prognostic value of amyloid-related CSF biomarkers.
For this purpose, we analyzed the APP-derived peptides
sAPPα, sAPPβ, Aβ38, Aβ40 and Aβ42, the APLP1derived
peptides APL1β25, APL1β27 and APL1β28 in CSF in 20
patients with iNPH (10 improved and 10 unchanged by
shunt operation) and 20 neurologically healthy controls.
Ten iNPH patients improved after shunt surgery and 10
non-improved were retrospectively selected. All were
diagnosed in accordance with the international
guidelines . The patients were selected from our local
database at the hydrocephalus unit at Sahlgrenska
University Hospital on the premises that full medical data
pre- and postoperatively were available and that there
was sufficient CSF stored to perform the analyses. In all,
the database contained 176 patients. From the database,
the 10 patients who benefitted the most from surgery (as
defined by improvement in the iNPH scale) and fulfilled
the inclusion criteria were selected. In the group that did
not benefit from surgery, medical records were scanned
in order to establish that at time for follow-up all shunts
were working, none had complications and that that
there be no other known cause for non-improvement.
Patients who had complications that could be attributed
to shunt surgery were excluded. In all, the groups were
selected in order to magnify the difference in
responsiveness to shunt surgery within the clinical material and
analyze two clearly-distinguishable extreme groups as
regards to shunt responsiveness.
The improved 10 patients consisted of five men and five
women, aged 70.3 ± 3.20 (mean ± SD) and the 10
unimproved patients (<5 points at the iNPH scale) consisted of
seven men and three women aged 71.6 ± 8 (mean ± SD).
The groups did not differ significantly in terms of
comorbidities, preoperative MMSE scores, extent of white
matter lesions (WML), age or sickness duration. The
baseline clinical data of the different groups are outlined
in Table 1.
All patients were examined clinically prior to
surgery and 6 months after by the iNPH scale, composed
Age (mean ± SD) 70.3 ± 3.2 71.6 ± 8.0 ns
Sex (male/female) 5/5 7/3 ns
Sickness duration (month) 42 ± 21 34 ± 28 ns
Diabetes (y/n) 2/8 2/8 ns
Hypertension (y/n) 5/5 6/4 ns
Cardiovascular disease (y/n) 2/8 1/9 ns
MMSE (median, IQ-range) 23 (22–28) 26 (24–28) ns
WML (median, IQ-range) 6 (4–10) 11 (5–20) ns
Evans index (median, IQ-range) 0.43 (0.38–0.46) 0.39 (0.36–0.41) ns
of items assessing gait, cognition, continence and
balance . The extent of WML was rated by the Wahlund
scale from MRI or CT scans at the time for diagnosis
. Lumbar puncture was performed preoperatively
with the patient in recumbent position. In the improved
group the median improvement was 26 points and in the
non-improved group the median was 1 point (Table 2).
All patients received a ventriculo-peritoneal shunt with
a programmable valve with an anti-siphon device and a
Rickham reservoir. All had working shunts and none had
complications at the time for evaluation.
Twenty control subjects were chosen from a
population of volunteers who had given consent to CSF
sampling prior to knee surgery. The controls had no history
of neurological or psychiatric disease, a normal
clinical neurological examination and a normal mini-mental
state examination score. They consisted of eight men
and 12 women aged 71.2 (±6.4). There was no difference
in age between the three subcategories (controls, iNPH
improved and iNPH non-improved).
Amyloid β isoforms (Aβ38, Aβ40, and Aβ42) were
analyzed by electrochemiluminescence assays (Meso
Scale Discovery, Gaithersburg, MD, USA). The
APLP1derived peptides APL1β25, APL1β27, and APL1β28
were analyzed using a commercial ELISA (IBL
International, Hamburg, Germany). The samples were analyzed
according to the kit insert with minor modifications.
The CSF samples were diluted 1:20 for APL1β25, 1:10
for APL1β27, and 1:5 for APL1β28 by the dilution buffer
contained in the kit. All samples were analyzed in
duplicate and the CV % for standards and samples was <5 %.
NFL was measured by ELISA technology using a
commercial kit (NF-Light, UmanDiagnostics, Umeå, Sweden)
with a lower limit of detection of 50 ng/L. For astroglia
activation, CSF YKL-40 concentration was measured by
Table 2 iNPH scale score pre op, post op and outcome (median and IQ-range)
n = 10
n = 10
n = 10
n = 10
n = 10
n = 10
solid phase sandwich ELISA (R&D Systems, Inc.,
Minneapolis, Minnesota, USA) according to the manufacturer’s
instructions. All analyses were performed batch-wise on
one occasion by board-certified laboratory technicians at
the Clinical Neurochemistry Laboratory at Sahlgrenska
University Hospital, Mölndal, Sweden. Intra-assay
coefficients of variation were below 10 %.
Non-parametric methods were used for analyses. For
comparisons between two groups the Mann–Whitney
U test was performed and for comparisons between the
three subgroups, the Kruskal–Wallis test was performed.
For comparison of two proportions, Fisher’s exact test
was used. For association between two independent
variables, the Spearman rank order correlation was chosen.
The level of significance chosen was p = 0.05, if not
otherwise stated. No correction for the mass-significance
effect was made in order to avoid type II errors.
Statistical analyses were made using IBM® SPSS® Statistics for
Windows version 21.
CSF concentrations of sAPPα, sAPPβ, Aβ38, Aβ40, Aβ42
and APL1β28 were significantly lower and APL1β25 and
27 significantly higher in iNPH patients compared to
healthy controls. Levels of NFL and YKL 40 did not
differ between iNPH patients and healthy controls (Table 3;
Fig. 1). The APL1β28/total APL1β ratio and the Aβ42/to
total Aβ ratio was lower in patients with iNPH in
comparison with healthy controls (Fig. 2).
There were no differences in any of the CSF
biomarkers between improved and non-improved iNPH patients
Our data showing substantially reduced CSF
concentrations of Aβ38, Aβ40, Aβ42, sAPPα and sAPPβ in patients
with iNPH, confirm earlier results [6–9, 11, 19–22]. In
contrast, APLP1 in CSF was mildly but significantly, changed
with an increase in APL1β25 and APL1β27 and a slight
decrease of APL1β28, compared with controls. The ratios
APL1β28/total APL1β and Aβ42/total Aβ were reduced in
patients with iNPH. However, there were no differences in
any CSF biomarker between improved and non-improved
iNPH patients after treatment with shunt surgery.
This explorative study was in part designed to identify
predictive alterations in the amyloid CSF pattern. We
included two small groups representing iNPH patients
that benefitted the most and those without any response
to surgical treatment with shunting, in order to identify
possible differences. However, we found no differences in
CSF biomarkers between improved and non-improved
patients. The low number of cases in each group may
have been a limitation in this study. However, if there are
subtle variances in CSF amyloid concentrations linked
to responsiveness that could be identified in larger
sample sets, we believe that these would be of minor clinical
importance. Lumbar CSF as opposed to ventricular CSF
was analysed to enhance the practical applicability of the
generated results. Ventricular CSF might however
provide a different pattern as it probably mirrors brain
metabolic processes more accurately.
The reduced CSF concentrations of Aβ38, Aβ40, Aβ42,
sAPPα and sAPPβ in iNPH is consistent with earlier
findings [6, 7, 9, 11, 19–23], and compatible with a reduction
in the concentrations of APP-derived proteins in the CSF
of iNPH-patients. iNPH is a disorder of disturbed CSF
dynamics and/or consequences thereof. Recent insights
into the glymphatic system, has provided possibilities for
a new route for clearance of excess fluid and interstitial
metabolites, including Aβ, from the brain parenchyma
[24, 25], together with clearance of Aβ across the blood–
brain barrier (BBB) via the LRP-1 receptor . In the
glymphatic system, there may be a para arterial influx of
CSF from the subarachnoid space into the brain
parenchyma where convective flow of interstitial fluid (ISF)
helps to clear metabolic waste by para venous clearance
towards the cervical lymph system, a system that seems
to impair with aging [25, 27]. However, clear evidence
Table 3 Biomarker levels in iNPH and controls (median
and IQ range)
for this clearance is still lacking. In iNPH the CSF flow
above the convexities is reduced and redirected into the
ventricles and iNPH patients often present with a
disproportionately enlarged subarachnoid-space [28, 29]. These
findings could hypothetically be in accordance with a
disturbance of CSF/ISF exchange as the dilated paravascular
spaces could impair CSF/ISF exchange. Although
speculative, it could be hypothesized that the reduced
concentrations of APP-derived proteins in the CSF of INPH
patients could be due to stagnation of the flow in the
periventricular ISF with reduced clearance of Aβ. This,
however, remains to be proven. Regardless, levels of
APPderived proteins in CSF are affected by both production
and clearance of APP, and also by the ISF/CSF itself. This
could make estimates of tissue levels in relation to CSF
concentration problematic in patients with iNPH .
CSF APP-derived proteins increase after surgery, more
in improved patients than in those that do not improve
p = < 0.0001
p = < 0.0001
p = < 0.0001
p = < 0.01
p = < 0.001
p = < 0.0001
p = < 0.001
p = < 0.0001
L p = < 0.0001 p = 0.0020
82 /42 0.10
PA itao 0.05
iittraevo00..2250 iltrevae 0.00
lae iNPH HI R iNPH HI
Fig. 2 The relative ratios of APL1β28 to total APL1β and Aβ42 to total Aβ in CSF in 20 patients with iNPH and 20 Controls. P values show the level of
Table 4 Levels of biomarkers in improved vs
nonimproved iNPH patents (median and IQ-range)
[6, 11]. Even if not designed to analyze such changes, the
present study does not contradict these findings. The
presumed reduction in CSF concentrations of the
amyloidderived proteins could reflect a pathophysiological aspect
of iNPH that is not directly linked with prediction. The
irreversibility in non-improved iNPH patients could be due
to either tissue damage related to iNPH or damage related
to other factors such as co-morbidities e.g. cerebrovascular
lesions, as there was a tendency of more profound WML in
the non-improved group even if not reaching statistical
significance. However, cerebrovascular disease is not a
negative predictor of outcome after shunt surgery .
Contrary to the profound alterations in APP
metabolites, the APLP1-derived peptides showed only
minor changes with a small elevation in APL1β25 and
APL1β27 and a slight reduction of APL1β28. APP and
APLP1 are processed by the same enzymes, including
γ-secretase [10, 12, 13, 32], and the results could
indicate that the two substrates compete with each other
at the active site of γ-secretase. If APP expression is
reduced, as most data suggest it is in iNPH, there would
be more γ-secretase available for the processing of
APLP1. The processing occurs by γ-secretase cleaving
at amino acid 28 of the membrane-spanning β-domain
of APLP1 and then working its way towards the
N-terminus of the protein. Increased processing of APLP1
by γ-secretase would thus result in decreased
concentration of APL1β and increased concentrations of the
shorter forms [33, 34]. This is exactly what we observe
in iNPH. Over-expression of APP results in a decrease
of APL1β, which supports this substrate competition
There is a difference in APP-metabolite production
pattern between iNPH and AD. In iNPH there is a general
suppression of APP-metabolites in CSF whereas in AD,
there is an isolated Aβ42 reduction, whereas the other
Aβ-isoforms are unaffected . Moreover, the internal
composition of Aβ production differs as shown in the
APL1β28/total APL1β ratio. In our opinion, this provides
further evidence against a common pathological etiology
and might aid in the differential diagnosis of iNPH from
AD by CSF biomarkers .
This data lends further support to a diagnostic profile in
iNPH consisting of a general reduction in CSF
concentration of APP-derived proteins. That the amyloid-like
proteins behave in a different pattern could support the
specificity and importance of the APP-down-regulation
in iNPH. The study indicates that the biomarker profile
in iNPH is consistent between patients who improve
by shunt insertion and those who do not; therefore, our
results do not lend support to the idea that these markers
can be used for predictive purposes, but rather as an aid
in the diagnosis of iNPH. Further studies will be needed
to replicate the results and to expand the knowledge on
the role of a possible altered amyloid metabolism for the
pathogenesis of iNPH and the potential use of markers of
amyloid metabolism to identify shunt responders needs
to be further elucidated.
iNPH: idiopathic normal pressure hydrocephalus; CSF: cerebrospinal fluid;
Aβ: amyloid-β; sAPPα: α-cleaved soluble forms of amyloid precursor protein;
sAPPβ: β-cleaved soluble forms of amyloid precursor protein; APLP1: APP-like
protein 1; APL1β: APLP1 β-derived Aβ-like peptide; NFL: neurofilament light;
WML: white matter lesion; ISF: interstitial fluid; BBB: blood–brain barrier.
AJ carried out the statistical analysis, participated in the design of the study
and conceived the study, drafted the manuscript and participated in the
coordination of the study. MK, HZ and KB carried out the laboratory analysis,
participated in the design of the study and conceived the study. CW and
MT conceived of the study and participated in the design and coordination
and helped to write the manuscript. All authors read and approved the final
The authors would like to thank the patients, and the staff at the
Hydrocephalus Research Unit and the Clinical Neurochemistry Laboratory, especially
Per Hellström who provided highly valuable help on statistical and clinical
K. B. has served as a consultant and at advisory boards for IBL International,
Fujirebio Europe and Roche Diagnostics. C. W. receives honoraria for lecturing
and consulting by Codman, Johnson and Johnson. The other authors have no
Availability of data and materials
Data will not be shared as all data are already presented in the main paper.
Ethics, consent and permissions
The study was approved by the Regional Ethical Review Board in Gothenburg
(Dnr 020-07) and written informed consent was given by the patient and/or a
This study was supported by grants from the Swedish Research Council,
the European Research Council, Swedish State Support for Clinical Research
(LUA-ALF), the Knut and Alice Wallenberg Foundation, the Torsten Söderberg
Foundation, the Swedish Brain Foundation, Frimurarestiftelsen, the Göteborg
Foundation for Neurological Research and the Neurological Research
Foundation. The sponsors were not involved in the study design, in the collection,
analysis and interpretation data; in the writing of the report; or in the decision
to submit the paper for publication.
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