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Citation: Farías GA, Arata L, Guzmán-Martínez L, Morales I, Tapia JP and Maccioni RB. Biochemical Markers
for Alzheimer’s and Parkinson’s Disease. Austin J Clin Neurol 2015;2(7): 1059.
Austin J Clin Neurol - Volume 2 Issue 7 - 2015
ISSN : 2381-9154 | www.austinpublishinggroup.com
Farías et al. © All rights are reserved
Austin Journal of Clinical Neurology
Open Access
Abstract
Many biomarkers are currently being searched in neurodegenerative
diseases like Alzheimer’s disease and Parkinson’s disease. These diseases
share some common pathophysiological mechanisms and the presence of
protein aggregates. Measurements of those proteins -like tau, amyloid-beta
peptide and α-synuclein-, as well other mediators of neurodegeneration in
cerebrospinal uid and peripheral uids have been explored as biomarkers.
Here we summarize some of the available data on biochemical markers for
neurodegenerative diseases, considering advantages and drawbacks of each
marker and method of analysis.
Keywords: Biomarkers, Alzheimer`s Disease, Parkinson`s Disease, Protein
misfolding diseases
Abbreviations
AD: Alzheimer’s Disease; PD: Parkinson’s Disease; FTD:
Frontotemporal Dementia; CBD: Corticobasal Degeneration; PSP:
Progressive Supranuclear Palsy; MSA: Multiple System Atrophy;
LBD: Lewy Body Dementia; PMDs: Protein Misfolding Diseases;
α-syn: α-synuclein; CSF: Cerebrospinal Fluid; Aβ: Amyloid-beta
Peptide; p-tau: Phosphorylated tau; AβPP: Aβ Precursor Protein;
BBB: Blood-brain Barrier; miRNA: Micro RNA; mRNA: Messenger
RNA; SPT: Serine Palmitoyltransferase; Sp 1: Specicity Protein 1;
NINDCs: Non-inammatory Neurological Disease Controls; EGF:
Epidermal Growth Factor; CNS: Central Nervous System; TNF-α:
Tumor Necrosis Factor-α; IL-1β: Interleukin-1β; IL-6: Interleukin-6;
INF-γ: Interferon-γ; PGE2: Prostaglandin E2; TGFβ: Transforming
Growth Factor β; IL-8: Interleukine 8
Background
As world population grows older, age related neurodegenerative
diseases like Alzheimer’s disease (AD) and Parkinson’s disease (PD)
have become important public health concerns. Many other age-
related conditions also share some combination of their most striking
clinical features (i.e. dementia and Parkinsonism), so dierentiation
between some diagnoses may be very dicult in individual patients.
Among dierential diagnoses for AD and PD we can mention many
forms of frontotemporal dementia (FTD), corticobasal degeneration
(CBD) progressive supranuclear palsy (PSP), multiple system atrophy
(MSA) and Lewy body dementia (LBD). All of the above also share
the presence of protein aggregates on neuropathology, so they have
been termed as protein misfolding diseases (PMDs) [1] and since tau
or α-synuclein (α-syn) can be found frequently in protein aggregates,
many of these diseases have been grouped as tauopathies i.e. AD,
many forms of FTD, CBD and PSP [2-4] or as synucleinopathies i.e.
PD, LBD and MSA [5]. Anyhow, is clear that multiple interactions
exist between proteins in PMDs, so many proteins are aected in each
PMD and conversely, most of the proteins described as responsible
for PMDs show some degree of modication in each isolated PMD
[5].
Review Article
Biochemical Markers for Alzheimer’s and Parkinson’s
Disease
Farías GA1,2,3*, Arata L1,2, Guzmán-Martínez L1,2,
Morales I1,2, Tapia JP2,4 and Maccioni RB1,2
1International Center for Biomedicine (ICC), Chile
2Laboratory of Cellular and Molecular Neurosciences,
Chile
3Department of Neurology, University of Chile, Chile
4Faculty of Sciences, University of Chile, Chile
*Corresponding author: Farías GA, Department of
Neurology, University of Chile, Santos Dumont 999,
Independencia, Santiago, Chile, Email: gfarias@med.
uchile.cl
Received: May 04, 2015; Accepted: June 22, 2015;
Published: June 28, 2015
Many pathological processes appear to be related upstream in
the process of protein aggregates generation, including misbalances
in inammatory responses, cell signaling and redox state. Even with
all of our advances in the study of neurodegenerative processes and
models of disease we have been unable to generate consensus on the
true role of protein aggregates, so we still are not sure what is the
true importance of protein deposition for PMDs and we don’t know
if there is a common pathway or generator of the pathological process
(like neuroinammation) in some or all of these diseases, and if there
is a common pathway of neurodegenerative process, we don’t fully
understand what is the dening feature that initiates the deposition
of one protein over the other and the neurodegenerative process of
some neuronal populations over the next [6-9].
Since one of the main problems in the diagnosis of chronic
neurodegenerative diseases is their late onset of symptoms many
years aer the disease has begun there is a big gap between initiation
of pathologic processes and development of clinical symptoms.
is is due to the brain extensive ability to compensate functions.
is adaptive characteristic generates the problem that in most
cases diagnosis is only possible late, when there is an advanced
neurodegenerative process, so any present or future treatment will
lose its eectiveness. ereby, the development of suitable test able
to identify diseases early, when symptoms are not so obvious has
become an essential task for neurodegenerative diseases studies [10].
e lack of certainty on the pathophysiology of PMDs doesn’t
deny the fact that we have made many interesting discoveries on the
biochemical and histopathological features that characterizes each
form of PMD. Furthermore many groups have made eorts to follow
up some of the changes in key biological markers a protein, cytokine,
RNA or other and use them as biological marker for any disease they
are interested on [7,9,11].
A biomarker can be dened as an indicator of the presence or
extent of a disease in particular and is directly associated with clinical
manifestations and prognosis [12,13]. ey can be measured and
evaluated as indicators of normal biological processes, pathogenic
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processes or pharmacological responses to therapeutic interventions.
Currently, due to the limited availability and reliability of markers for
PMDs scientists from several countries have focused on the discovery
of these biomarkers [11].
e most important problem in the search for new biochemical
markers of PMDs is the lack of standardization of sampling collection,
handling and storage, as well as, the procedures that are performed
for analysis -i.e. sample processing by western blot, ELISA, micro
array, RT-q PCR or other. All of the above makes very dicult to
achieve consistent results.
Since cerebrospinal uid (CSF) is in close proximity with neural
structures and is constantly exchanging dierent substances including
all sorts of proteins -like the ones forming extracellular accumulates
in PMDs, many research groups have focused on analyses of markers
that may be present in CSF. Among those we can mention studies on
levels of amyloid-beta peptide (Aβ), total tau protein, phosphorylated
tau (p-tau) and α-syn for AD, PD and other PMDs [14]. Research
has highlighted the increased hyperphosphorylated tau in the CSF of
patients with AD and the close correlation between the levels of p-tau
in CSF and cognitive impairment [14,15].
Aβ, tau and α-synas biomarkers for AD and PD
Aβ is one of the most prominent and well characterized aggregated
proteins in neurodegenerative diseases, since it was initially reported
by Glenner and Wong [16] it has become a cornerstone leading to a
new front for research for the study of AD.
e amyloid precursor protein (AβPP) may be subject to the
β-secretase pathway where two peptides may result, Aβ (1-40) and
Aβ (1-42), however the Aβ (1-42) isoform has shown to be more
toxic, it aggregates faster than Aβ40 and it is the main component of
amyloid plaques in the extracellular space [17,18]. On the other hand,
α-secretase acts in the non-amyloidogenic pathway, which doesn’t
lead to the Aβ formation [19]. Since Aβ deposition can be found in
many neurodegenerative diseases, such as PD, AD [20], and LBD
[21], it’s been one of the most studied biomarker candidates.
Cerebrospinal uid (CSF) is the main source for sampling Aβ and
tau in vivo [4]. CSF is in intimate contact with nerve tissue, and there
is an important exchange of substances with neural environment.
For this reason, various groups have focused in modications of
various proteins and substances related to the pathogenesis of AD
and PD [12,15,22,23] Considering a possible pathogenic role of Aβ,
there have been lots of analyses of this protein. Measures of Aβ levels
with immune assays in AD patients demonstrate a typical decrease in
CSF’s Aβ (1-42) levels, is sole analysis has a sensitivity of 78% and
a specicity of 81-83% for the diagnosis of AD [4,24]. e reduction
in Aβ has been attributed to aggregation and sequestration of Aβ
(1-42) in brain senile plaques [25]. In AD there is also an increase
in tau protein levels over time that has been attributed to neuronal
degeneration and release of this intracellular protein [15]. As for other
PMDs, studies in PD patients shows that tau levels seem unchanged
and only Aβ (1-42) shows a decrease below base lines [20].
Previous studies demonstrate that even thought Aβ (1-42)
measurements in CSF have sucient accuracy over 85%- for
discriminating between AD and control subjects [17,26]. e capacity
of this biomarker for early dierential diagnosis is still to low, because
of a neuropathological overlap between AD and other PMDs like PD.
Anyways Aβ (1-42) levels in CSF appear to be lower in AD patients
than in PD [20,27].
Moreover, Siderowf et al. (2010), concluded that lower levels
of CSF Aβ (1-42) were associated with cognitive decline in PD.
Evaluating the relationship between Aβ (1-42), total tau and p-tau
levels in CSF, and the change in cognition measured with Mattis
Dementia Rating Scale (DRS-2), they showed that tau and p-tau
didn’t have any signicant relationship with cognitive decline,
however, when evaluating Aβ (1-42) they found that those with levels
≤ 192 pg/mL had a 6.1 points increase in annual decline compared to
those above that level [25].
Low Aβ levels in CSF can predict the onset of cognitive decline
in older women without dementia [28]. With respect to PD, studies
by Bekris et al. 2015, found that Aβ levels are abnormal in the CSF
of patients with PD. e objective of this exploratory study was to
determine whether genetic variation within the AβPP is correlated
with the levels of CSF Aβ (1-42) in PD. ey studied single nucleotide
polymorphisms (SNPs) from 19 regulatory regions of the nine genes
(AβPP, ADAM10, BACE1, BACE2, PSEN1, PSEN2, PEN2, NCSTN
and APH1B) involved in the cleavage of AβPP. ey observed a
signicant correlation with Aβ (1-42) levels CSF in PD for two SNPs
(AβPP rs466448 and APH1B rs2068143). In addition, the researchers
suggest that SNP AβPP and SNP APH1B marginally associated with
PD CSF Aβ (1-42) levels in non-carriers of APOEε4 [29].
Studies focused on tau protein in CSF, showed that p-tau levels
can be very useful, for example, p-tau phosphorylated at threonine
181 can discriminate between AD patients and control subjects and
in patients with dementia with Lewy bodies. P-tau proved to be a
better biomarker for AD compared to Aβ (1-42), and total tau [30].
Studies Maccioni et al. show increased hyperphosphorylated tau in
AD patients, whereas only the subpopulation of patients with mild
cognitive impairment (MCI) with greater cognitive impairment
-which could be considered as preclinical AD showed abnormal
increases in this tau variant [15]. During preclinical stages of AD, it is
proposed that CSF Aβ levels may be a useful marker of asymptomatic
cerebral amyloidosis, while evaluations of CSF tau and p-tau are best
correlated with the later stages of synaptic dysfunction and early
neurodegeneration [31,32].
Although CSF has proven to be a reliable source for biomarkers
research, these kinds of analyses are not suitable for day-to-day
diagnosis in clinical practice since lumbar puncture is considered too
invasive as a routine diagnostic procedure. us, the search for less
invasive and inexpensive diagnostic tools has driven researchers to
explore peripheral biological uids such as blood and saliva.
Plasma Aβ has been examined as a peripheral biomarker.
However, the pool of circulating Aβ in plasma comes not only form
brain tissue transported across the blood-brain barrier (BBB), but also
from peripheral tissues and organs. is could be troublesome since
Aβ measurements might not reect the dynamics of senile plaque
formation in the brain [18]. Platelets are an important peripheral
reservoir for Aβ generation since they express AβPP. Furthermore
platelets express the enzymatic mechanism necessary to process and
release Aβ. Also, platelets can modify the soluble Aβ oligomers into
Aβ (1-42). Gowert et al. (2014) have recently shown that Aβ improves
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platelets activation and generation of reactive species of oxygen, thus
they concluded that platelets may have a role in cerebral amyloid
angiopathy [33]. Modications in platelets AβPP has been described
in AD since an altered proportion of the dierent forms AβPP can be
found in western blot with a decreased ratio high molecular weight
(130kDa) to lower molecular weight (106 and 110kDa) forms of
AβPP in AD patients compared to control groups [34,35]. However,
it is important to consider that the changes in plasma concentration
of Aβ (1-40) are nonspecic for AD and are closely related to age [36].
Tau has also been described in platelets. Studies by Farías et al.
2012 propose a new biomarker for AD, based on the detection of tau
protein in platelets with specic antibodies. Some immunoreactive
bands that have a higher molecular weight and appear to be oligomeric
forms of the protein are increased in AD patients compared to healthy
elderly subjects [12,22]. Later studies showed a close correlation
between the degree of tau modication in platelets and the level
of cognitive impairment measured by neuropsychological tests in
subjects with AD and has been proposed as an AD biomarker with
sensitivity of 75.7% and a specicity of 79.7% [4].
But plasma and platelets are not the only source for biomarkers
in blood, Sotolongo-Grau et al. 2014, evaluated Aβ bounded in blood
cells and searched a correlation between these Aβ levels and 45
regions of interest in the brain using magnetic resonance imaging.
Surprisingly enough, the cell bounded Aβ (1-40) in blood was
correlated with the volume of the le hippocampus while plasma Aβ
showed no correlation with any of the studied brain regions [37].
Based on the research on Aβ and tau in CSF as AD biomarkers
some groups have proposed a similar strategy for the search of PD
biomarkers. Recent ndings showed leading evidence for high
specicity and sensitivity of α-syn and DJ-1 measurements in CSF
in PD. Hong et al. (2010), evaluated 117 PD patients and 132 healthy
controls. ey found that levels of both proteins are lower in PD than
in healthy controls [38]. Little is known about the exact biochemical
role of DJ-1 in PD, however a study have shown evidence that DJ-1
eliminates the hydrogen peroxide, protecting the cells in oxidative
stress. is is particularly interesting since, mutations on DJ-1
(L166P) are the cause of one familial form of PD (PARK7) [39].
Peripheral α-syn and DJ-1 have also been studied as peripheral
PD biomarkers. It is described that the submandibular gland is
intimately linked with synucleopathies since this gland is aected by
histopathological changes typical of PD [21]. In this context, Devic
et al. 2011 measured α-syn and DJ-1 in saliva, a really accessible and
non-invasive uid. For this study saliva samples were obtain from
24 PD patients and 25 healthy controls and. Even though results
did not reach signicance, they showed a trend towards decreased
levels of α-syn levels and increased DJ-1 in PD patients. Additionally,
they look for a correlation between these proteins and motor scores
of the Unied Parkinson’s disease Rating Scale (UPDRS), searching
for a relation between these proteins and motor decline. Only α-syn
levels showed a trend with UPDRS, but it didn’t reach signicance.
Nonetheless, this study leads to an important hope for biomarkers on
PD, as salivary uid it’s an ideal source for high-throughput assays
[40].
MicroRNAs as biomarkers for PMDs
MicroRNAs (miRNA) are small RNA fragments from about 22
nucleotides length that regulates posttranscriptional processes by
pairing with messenger RNA (mRNA).
miRNA expression varies depending on the physiological
conditions of the cell, therefore that the study of circulating miRNA
is a clue of what happens at the intracellular level in normal and
pathological situations.
In their study, Geekiyanage and Chan (2011) showed that certain
miRNAs related to modulation of ceramides levels-i.e. miR-137,
-181c, -9, -29a/b-are down regulated in patients with AD, increasing
the expression of the two subunits of serine palmitoyltransferase
(SPT). mRNA levels did not dier in relation to control subjects,
demonstrating that these are regulated post-transcriptionally, SPT1
by miR-137/-181c and SPT2 by -9, -29a/b, postulating these miRNAs
as potential markers. A high level of ceramides in the brain has been
associated with sporadic AD. In addition, it was demonstrated that
down regulated miR-9 and miR-29 family members control BACE 1
in sporadic AD patients, inducing Aβ accumulation [41].
Sheinerman et al. (2012) took plasma from AD and MCI patients
and control and identied several miRNA pairs (miR-128/miR-491-
5p, miR-132/miR-491-5p, miR-323-3p/miR-491-5p, miR-134/miR-
370, miR-323-3p/miR-370 and miR-382/miR-370). ey conclude
that although these miRNA pairs did not allow distinguishing between
AD and MCI, they could be characteristics of neurodegenerative
processes [42].
Leidinger et al. (2013) Identied 12 miRNAs in blood samples,
that together, allowed to dierentiate AD patients from control
whit an accuracy of 93%, specicity of 95% and a sensitivity of
92%. ese miRNAs can even dierentiate between AD and other
neurodegenerative diseases [43].
Transcription factor Sp1 (specicity protein 1) can control the
expression of several protein associated with AD, including AβPP
and tau. ere is an inverse relationship between Sp1 mRNA and
Biomarker Sample type AD PD Reference
CSF amyloid-β CSF ↓ ↓ (4, 15, 24, 25, 29)
CSF tau CSF ↑ ↑ (4, 15, 31, 109)
Platelet AβPP (130/110kDa) Blood ↓NA (33-36)
Platelet tau (HMW/LMW) Blood ↑NA (4, 12, 22)
α-syn and DJ1 CSF NA α-syn ↓; DJ1 ↑ (38)
α-syn and DJ1 Saliva NA α-syn ↓; DJ1 ↑ (40)
Table 1: Summary of biomarkers for Alzheimer’s disease and Parkinson’s disease.
Note: ↑: increase, ↓: decreases, NA: Not Applicable
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miRNA 29b levels in peripheral blood mononuclear cells [44]. Sp1
and its regulatory hsa-miR-29b are deregulated in AD patients, may
be causing abnormal expression of genes that are involved in illness.
A study observes the prole of circulating miRNA in serum and
CSF of AD patients compared to non-inammatory (NINDCs) and
inammatory neurological disease controls and patients with FTD. At
the beginning, 84 miRNA were identied but it was demonstrated that
only miR-125b levels are decreased in serum from patients with AD
as compared with NINDC and distinguish between AD and NINDCs
with an accuracy of 82% [45]. is result conrms a previous report
for miR-125b [46], in which miR-125b was also postulated as a good
candidate as a biomarker. miR-125b is brain-enriched and probably
is involved in neurodegenerative processes [47].
In other study six miRNA that were increased in AD patients
compared to control i.e. miR-98-5p, miR-885-5p, miR-483-3p, miR-
342-3p, miR-191-5p, and miR-let-7d-5p- were identied. Within
these six miRNA, it was found that miR-342-3p has the highest
sensitivity and specicity and so, may serve as a novel, noninvasive
biomarker for AD [48].
miRNAs have also been studied as a biomarker for PD; analysis
from PD patient’s blood reveled that three miRNA (miR-1, miR-22*,
miR-29a) were down regulated in non-treated patients compared
to control. A second group of three miRNA (miR-16-2*, miR-26-
2*, miR-30a) presented a 50% increased in their relative expression
between treated PD patients and control. In addition, miR-16-2*,
miR-26-2* showed an increase in treated compared to non-treated
patients [49].
Khoo et al. (2012) identied several circulating miRNA and their
results were analyzed by two dierent strategies. k-TSP1 (miR1826/
miR450b-3p), miR-626 and miR-505 attained the highest predictive
power of 91% sensitivity, 100% specicity, 100% positive predicted
value. However, in the replication set reached 88% negative predicted
value [50].
In other work, plasma from PD patients and control was used and
analyzed by microarray and qRT-PCR. A signicant increased for
miR-331-5 was found in PD patient’s plasma versus control subjects.
Moreover, bioinformatics analysis predicted that miR-331-5 could be
involved in gene regulation implicated in PD. No other previously
published miRNA was found [50].
Another report explored the alterations at the expression level
of serum miRNAs in 10 idiopathic PD patients, 10 PD patients
carrying LRRK2 G2019S mutation, and 10 controls by using RT-
qPCR and miRNA arrays. Four statistically signicant miRNAs were
downregulated in either LRRK2 or idiopathic PD (miR-29a, miR-29c,
miR-19a, and miR-19b). ey validate the study, with another sample
set, and conrmed the association of downregulated levels of miR-
29c, miR-29a, and miR- 19b in idiopathic PD [51].
Inammatory biomarkers
e inammatory process is associated to the development of
several neurodegenerative diseases. is process has cellular and
molecular immune components such as microglial cells, cytokines and
complement; they are main agents involved in the neuroinammation,
and act as inammatory mediators. ese proinammatory
mediators are either produced locally within the Central nervous
system (CNS) or recruited from the peripheral circulatory system
following disruption of the BBB. Based in this context, it is possible
that the peripheral concentrations of inammatory proteins may thus
reect changes in neuroinammation in the CNS.
is in turn, leads to the activation of the glial cells, such
as microglia and astrocytes. Neuroinammatory mechanisms
probably also contribute to the cascade of events leading to neuronal
degeneration [52].
e identication and validation of molecules involved in this
process could be a good strategy for nding new biomarkers. Usually,
the inammation does not trigger neurodegenerative process, but
there is evidence that this constant inammatory process leads to
chronic activation of astrocytes and microglial cells contributing to
disease progression [53].
Neuroinammation characterized by microglial activation serves
as an engine driving PD progression. In substantia nigra, many
endogenous and exogenous factors activate microglia and produce
neuroinammatory factors [54], such as tumor necrosis factor-α
(TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), interferon-γ
(INF-γ) and prostaglandin E2 (PGE2), which cause progressive
neurodegeneration in dopaminergic neurons, and play an important
role in the pathogenesis of PD [55,56]. Aer that, dead neurons release
many substances to extracellular space including iron, aggregated
α-synuclein and neuromelanin, inducing neuroinammation,
because all these components can trigger the activation of adjacent
microglial cells [57], propagating progressive degeneration of
dopaminergic neurons and deterioration of motor symptoms of PD
[56]. In this way, the inammation produced by microglial activation
contributes to the cascade events leading to neuronal degeneration
in PD [52].
Studies by Song group describes that the levels of hs-CRP (high-
sensitivity C-reactive protein) and brinogen are signicantly higher
in groups of PD patients, more than those observed in a control
patients. ese ndings are consistent with those reported previously
and support the hypothesis that neuroinammatory reactions are
involved in the degenerative processes observed in PD [58,59].
Studies of biological uids like serum or CSF also support a role for
neuroinammatory processes in Parkinson’s disease. Specically,
an increase in TNFα, interleukin 1β, interleukin 6 and osteopontin
(a member of the integrins family) has been reported in the CSF of
patients with PD. e inammatory changes are detectable during
the course of the disease before the death of the patients and are
associated with the progression of the disease [52].
In the other hand, studies by group of Lindqvist, in serum and
CSF, show that PD patients had a signicant increase in levels of IL-6
[60]. It is of some interest, therefore, that increased levels of IL-1b,
IL-6 and TNFα have been found in the basal ganglia and CSF of PD
patients [58], and the increase in TNFα, was particularly dramatic,
being 366% in tissue and 432% in CSF [58].
Cognitive impairment is a very common non-motor symptom in
PD patients, thus two major types of patients can be distinguished: the
patients without cognitive impairment or dementia and PD patients
with cognitive impairment or dementia. It may be very dicult to
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diagnose these cases, therefore, identify a biomarker for severity of
cognitive impairment becomes a necessity [56].
Also, PD patients with a high incidence of cognitive impairment
(which mainly involves the cognitive domains of vocabulary memory,
abstraction, visual-spatial and executive function and language),
show elevated levels of IL-6 in CSF [56,60]. In this way it’s possible
to assume that IL-6 could be potential biomarkers for cognitive
impairment in PD patients. Studies by Yu’s group, show that
demented PD patients have signicantly higher level of C-reactive
protein in CSF than non-demented PD and in the other hand, IL-6
level in CSF of cognitive impaired PD group is not only prominently
enhanced comparing with the group of PD without cognitive
impairment, but also has a strikingly negative correlation with MoCA
score, indicating that IL-6 may be a potential neuroinammatory
biomarker for the development and severity of cognitive impairment
in PD patients [56]. is may have important clinical utility for
improving diagnostic accuracy, allowing better prognostication and
earlier access to potential disease-modifying therapies [61].
In AD -the most common neurodegenerative disorder two
characteristic lesions can be observed: extracellular amyloid
aggregates containing Aβ and intracellular neurobrillary tangles
of hyperphosphorylated tau protein. e relationship between
misfolding and aggregation of these two proteins and inammation
is based on the hypothesis that the complex nature of plaques and
tangles stimulates a chronic inammatory reaction to scavenge these
wastes [62].
e presence of inammatory process in AD brain has led to the
discovery of increases in levels of various inammatory mediators in
cerebrospinal uid (CSF). Further, abnormalities in immune-related
molecules and functions have also been described in peripheral
blood [63]. To date, studies of inammatory biomarkers, in CSF
or peripheral blood, of AD patients have also yielded inconclusive
results.
It has been demonstrated that the lymphocyte biology is altered in
AD. In blood samples from patients with AD, it’s possible to observe
alterations in intracellular calcium [64] and there is impaired release
of IL-1β and IL-6 in response to stimulation with lipopolysaccharide
(LPS). Furthermore there is a worsening of this process with disease
progression [65]. In another study, LPS-stimulation resulted in
exaggerated release of IL-1β, TNF-α, IL-6, and IL-10 [66].
Peskind measured levels of s100B, a protein secreted by astrocytes
and directly linked to the inammatory response, in the CSF of AD
patients and healthy controls and found signicantly elevated levels
of s100B in CSF of mild or moderate AD patients, but declines to
normal levels in more advanced stages of the disease [67]. S100B
induces release of IL-6, which is one of components involved in the
neuroinammatory process [63]. IL-6 is a pleiotropic cytokine that
mediates immune responses and inammatory reactions aecting
CNS cell growth and dierentiation [68]. Also, IL-6 immunoreactivity
is found within extracellular Aβ deposits [69]. Despite this, Mrak
group have collected information about brain tissue levels of IL-6
that are not increased in AD, although increased levels of IL-6 mRNA
have been reported in AD brain [63]. Cerebrospinal uid IL-6 levels
have revealed contradictory results unchanged [70,71] and increased
[72,73]. One study found a correlation between CSF levels of IL-6 and
tau levels in AD patients [63], but serum levels of IL-6 have reported
controversial results, like increased [74] or normal [66].
Transforming growth factor β (TGFβ) is an important astrocytes
derived cytokine that manifests both pro-inammatory and anti-
inammatory properties. CSF levels of TGFβ were found to be
increased in AD in one study [75] but decreased in other [76].
IL-1 is an immunoregulatory cytokine that is overexpressed
within aected cerebral cortical regions of the AD brain [68]. Studies
of IL-1 show opposite results, so it’s like two groups found signicant
increases in AD patients [77] and others found no increase [78].
e pro-inammatory cytokine TNFα has synergistic eects with
IL-1 in inammatory processes [63]. TNFα is an important mediator
of systemic inammation, activating the central innate immune
response [79]. Studies in CSF of AD patients are conicting since one
group found elevated CSF TNFα levels [80] but a second group did not
[81]. On the other hand, although most studies report an increase in
the serum TNFα levels of patients suering from neurodegeneration
[82-84], one study reported TNFα attenuation in early-onset AD and
late-onset AD patients [85].
Many studies have examined the correlation between TNFα levels
and age. Production of TNFα is reported to be signicantly higher in
the elderly than in younger healthy volunteers, and results showed
a signicant positive correlation with age [74]. Another research
by Angelopoulos et al. found a signicant correlation between IL-6
and TNFα levels and age [86], and Holmes et al. 2011 demonstrated
that elevated serum TNFα and IL-6 levels were associated with an
approximately 2-fold increase in Neuropsychiatric Inventory scores
and an increased frequency of adverse neuropsychiatric symptoms,
independent of delirium [82]. ose studies suggested that acute and
chronic systemic inammation, which is associated with an increase
in serum TNFα, is associated with an increased cognitive decline in
AD [84].
Other component of the inammatory process is interleukin
8 (IL-8), but the role of the IL-8 in AD progression is not well
understood. IL-8 probably represents an additional recruitment
mechanism for the migration of microglia to Aβ deposits, followed
by a subsequent and persistent activation of microglial cells, favoring
the neuroinammatory context [87]. It is also known that IL-8
receptor has been localized in dystrophic neurites, suggesting that
IL-8 mediates glial interactions with neurons and thereby contributes
to neuronal damage [88]. Zhang et al. showed that levels of IL-8 in
CSF of AD patients was signicantly increased compared to healthy
controls [89], whereas plasma levels of IL-8 in late-onset AD and
vascular dementia did not dier from controls [90].
Currently, there is not a prole of inammatory markers in CSF
or plasma that may serve in the diagnosis of AD. In this context, Ray
et al. performed combined multivariate analysis of plasma signaling
and inammatory proteins and found 18 plasma proteins that may
identify AD patients and predict future AD with high accuracy in
mild cognitive impairment (MCI) patients [91]. Another research
group, Martins et al., found that a set of 18 markers in blood had
sensitivity and specicity of more than 80 % for distinguishing
patients with Alzheimer’s disease from healthy controls [92].
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is is very relevant because all of these results could support the
clinical diagnosis. Furthermore, it is important to consider that the
incorporation of plasma biomarkers yielded high sensitivity with
improved specicity, supporting their usefulness as a screening tool
in the search of biological diagnosis of AD [93]. However, it will be
very important for future clinical applications to nd markers capable
of dierentiating AD from other dementias [62].
Others biomarkers for AD
Alteration in retina and visual defects are related to MCI and AD
[94]. In addition, variations in visuospatial perception can be detected
at rst stage of AD [95].
Neurons need highly amounts of energy that is generated by
mitochondria. Mitochondrial DNA is resistant to degradation
because of its characteristic closed circular form, thus it can be present
in CSF as a marker of neurodegeneration. It was demonstrated
that low concentration mitochondrial DNA can be found in CSF
of presymptomatic subjects who will develop AD, even before any
change in Aβ or tau [96].
Ubiquitin is a protein involved in degradation of other proteins;
it interacts with lysine residues and signals for degradations by
proteases. In AD patients, PHF are ubiquitinated and ubiquitin
conjugated protein can exist into the cell indenitely [97]. It was
demonstrated that increased levels of free and conjugated ubiquitin
are found in CSF of patients with MCI progressing to AD [98]. Other
group demonstrated that ubiquitin level were signicantly higher in
AD patients and found that a positive correlation between ubiquitin,
tau and apolipoprotein Eε 4 genotype exists while there is a negative
correlation with Aβ42 [99].
Plasma of AD patients has abnormal levels of phospholipids.
Diminished level was observed also in people who will develop MCI
and AD within 2-3 years -over 90% accuracy. at could be reecting
cell membrane integrity and consequently early neurodegeneration
of preclinical AD [100].
Others biomarkers for PD
DJ-1 was a protein rstly identied in familial PD [101]. It is a
multifunctional protein that plays an important role principally
in oxidative stress. A study performed using whole blood from PD
patients and healthy control found signicant dierence between
DJ-1 isoforms levels, using 2D-electrophoresis, immunoblotting
techniques and mass spectroscopy analysis. Although it was
conrmed that not dierences exists between total DJ-1 levels from
PD patients and control, some isoforms in whole blood samples with
4-hydroxy-2-nonenal modications were signicantly increased and
related to both PD diagnosis and PD severity [102].
Results from studies in CSF are not very consistent but one
showed decreased level of DJ-1 in PD patients compared to control
with a sensitivity of 90% and specicity of 70% [38].
Urate circulates at high concentrations in humans and also
represents the principal end product of purine metabolism. It has
antioxidant characteristics and thus protects against oxidative
damage. Lower levels of uric acid could indicate increased risk and
severity for motor symptoms of PD [103,104].
People with PD may develop cognitive impairment. Immunoassays
from plasma samples, allowed identifying eleven proteins associated
with cognitive performance, of which the most signicant was
epidermal growth factor (EGF). Suggesting that plasma EGF may be
a biomarker for progression to cognitive impairment in PD [105].
Dihydroxyphenylacetic acid a neuronal metabolite of
catecholamines metabolism- is diminished in patients with recent
onset of Parkinsonism and may be used as a biomarker separating
these patients from controls with 100% sensitivity and 89% specicity
in [106].
Lower ApoA1 levels can be found in symptomatic PD patients
and in asymptomatic individuals with physiological reductions in
dopamine transporter density consistent with prodromal PD. It has
been suggested that increasing plasma ApoA1 level in small amounts
could reduce the risk of developing PD [107].
e Lewy body formation is due to the decient protein
degradation. Lysosomal hydrolases like GCase have been measured
in CSF from PD patients and in other neurodegenerative disorders
including LBD. e activity of GCase is reduced in PD and LBD
patients in contrast to controls [108]. erefore, the lysosomal
dysfunction represents a good target to search for biomarkers.
Concluding remarks
AD and PD are currently recognized as the most common
neurodegenerative diseases. Many eorts have been made to
understand the pathophysiological mechanisms that underlie both
diseases. Even though they appear as dissimilar conditions i.e. PD
predominantly a motor disease and AD predominantly a cognitive
disease- both are considered as PMDs and as such, share a lot of
common mechanisms, including regulation of processes by miRNAs,
generation of inammatory signals, misfolding and aggregation of
proteins. Our search for biomarkers must consider those markers that
account for common neurodegenerative pathways from those that
are specic for any PMD. Even if a perfect biomarker is not currently
available we can advance in the denition of biomarkers prole
that characterizes any neurodegenerative disease. Anyhow we must
recognize that in order to validate any present or future biomarker
is crucial to standardize the conditions for sample collection and
processing. CSF is the most validated source for PMDs biomarkers’
considering it reects biochemical changes occurring in the CNS, but
applicability of these biomarkers is limited because lumbar puncture
is considered an invasive collection method [62]. On the other hand,
blood samples are much easier to obtain, but concentrations of most
potential neuronal biomarkers are several fold lower in blood than in
CSF and there is a lot of “contamination” by plasma proteins that are
not related to neuropathological processes. Given the multiplicity of
pathophysiological processes implicated in PMDs, a combination of
biomarkers related to dierent mechanisms might increase diagnostic
accuracy and validity of any biomarker [62].
Acknowledgement
is work was funded by FONDECYT 11130233 grant to GAF.
References
1. Jellinger KA. Interaction between α-synuclein and other proteins in
neurodegenerative disorders. ScienticWorldJournal. 2011; 11: 1893-1907.
Austin J Clin Neurol 2(7): id1059 (2015) - Page - 07
Farías GA Austin Publishing Group
Submit your Manuscript | www.austinpublishinggroup.com
2. Spillantini MG, Goedert M. Tau protein pathology in neurodegenerative
diseases. Trends Neurosci. 1998; 21: 428-433.
3. Weaver CL, Espinoza M, Kress Y, Davies P. Conformational change as one
of the earliest alterations of tau in Alzheimer’s disease. Neurobiol Aging.
2000; 21: 719-727.
4. Guzmán-Martínez L, Farías GA, Maccioni RB. Emerging noninvasive
biomarkers for early detection of Alzheimer’s disease. Arch Med Res. 2012;
43: 663-666.
5. Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M. alpha-
Synuclein in lamentous inclusions of Lewy bodies from Parkinson’s disease
and dementia with lewy bodies. Proc Natl Acad Sci U S A. 1998; 95: 6469-
6473.
6. Morales I, Guzmán-Martínez L, Cerda-Troncoso C, Farías GA, Maccioni RB.
Neuroinammation in the pathogenesis of Alzheimer’s disease. A rational
framework for the search of novel therapeutic approaches. Front Cell
Neurosci. 2014; 8: 112.
7. Maccioni RB, Farías GA, Rojo LE, Jiménez JM. In Search of Therapeutic
Solutions for Alzheimer’s Disease. In: Mantamadiotis T, editor. Brain
WTGW-DaDotH, editor. 2012. 125-150.
8. Jellinger KA. Interaction between pathogenic proteins in neurodegenerative
disorders. J Cell Mol Med. 2012; 16: 1166-1183.
9. Alberio T, Fasano M. Proteomics in Parkinson’s disease: An unbiased
approach towards peripheral biomarkers and new therapies. J Biotechnol.
2010; 156: 325-337.
10. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM,
et al. Toward dening the preclinical stages of Alzheimer’s disease:
recommendations from the National Institute on Aging-Alzheimer’s
Association workgroups on diagnostic guidelines for Alzheimer’s disease.
Alzheimers Dement. 2011; 7: 280-292.
11. Maccioni RB, Lavados M, Maccioni CB, Mendoza-Naranjo A. Biological
markers of Alzheimer’s disease and mild cognitive impairment. Curr
Alzheimer Res. 2004; 1: 307-314.
12. Farías G, Pérez P, Slachevsky A, Maccioni RB. Platelet tau pattern
correlates with cognitive status in Alzheimer’s disease. J Alzheimers Dis.
2012; 31: 65-69.
13. McKhann GM. Changing concepts of Alzheimer disease. JAMA. 2011; 305:
2458-2459.
14. Lavados M, Guillón M, Mujica MC, Rojo LE, Fuentes P, Maccioni RB. Mild
cognitive impairment and Alzheimer patients display different levels of
redox-active CSF iron. J Alzheimers Dis. 2008; 13: 225-232.
15. Maccioni RB, Lavados M, Guillón M, Mujica C, Bosch R, Farías G, et al.
Anomalously phosphorylated tau and Abeta fragments in the CSF correlates
with cognitive impairment in MCI subjects. Neurobiol Aging. 2006; 27: 237-
244.
16. Glenner GG, Wong CW. Alzheimer’s disease: initial report of the purication
and characterization of a novel cerebrovascular amyloid protein. 1984.
Biochem Biophys Res Commun. 2012; 425: 534-539.
17. Blennow K. CSF biomarkers for mild cognitive impairment. J Intern Med.
2004; 256: 224-234.
18. Schneider P, Hampel H, Buerger K. Biological marker candidates of
Alzheimer’s disease in blood, plasma, and serum. CNS Neurosci Ther.
2009; 15: 358-374.
19. Bohm C, Chen F, Sevalle J, Qamar S, Dodd R, Li Y, et al. Current and
future implications of basic and translational research on amyloid-β peptide
production and removal pathways. Mol Cell Neurosci. 2015; 66: 3-11.
20. Přikrylová Vranová H, Mareš J, Hluštík P, Nevrlý M, Stejskal D, Zapletalová J,
et al. Tau protein and beta-amyloid(1-42) CSF levels in different phenotypes
of Parkinson’s disease. J Neural Transm. 2012; 119: 353-362.
21. Del Tredici K, Hawkes CH, Ghebremedhin E, Braak H. Lewy pathology in
the submandibular gland of individuals with incidental Lewy body disease
and sporadic Parkinson’s disease. Acta Neuropathol. 2010; 119: 703-713.
22. Neumann K, Farías G, Slachevsky A, Perez P, Maccioni RB. Human platelets
tau: a potential peripheral marker for Alzheimer’s disease. J Alzheimers Dis.
2011; 25: 103-109.
23. Lin CH, Wu RM. Biomarkers of cognitive decline in Parkinson’s disease.
Parkinsonism Relat Disord. 2015; 21: 431-443.
24. Wiltfang J, Esselmann H, Bibl M, Hüll M, Hampel H, Kessler H, et al. Amyloid
beta peptide ratio 42/40 but not A beta 42 correlates with phospho-Tau in
patients with low- and high-CSF A beta 40 load. J Neurochem. 2007; 101:
1053-1059.
25. Siderowf A, Xie SX, Hurtig H, Weintraub D, Duda J, Chen-Plotkin A, et al.
CSF amyloid {beta} 1-42 predicts cognitive decline in Parkinson disease.
Neurology. 2010; 75: 1055-1061.
26. Tapiola T, Alafuzoff I, Herukka SK, Parkkinen L, Hartikainen P, Soininen H,
et al. Cerebrospinal uid {beta}-amyloid 42 and tau proteins as biomarkers
of Alzheimer-type pathologic changes in the brain. Arch Neurol. 2009; 66:
382-389.
27. Schade S, Mollenhauer B. Biomarkers in biological uids for dementia with
Lewy bodies. Alzheimers Res Ther. 2014; 6: 72.
28. Gustafson DR, Skoog I, Rosengren L, Zetterberg H, Blennow K.
Cerebrospinal uid beta-amyloid 1-42 concentration may predict cognitive
decline in older women. J Neurol Neurosurg Psychiatry. 2007; 78: 461-464.
29. Bekris LM, Tsuang DW, Peskind ER, Yu CE. Cerebrospinal uid Aβ42 levels
and APP processing pathway genes in Parkinson’s disease. Mov Disord.
2015; 30: 936-944.
30. Vanderstichele H, De Vreese K, Blennow K, Andreasen N, Sindic C,
Ivanoiu A, et al. Analytical performance and clinical utility of the INNOTEST
PHOSPHO-TAU181P assay for discrimination between Alzheimer’s disease
and dementia with Lewy bodies. Clin Chem Lab Med. 2006; 44: 1472-1480.
31. Lavados M, Farías G, Rothhammer F, Guillon M, Mujica MC, Maccioni C, et
al. ApoE alleles and tau markers in patients with different levels of cognitive
impairment. Arch Med Res. 2005; 36: 474-479.
32. Cummings JL, Doody R, Clark C. Disease-modifying therapies for Alzheimer
disease: challenges to early intervention. Neurology. 2007; 69: 1622-1634.
33. Gowert NS, Donner L, Chatterjee M, Eisele YS, Towhid ST, Münzer P, et
al. Blood platelets in the progression of Alzheimer’s disease. PLoS One.
2014; 9: e90523.
34. Padovani A, Borroni B, Colciaghi F, Pastorino L, Archetti S, Cottini E, et al.
Platelet amyloid precursor protein forms in AD: a peripheral diagnostic tool
and a pharmacological target. Mech Ageing Dev. 2001; 122: 1997-2004.
35. Borroni B, Colciaghi F, Caltagirone C, Rozzini L, Broglio L, Cattabeni F, et al.
Platelet amyloid precursor protein abnormalities in mild cognitive impairment
predict conversion to dementia of Alzheimer type: a 2-year follow-up study.
Arch Neurol. 2003; 60: 1740-1744.
36. Luchsinger JA, Tang MX, Miller J, Green R, Mehta PD, Mayeux R. Relation
of plasma homocysteine to plasma amyloid beta levels. Neurochem Res.
2007; 32: 775-781.
37. Sotolongo-Grau O, Pesini P, Valero S, Lafuente A, Buendía M, Pérez-
Grijalba V, et al. Association between cell-bound blood amyloid-β(1-40)
levels and hippocampus volume. Alzheimers Res Ther. 2014; 6: 56.
38. Hong Z, Shi M, Chung KA, Quinn JF, Peskind ER, Galasko D, et al. DJ-1 and
alpha-synuclein in human cerebrospinal uid as biomarkers of Parkinson’s
disease. Brain. 2010; 133: 713-726.
39. Taira T, Saito Y, Niki T, Iguchi-Ariga SM, Takahashi K, Ariga H, et al. DJ-1
has a role in antioxidative stress to prevent cell death. EMBO Rep. 2004;
5: 213-218.
40. Devic I, Hwang H, Edgar JS, Izutsu K, Presland R, Pan C. Salivary
α-synuclein and DJ-1: potential biomarkers for Parkinson’s disease. Brain.
2011; 134: e178.
41. Hébert SS, Horré K, Nicolaï L, Papadopoulou AS, Mandemakers W,
Silahtaroglu AN, et al. Loss of microRNA cluster miR-29a/b-1 in sporadic
Alzheimer’s disease correlates with increased BACE1/beta-secretase
expression. Proc Natl Acad Sci U S A. 2008; 105: 6415-6420.
Austin J Clin Neurol 2(7): id1059 (2015) - Page - 08
Farías GA Austin Publishing Group
Submit your Manuscript | www.austinpublishinggroup.com
42. Sheinerman KS, Tsivinsky VG, Crawford F, Mullan MJ, Abdullah L,
Umansky SR. Plasma microRNA biomarkers for detection of mild cognitive
impairment. Aging (Albany NY). 2012; 4: 590-605.
43. Leidinger P, Backes C, Deutscher S, Schmitt K, Mueller SC, Frese K, et al.
A blood based 12-miRNA signature of Alzheimer disease patients. Genome
Biol. 2013; 14: R78.
44. Villa C, Ridol E, Fenoglio C, Ghezzi L, Vimercati R, Clerici F, et al.
Expression of the transcription factor Sp1 and its regulatory hsa-miR-29b in
peripheral blood mononuclear cells from patients with Alzheimer’s disease.
J Alzheimers Dis. 2013; 35: 487-494.
45. Galimberti D, Villa C, Fenoglio C, Serpente M, Ghezzi L, Ciof SM, et al.
Circulating miRNAs as potential biomarkers in Alzheimer’s disease. J
Alzheimers Dis. 2014; 42: 1261-1267.
46. Tan L, Yu JT, Liu QY, Tan MS, Zhang W, Hu N, et al. Circulating miR-125b
as a biomarker of Alzheimer’s disease. J Neurol Sci. 2014; 336: 52-56.
47. Sethi P, Lukiw WJ. Micro-RNA abundance and stability in human brain:
specic alterations in Alzheimer’s disease temporal lobe neocortex. Neurosci
Lett. 2009; 459: 100-104.
48. Tan L, Yu JT, Tan MS, Liu QY, Wang HF, Zhang W, et al. Genome-wide
serum microRNA expression proling identies serum biomarkers for
Alzheimer’s disease. J Alzheimers Dis. 2014; 40: 1017-1027.
49. Margis R, Margis R, Rieder CR. Identication of blood microRNAs associated
to ParkinsonÄ s disease. J Biotechnol. 2011; 152: 96-101.
50. Khoo SK, Petillo D, Kang UJ, Resau JH, Berryhill B, Linder J, et al.
Plasma-based circulating MicroRNA biomarkers for Parkinson’s disease. J
Parkinsons Dis. 2012; 2: 321-331.
51. Botta-Orla T, Morató X, Compta Y, Lozano JJ, Falgàs N, Valldeoriola F, et
al. Identication of blood serum micro-RNAs associated with idiopathic and
LRRK2 Parkinson’s disease. J Neurosci Res. 2014; 92: 1071-1077.
52. Hirsch EC, Hunot S. Neuroinammation in Parkinson’s disease: a target for
neuroprotection? Lancet Neurol. 2009; 8: 382-397.
53. Meraz-Ríos MA, Toral-Rios D, Franco-Bocanegra D, Villeda-Hernández J,
Campos-Peña V. Inammatory process in Alzheimer’s Disease. Front Integr
Neurosci. 2013; 7: 59.
54. Block ML, Hong JS. Microglia and inammation-mediated neurodegeneration:
multiple triggers with a common mechanism. Prog Neurobiol. 2005; 76: 77-
98.
55. Çomoğlu SS, Güven H, Acar M, Öztürk G, Koçer B. Tear levels of tumor
necrosis factor-alpha in patients with Parkinson’s disease. Neurosci Lett.
2013; 553: 63-67.
56. Yu SY, Zuo LJ, Wang F, Chen ZJ, Hu Y, Wang YJ, et al. Potential biomarkers
relating pathological proteins, neuroinammatory factors and free radicals in
PD patients with cognitive impairment: a cross-sectional study. BMC Neurol.
2014; 14: 113.
57. Zhang W, Phillips K, Wielgus AR, Liu J, Albertini A, Zucca FA, et al.
Neuromelanin activates microglia and induces degeneration of dopaminergic
neurons: implications for progression of Parkinson’s disease. Neurotox Res.
2011; 19: 63-72.
58. McGeer PL, McGeer EG. Inammation and neurodegeneration in
Parkinson’s disease. Parkinsonism Relat Disord. 2004; 10 Suppl 1: S3-7.
59. Song IU, Kim YD, Cho HJ, Chung SW. Is neuroinammation involved in the
development of dementia in patients with Parkinson’s disease? Intern Med.
2013; 52: 1787-1792.
60. Lindqvist D, Kaufman E, Brundin L, Hall S, Surova Y, Hansson O. Non-
motor symptoms in patients with Parkinson’s disease - correlations with
inammatory cytokines in serum. PLoS One. 2012; 7: e47387.
61. Magdalinou NK, Paterson RW, Schott JM, Fox NC, Mummery C, Blennow
K, et al. A panel of nine cerebrospinal uid biomarkers may identify patients
with atypical parkinsonian syndromes. J Neurol Neurosurg Psychiatry. 2015.
62. Nuzzo D, Picone P, Caruana L, Vasto S, Barera A, Caruso C, et al.
Inammatory mediators as biomarkers in brain disorders. Inammation.
2014; 37: 639-648.
63. Mrak RE, Grifn WS. Potential inammatory biomarkers in Alzheimer’s
disease. J Alzheimers Dis. 2005; 8: 369-375.
64. Adunsky A, Baram D, Hershkowitz M, Mekori YA. Increased cytosolic free
calcium in lymphocytes of Alzheimer patients. J Neuroimmunol. 1991; 33:
167-172.
65. Sala G, Galimberti G, Canevari C, Raggi ME, Isella V, Facheris M, et al.
Peripheral cytokine release in Alzheimer patients: correlation with disease
severity. Neurobiol Aging. 2003; 24: 909-914.
66. Lombardi VR, Garcia M, Rey L, Cacabelos R. Characterization of cytokine
production, screening of lymphocyte subset patterns and in vitro apoptosis
in healthy and Alzheimer’s Disease (AD) individuals. J Neuroimmunol. 1999;
97: 163-171.
67. Peskind ER, Grifn WS, Akama KT, Raskind MA, Van Eldik LJ.
Cerebrospinal uid S100B is elevated in the earlier stages of Alzheimer’s
disease. Neurochem Int. 2001; 39: 409-413.
68. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, et al.
Inammation and Alzheimer’s disease. Neurobiol Aging. 2000; 21: 383-421.
69. Bauer J, Konig G, Strauss S, Jonas U, Ganter U, Weidemann A, et al. In-
vitro matured human macrophages express Alzheimer’s beta A4-amyloid
precursor protein indicating synthesis in microglial cells. FEBS Lett. 1991;
282: 335-340.
70. Hampel H, Schoen D, Schwarz MJ, Kötter HU, Schneider C, Sunderland T,
et al. Interleukin-6 is not altered in cerebrospinal uid of rst-degree relatives
and patients with Alzheimer’s disease. Neurosci Lett. 1997; 228: 143-146.
71. März P, Heese K, Hock C, Golombowski S, Müller-Spahn F, Rose-John S,
et al. Interleukin-6 (IL-6) and soluble forms of IL-6 receptors are not altered
in cerebrospinal uid of Alzheimer’s disease patients. Neurosci Lett. 1997;
239: 29-32.
72. Wada-Isoe K, Wakutani Y, Urakami K, Nakashima K. Elevated interleukin-6
levels in cerebrospinal uid of vascular dementia patients. Acta Neurol
Scand. 2004; 110: 124-127.
73. Blum-Degen D, Müller T, Kuhn W, Gerlach M, Przuntek H, Riederer P.
Interleukin-1 beta and interleukin-6 are elevated in the cerebrospinal uid of
Alzheimer’s and de novo Parkinson’s disease patients. Neurosci Lett. 1995;
202: 17-20.
74. Maes M, DeVos N, Wauters A, Demedts P, Maurits VW, Neels H, et al.
Inammatory markers in younger vs elderly normal volunteers and in
patients with Alzheimer’s disease. J Psychiatr Res. 1999; 33: 397-405.
75. Chao CC, Ala TA, Hu S, Crossley KB, Sherman RE, Peterson PK, et al.
Serum cytokine levels in patients with Alzheimer’s disease. Clin Diagn Lab
Immunol. 1994; 1: 433-436.
76. Mocali A, Cedrola S, Della Malva N, Bontempelli M, Mitidieri VA, Bavazzano
A, et al. Increased plasma levels of soluble CD40, together with the decrease
of TGF beta 1, as possible differential markers of Alzheimer disease. Exp
Gerontol. 2004; 39: 1555-1561.
77. De Luigi A, Fragiacomo C, Lucca U, Quadri P, Tettamanti M, Grazia De
Simoni M, et al. Inammatory markers in Alzheimer’s disease and multi-
infarct dementia. Mech Ageing Dev. 2001; 122: 1985-1995.
78. Pirttila T, Mehta PD, Frey H, Wisniewski HM. Alpha 1-antichymotrypsin
and IL-1 beta are not increased in CSF or serum in Alzheimer’s disease.
Neurobiol Aging. 1994; 15: 313-317.
79. Rosenberg PB. Clinical aspects of inammation in Alzheimer’s disease. Int
Rev Psychiatry. 2005; 17: 503-514.
80. Tarkowski E, Blennow K, Wallin A, Tarkowski A. Intracerebral production
of tumor necrosis factor-alpha, a local neuroprotective agent, in Alzheimer
disease and vascular dementia. J Clin Immunol. 1999; 19: 223-230.
81. Engelborghs S, De Brabander M, De Crée J, D’Hooge R, Geerts H,
Verhaegen H, et al. Unchanged levels of interleukins, neopterin, interferon-
gamma and tumor necrosis factor-alpha in cerebrospinal uid of patients
with dementia of the Alzheimer type. Neurochem Int. 1999; 34: 523-530.
Austin J Clin Neurol 2(7): id1059 (2015) - Page - 09
Farías GA Austin Publishing Group
Submit your Manuscript | www.austinpublishinggroup.com
82. Holmes C, Cunningham C, Zotova E, Culliford D, Perry VH. Proinammatory
cytokines, sickness behavior, and Alzheimer disease. Neurology. 2011; 77:
212-218.
83. Guerreiro RJ, Santana I, Bras JM, Santiago B, Paiva A, Oliveira C.
Peripheral inammatory cytokines as biomarkers in Alzheimer’s disease and
mild cognitive impairment. Neurodegener Dis. 2007; 4: 406-412.
84. Gezen-Ak D, Dursun E, Hanağası H, Bilgiç B, Lohman E, Araz ÖS, et al.
BDNF, TNFα, HSP90, CFH, and IL-10 serum levels in patients with early or
late onset Alzheimer’s disease or mild cognitive impairment. J Alzheimers
Dis. 2013; 37: 185-195.
85. Alvarez XA, Franco A, Fernández-Novoa L, Cacabelos R. Blood levels
of histamine, IL-1 beta, and TNF-alpha in patients with mild to moderate
Alzheimer disease. Mol Chem Neuropathol. 1996; 29: 237-252.
86. Angelopoulos P, Agouridaki H, Vaiopoulos H, Siskou E, Doutsou K, Costa
V, et al. Cytokines in Alzheimer’s disease and vascular dementia. Int J
Neurosci. 2008; 118: 1659-1672.
87. Alsadany MA, Shehata HH, Mohamad MI, Mahfouz RG. Histone
deacetylases enzyme, copper, and IL-8 levels in patients with Alzheimer’s
disease. Am J Alzheimers Dis Other Demen. 2013; 28: 54-61.
88. Xia M, Qin S, McNamara M, Mackay C, Hyman BT. Interleukin-8 receptor B
immunoreactivity in brain and neuritic plaques of Alzheimer’s disease. Am J
Pathol. 1997; 150: 1267-1274.
89. Zhang J, Sokal I, Peskind ER, Quinn JF, Jankovic J, Kenney C, et al. CSF
multianalyte prole distinguishes Alzheimer and Parkinson diseases. Am J
Clin Pathol. 2008; 129: 526-529.
90. Zuliani G, Guerra G, Ranzini M, Rossi L, Munari MR, Zurlo A, et al. High
interleukin-6 plasma levels are associated with functional impairment in
older patients with vascular dementia. Int J Geriatr Psychiatry. 2007; 22:
305-311.
91. Ray S, Britschgi M, Herbert C, Takeda-Uchimura Y, Boxer A, Blennow K, et
al. Classication and prediction of clinical Alzheimer’s diagnosis based on
plasma signaling proteins. Nat Med. 2007; 13: 1359-1362.
92. Doecke JD, Laws SM, Faux NG, Wilson W, Burnham SC, Lam CP, et al.
Blood-based protein biomarkers for diagnosis of Alzheimer disease. Arch
Neurol. 2012; 69: 1318-1325.
93. Soares HD, Potter WZ, Pickering E, Kuhn M, Immermann FW, Shera DM,
et al. Plasma biomarkers associated with the apolipoprotein E genotype and
Alzheimer disease. Arch Neurol. 2012; 69: 1310-1317.
94. Paquet C, Boissonnot M, Roger F, Dighiero P, Gil R, Hugon J. Abnormal
retinal thickness in patients with mild cognitive impairment and Alzheimer’s
disease. Neurosci Lett. 2007; 420: 97-99.
95. Mandal PK, Joshi J, Saharan S. Visuospatial perception: an emerging
biomarker for Alzheimer’s disease. J Alzheimers Dis. 2012; 31 Suppl 3:
S117-135.
96. Podlesniy P, Figueiro-Silva J, Llado A, Antonell A, Sanchez-Valle R, Alcolea
D, et al. Low cerebrospinal uid concentration of mitochondrial DNA in
preclinical Alzheimer disease. Ann Neurol. 2013; 74: 655-668.
97. Perry G, Friedman R, Shaw G, Chau V. Ubiquitin is detected in neurobrillary
tangles and senile plaque neurites of Alzheimer disease brains. Proc Natl
Acad Sci U S A. 1987; 84: 3033-3036.
98. Simonsen AH, McGuire J, Hansson O, Zetterberg H, Podust VN, Davies
HA, et al. Novel panel of cerebrospinal uid biomarkers for the prediction
of progression to Alzheimer dementia in patients with mild cognitive
impairment. Arch Neurol. 2007; 64: 366-370.
99. Kandimalla RJ, Anand R, Veeramanikandan R, Wani WY, Prabhakar
S, Grover VK, et al. CSF ubiquitin as a specic biomarker in Alzheimer’s
disease. Curr Alzheimer Res. 2014; 11: 340-348.
100. Mapstone M, Cheema AK, Fiandaca MS, Zhong X, Mhyre TR, MacArthur
LH, et al. Plasma phospholipids identify antecedent memory impairment in
older adults. Nat Med. 2014; 20: 415-418.
101. Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, et al.
Mutations in the DJ-1 gene associated with autosomal recessive early-onset
parkinsonism. Science. 2003; 299: 256-259.
102. Lin X, Parisiadou L, Sgobio C, Liu G, Yu J, Sun L, et al. Conditional
expression of Parkinson’s disease-related mutant alpha-synuclein in the
midbrain dopaminergic neurons causes progressive neurodegeneration and
degradation of transcription factor nuclear receptor related 1. J Neurosci.
2012; 32: 9248-9264.
103. Chahine LM, Stern MB, Chen-Plotkin A. Blood-based biomarkers for
Parkinson’s disease. Parkinsonism Relat Disord. 2014; 20 Suppl 1: S99-
103.
104. Schwarzschild MA, Schwid SR, Marek K, Watts A, Lang AE, Oakes D, et
al. Serum urate as a predictor of clinical and radiographic progression in
Parkinson disease. Arch Neurol. 2008; 65: 716-723.
105. Chen-Plotkin AS, Hu WT, Siderowf A, Weintraub D, Goldmann Gross R,
Hurtig HI, et al. Plasma epidermal growth factor levels predict cognitive
decline in Parkinson disease. Ann Neurol. 2011; 69: 655-663.
106. Goldstein DS, Holmes C, Sharabi Y. Cerebrospinal uid biomarkers
of central catecholamine deciency in Parkinson’s disease and other
synucleinopathies. Brain. 2012; 135: 1900-1913.
107. Qiang JK, Wong YC, Siderowf A, Hurtig HI, Xie SX, Lee VM, et al. Plasma
apolipoprotein A1 as a biomarker for Parkinson disease. Ann Neurol. 2013;
74: 119-127.
108. Parnetti L, Balducci C, Pierguidi L, De Carlo C, Peducci M, D’Amore C, et al.
Cerebrospinal uid beta-glucocerebrosidase activity is reduced in Dementia
with Lewy Bodies. Neurobiol Dis. 2009; 34: 484-486.
109. Ewers M, Buerger K, Teipel SJ, Scheltens P, Schröder J, Zinkowski RP, et
al. Multicenter assessment of CSF-phosphorylated tau for the prediction of
conversion of MCI. Neurology. 2007; 69: 2205-2212.
Citation: Farías GA, Arata L, Guzmán-Martínez L, Morales I, Tapia JP and Maccioni RB. Biochemical Markers
for Alzheimer’s and Parkinson’s Disease. Austin J Clin Neurol 2015;2(7): 1059.
Austin J Clin Neurol - Volume 2 Issue 7 - 2015
ISSN : 2381-9154 | www.austinpublishinggroup.com
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