15 Cerebrospinal fluid biomarkers in idiopathic normal pressure hydrocephalus
Adult Hydrocephalus, ed. Daniele Rigamonti. Published by Cambridge University Press. © Cambridge University Press 2014.
History of setting up biomarkers in idiopathic normal pressure hydrocephalus
Biological markers have been traditionally used in clinical practice to support a diagnosis, or monitor the progression of a disease by surveying levels longitudinally.
The definition as given by the Biomarkers Definition Working Group was “A characteristic that is objectively measured and evaluated as an indicator of normal biological, pathogenic processes or pharmacological responses to a therapeutic intervention” [1]. Biomarkers can aid us in this task as they provide an insight to the changes in the milieu associated with a condition.
To establish their use in routine clinical practice they should display high sensitivity and specificity. As in other medical specialties, in neurosciences there is a currently a tendency to develop disease-specific biomarkers.
Biomarkers have been proposed as an aid in the diagnosis of several neurodegenerative disorders. “The ideal biomarker for Alzheimer’s disease (AD) should detect a fundamental feature of neuropathology and be validated in neuropathologically-confirmed cases; it should have a sensitivity of 80% for detecting AD and a specificity of 80% for distinguishing other dementias; it should be reliable, reproducible, non-invasive, simple to perform, and inexpensive. Recommended steps to find out a biomarker include confirmation by at least two independent studies conducted by qualified investigators with the results published in peer-reviewed journals.” This definition given by the Consensus Report of the Working Group on Molecular and Biochemical Markers of Alzheimer’s Disease (Ronald and Nancy Reagan Research Institute and the NIA Working Group-1998) [2] highlights adequately the problems any attempts to find biomarkers for idiopathic normal pressure hydrocephalus (iNPH) may face. The role of a biomarker is to confirm a diagnosis, serve for epidemiological studies, assess for prediction, monitoring the progression and response to treatment and studying brain–behavior relationships. Any marker will need to be validated against a definite diagnosis.
The first attempts to develop biomarkers specific for idiopathic normal pressure hydrocephalus (iNPH) to distinguish it from other neurodegenerative conditions were by Sørensen et al. in 1983 [3,4], Ahlberg et al. [5] and Albrechtsen et al. in 1985 [6]. Kudo et al. in 2000 were the first to measure the ventricular levels of tau protein, comparing it with orthopedic controls and hence investigating the role of tau protein as a potential marker of severity of the condition [7]. Four years later Lins et al. in 2004 assessed the levels of amyloid beta peptide (1–42) (Aβ (1–42)) and total tau protein (t-tau) in a group with the idiopathic form of NPH [8]. Theirs was the first group to realize the potential of using the two most commonly assessed cerebrospinal fluid (CSF) biomarkers for dementia patients for assessing the CSF biochemistry of an iNPH group. Two literature reviews in 2006 and 2009 [9,10] highlighted the potential of establishing biomarkers for this condition. Since then further studies have been published attempting to establish diagnostic or prognostic biomarkers in iNPH by exploring the possibility of other neurodegenerative processes coexisting in a cohort of the elderly population.
Rationale for their use
The case for emerging biomarkers in iNPH has arisen because of similar developments in other common causes of dementia and the increasing awareness of both the epidemiology of NPH [11,12] and its impact on the quality of life of elderly patients [13]. Geriatricians and neurologists are often faced with the difficult task of identifying those patients with a probable diagnosis of NPH to refer them to a neurosurgeon to consider surgical CSF diversion. Up to 90% of patients can improve within 6 months [14].
Over the years, different diagnostic tests have been developed to improve the shunt-response prediction and, subsequently, guidelines were developed for selecting the patients for shunt surgery [15]. However, none of these tests achieved 100% sensitivity or specificity and it was thought that a combination of tests, rather than a single one, was needed to increase the chances of selecting the right patients to offer a surgical CSF diversion procedure [16]. Changes in the neurochemical composition of CSF due to hydrocephalus have been widely documented and reviewed and therefore analysis of the biochemical milieu in the CSF is becoming an attractive, yet invasive method of developing markers of sufficient accuracy to either help establish a diagnosis (a diagnostic marker) or be able to predict the prognosis of surgical CSF diversion (a prognostic marker) [17].
Comorbidities may affect surgical outcomes adversely [18]. The probable coexistence of AD and NPH has been raised in the past by various authors. A recent large series of autopsies of 563 cases with dementia found an average 1.6% of autopsied cases with a clinical picture of NPH [19]. The combination of abnormally low CSF Aβ (1–42) level and abnormally high CSF tau level is a hallmark of AD pathology. Such markers may be measured reliably in CSF by commonly used and fairly affordable laboratory methods such as ELISA. Amyloid plaques and hyperphosphorylated tau in cortical brain biopsies are reflected by low CSF Aβ (1–42) and high CSF total tau and phosphorylated form of tau protein (p-tau) levels, respectively [20]. In addition, altered CSF dynamics impair amyloid beta clearance in experimental NPH models [21]. The implications of such research findings mean that we can use commonly assessed markers to help us with the differential diagnosis of different pathologies with similar phenotypes.
Diagnostic versus prognostic biomarkers
CSF biomarkers in the differential diagnosis with Alzheimer’s dementia
The problem with identifying diagnostic biomarkers between NPH and AD is that NPH was used in those studies more as a comparative control group rather than as the primary studied group, apart from a few exceptions [22–24]. In addition, it is well recognized that idiopathic and secondary NPH represent entities with different pathophysiological backgrounds and response to surgery [25,26]; therefore any attempts to identify diagnostic biomarkers in NPH should focus on the idiopathic form. A successful biomarker able to distinguish between NPH and AD would be able to reflect the pathological changes characteristic of AD and in particular abnormal phosphorylation of the tau protein [27], the synaptic and axonal degeneration, and the aggregation of amyloid with resulting deposition in plaques [28]. So far only the results of one study by Kapaki et al. [22] have reached clinical significance. The authors identified a cut-off level of the p-tau greater than 47 (pg/ml) which is able to distinguish between AD and idiopathic NPH with a sensitivity of 88.7% and specificity of 88.6%. The authors used a commercial ELISA assay (Innotest, Innogenetics, Gent, Belgium) to determine the total tau and p-tau, and Aβ (1–42). The authors also found that total tau was increased in both conditions when compared with controls, whereas β-amyloid levels were decreased in both. The diagnosis of iNPH was based on history, examination, and relevant imaging but no external lumbar drainage or tap test. A lumbar puncture was performed but the authors do not mention the pressures obtained.
Increased tau levels when compared with a control group (orthopedic subjects) were also detected by Kudo et al. [7] in a mixed NPH group using the same commercial assay (Innotest, Belgium). However, their results contradict the studies of Agren-Wilsson [23], Zemlan [29], Lins [8] and Gloeckner [30], where the levels of tau were either lower than the control group or within the normal range. Agren-Wilsson et al. used an “in-house” ELISA published previously [31], using patients undergoing orthopedic surgery as controls. This sample (n = 62) of iNPH patients is of value in providing a more accurate reflection of the markers’ value because of its size and its proper selection (lumbar infusion test and tap test performed in patients with relevant history and imaging). In the study by Zemlan et al. the levels of the cleaved form of the tau protein were barely detectable with their in-house ELISA and Western Blot assays. Lins et al. used a commercial assay (Innotest, Belgium) to measure amyloid as well as total tau immunoreactivities. They formed a combined evaluation of Aβ (1–42) and total tau protein-immunoreactivities (TTIR) plot described previously [8], which discriminated all NPH from the AD samples. They concluded that the combined use of both markers rather than one separately is of diagnostic use. No separate sensitivity or specificity figures were provided though. TTIR was not higher when compared with controls. Gloeckner et al. in their study using the same commercial assay found lower tau levels than controls [30].
Miyajima et al. assessed the levels of lumbar CSF of total tau (t-tau), phosphorylated tau (p-tau), soluble amyloid precursor protein (sAPP) sAPPa, sAPPb, and Aβ (1–42) in 46 iNPH subjects and compared the levels with AD patients and healthy controls [32]. All proteins except Aβ (1–42) were statistically different between AD and iNPH patients. Receiver operating characteristic (ROC) analysis revealed that sAPPa is the most reliable marker to distinguish iNPH from AD and normal controls (NC), with an area under the curve (AUC) of 0.994, which suggests high accuracy. With a cut-off of 234.5 ng/ml, sensitivity and specificity were 95.5% and 100%, respectively, thus allowing differentiation of iNPH from AD and NC.
In patients with NPH, the average value of total tau levels of the five studies that used the same commercial assay (Innotest, Belgium) [7,8,22,30,32] was 266 pg/ml (see Table 15.1). The range of total tau in two studies was 75–1040 pg/ml. The average level of total tau from control subjects was 195.1 pg/ml and in AD subjects it was 580.7 pg/ml in the four studies that reported AD levels.
Table 15.1 Mean values of total tau protein (pg/ml) in five studies using the same commercial ELISA kit compared with patients with AD and controls (numbers of subjects studied in brackets)
a Only median values presented in the paper.
With regard to Aβ (1–42) levels, these were assayed in three studies using the same commercial ELISA [8,22,30] (Table 15.2). The average value for patients with NPH was 455.23 pg/ml, whereas that of the control subjects was 752.16 pg/ml and 418.13 pg/ml in AD subjects. If we examine the ratio of total tau/Aβ (1–42), this was 0.58 in iNPH, 0.25 in control subjects, and 1.38 in patients with AD.
Table 15.2 Mean values of Aβ (1–42) protein (pg/ml) in three studies using the same commercial ELISA kit compared with patients with AD and controls (numbers of subjects studied in brackets)
Other studies that provided significant differences in levels of CSF markers were those of Mazurek [33] who found that levels of vasopressin were normal in NPH when compared with AD; however, this study lacked an accurate description of its NPH subjects. Cacabelos et al. also detected significantly higher levels of interleukin-1 in NPH when compared with AD [34]. Nooijen et al. [35] proposed that lactate could act as a diagnostic marker since levels in NPH were much higher than they were in AD. However in the study by Malm et al., although lactate in both NPH and AD was significantly lower than in controls, there was no difference between NPH and AD [36]. Futakawa et al. assessed the CSF levels of two isoforms of transferrin (Tf-1 and Tf-2). The Tf-2/Tf-1 ratios of iNPH patients were significantly higher than those of controls (p = 0.0019) and AD patients (p = 0.0010), suggesting this ratio as a useful marker to distinguish iNPH from AD, and possibly other dementias [37].
CSF biomarkers in the differential diagnosis with vascular dementia
The problems of clinically distinguishing NPH patients from those with subcortical ischemic vascular dementia (SIVD) are clear since the clinical phenotype of the cognitive profile, as well as the gait disturbance noted, is similar in both conditions. In this sense, it is more difficult to distinguish a patient who has NPH from one who has SIVD than from a patient who has features of AD, since careful clinical or neuropsychological evaluation will distinguish the latter group. So far similar CSF markers to the ones used to differentiate between iNPH and AD have been assayed. This is a reflection of the design of most studies, which included both patients with AD and SIVD as the primary studied cohorts and patients with NPH were used as a comparative control group. Besides, there are no condition-specific CSF biomarkers for patients with vascular dementia as there has been significant overlap with patients with AD in published results to date.
Only a few studies focused on studying the NPH and SIVD conditions separately, namely those of Tullberg et al. [38,39] and Agren-Wilsson et al. [23]. The former group found that a cut-off level of sulfatide equal to 400 nmol/l can distinguish between cases of SIVD with a sensitivity of 74% and specificity of 94%; the same lower sulfatide values in a mixed NPH group when compared with SIVD were reported in a later study [39] by the same group. However, the latter group [23] did not find any significant difference in levels; they explained this difference in their results by suggesting that this is due to their cohort being composed purely of idiopathic cases, whereas that of the former group contained both idiopathic and secondary cases.
With regard to tau no significant difference was found in the study by Tullberg et al. [38], whereas in the study by Agren-Wilsson et al. [23] tau was found to be significantly lower than in patients with SIVD. The latter group devised a multinomial logistic regression model to calculate the probability of diagnosing NPH by combining the concentrations of neurofilament light chain protein (NFL), p-tau, and Aβ (1–42); the model provided a high overall accuracy of 84.5% [23].
NFL is found mostly in large unmyelinated axons. In a meta-analysis NFL levels appear higher in patients with vascular dementia when compared with control subjects. Tullberg et al. found that NFL is increased in NPH patients when compared with patients with Binswanger’s disease (BD, or subcortical leukoencephalopathy, a rare form of multi-infarct dementia) [39]. Higher NFL in NPH (854 ng/l) and SAE (subcortical arteriosclerotic encephalopathy of Binswanger’s type) patients (1268 ng/l) when compared with controls (395 ng/l) were detected by Agren-Wilsson et al. [23]. There was not a statistical significant difference between NPH and SAE NFL levels in this latter study. Unfortunately, neither of those studies provided a cut-off value to calculate sensitivity and specificity of the marker.
Vasoactive intestinal peptide (VIP) has been consistently lower in NPH when compared with SIVD groups [38,40]. However, neither of those studies provides us with a cut-off value. The difference in VIP levels might be attributed to VIP’s neuroprotective and anti-inflammatory role which has been highlighted recently [41]. Ferrero et al. found higher levels of the diazepam binding inhibitor receptor when compared with AD and SIVD groups [42]. 5-HIAA, NPY, and GABA were significantly lower in NPH when compared with SAE [38]. Lipocalin-type prostaglandin D synthase was also found to be lower in NPH patients than in patients with SIVD [43].
CSF biomarkers in the differential diagnosis with Parkinson’s disease
Gait disorders are frequent among neurological patients. Up to 93% of patients with Parkinson’s disease (PD) may exhibit gait disorder. The difficulty in the differential diagnosis of PD with patients with NPH lies in the features of the gait disorder. Therefore NPH and vascular dementia have been described as the two causes of “lower parkinsonism” [44]. Symptoms similar to those of extrapyramidal disturbance are frequent in patients with iNPH [45]. Up to 86% of patients with iNPH have demonstrated symptoms of akinesia, tremor, hypertonia, or hyperkinesia [46]. External visual or auditory cues improve walking in iNPH only slightly, but are more effective in PD [44].
Reduced stride length and reduced step height characterize the gait of iNPH together with a disturbance of balance leading to loss of the dynamic equilibrium required for normal gait. The normal variability of step width and foot angles appears decreased, leading to an insufficient compensation of body sway, which is of particular importance during obstacle avoidance [47].
The study by Beal et al. that assessed somatostatin-like immunoreactivity provided no help in discriminating between these two conditions [48]. Ferrero et al. also compared the levels of diazepam binding inhibitor receptor and found higher levels of the marker in NPH and depressed PD patients when compared with other groups [42]. Arai et al. in their first study investigating tau as a marker found increased levels in NPH when compared with PD and other control groups [49]. Although this marker may prove useful, its use must be evaluated against latest research that shows clear pathogenic links between mutations in α-synuclein, tau or leucine-rich repeat kinase 2 (LRRK2), and a familial form of PD. LRRK2 PD is phenotypically similar to the sporadic form of PD, and therefore any future research would have to distinguish between sporadic or familial types of PD [50].
Lins et al. investigated both tau and Aβ (1–42) as a means of discriminating between AD, SIVD, PD, and NPH [6]. NPH patients showed no significant TTIR (total tau immunoreactivities) changes compared with SIVD, PD, and controls. Aβ (1–42) 42-immunoreactivity (IR) in the NPH group was significantly lower compared with PD. However, using a TTIR by Aβ (1–42) 42 plot, all NPH, PD, and control samples were within the non-AD plot region, therefore not offering any help in the differential diagnosis between NPH and PD [8]. Rota et al. studied a group of cytokines comparing patients with probable PD, AD, and SIVD with patients with NPH. None of the cytokines was of aid as a diagnostic marker [51].
Prognostic biomarkers
There have been much fewer studies developing prognosis biomarkers when compared with those assessing diagnostic biomarkers. Even though CSF is an easily accessed biological fluid by lumbar puncture or ventricular cannulation, the follow-up and measurement of outcomes is more difficult to monitor and therefore development of prognostic biomarkers becomes more cumbersome. There can of course be no prognostic biomarkers for presymptomatic individuals stratifying the risk of developing the syndrome, but only prognostic of surgical outcome if the individual undergoes surgical treatment. Multidisciplinary collaboration among physicians dealing with the diagnosis, treatment, and further follow-up of patients with iNPH is more problematic. Often there is no set protocol among different teams on how to follow up these patients; in real life practice surgical teams tend to focus less on established outcome scales and more on monitoring of surgical complications. Besides, elderly patients with other chronic conditions may fail to attend follow-up clinics. The average age of patients having surgery is early to mid seventies, therefore achieving a 10-year follow-up is proving to be more difficult than with other conditions. Other chronic conditions that may develop in time (e.g. degenerative spinal and cardiovascular conditions) may add to the overall medical burden of an individual and therefore influence overall outcomes. We discuss below studies that have focused only on surgical outcomes.
Miyajima et al. in their study of lumbar CSF for 46 patients with iNPH attempted to predict outcomes by analyzing cognitive outcomes (using the mini-mental state examination [MMSE]) after 6 months of follow-up [32]. Total tau and p-tau levels proved to be lower in patients who showed improved cognitive function after surgery. Also in groups that had MMSE ≥25 both p-tau and sAPPa were significantly lower than in the worse performing group. The only marker with the highest sensitivity and specificity (≥80%) for predicting a better cognitive outcome, MMSE ≥25, was sAPPAa [32].
Patel et al. studied 39 patients and evaluated their outcomes at 4 months using a disease-specific outcomes scale, and a psychometric battery [52]. Higher p-tau/Aβ (1–42) ratios were associated with poorer improvement in both cognition and gait after shunting. The finding that patients with high p-tau/Aβ (1–42) ratios show less recovery of gait after shunting is accounted for at least partly by their higher baseline gait performance compared with patients lacking comorbid AD pathology. Patients with high p-tau/Aβ (1–42) ratios showed poorer post-shunt improvement mainly on tests of memory (immediate and delayed word list recall) and visuospatial function (clock copy) – cognitive domains that are typically impaired in patients with AD [52].
Leinonen et al. analyzed seven markers in total and in particular total tau, p-tau181, Aβ (1–42), NFL, TNF-α, TGF-β1, and VEGF in lumbar CSF of 35 patients with suspected NPH and correlated the findings with the outcomes of external lumbar drainage (ELD) rather than surgical CSF diversion. It is known that ELD is a useful ancillary test in predicting surgical outcomes because it simulates the physiological changes occurring with permanent surgical CSF diversion. To that effect, the authors found that none of the markers studied in lumbar CSF could predict which patients would respond to ELD [53]. It would be important for this team to study the surgical outcomes of the cohort that was selected for surgical CSF diversion and report on them in a future study.
In a study of 22 patients Tarnaris et al. found that a combination of Aβ (1–42) levels and total tau protein levels predicted favorable surgical outcomes at 6 months with acceptable accuracy to be of clinical use [54]. The authors used a disease-specific outcome scale to record the outcomes. Although neither Aβ (1–42) nor t-tau levels had sufficient sensitivity or specificity, their combined calculation predicted favorable outcomes in more than 80% of cases.
Scollato et al. analyzed the proteome of 17 patients with NPH selected by ICP monitoring. They found no differences in the proteome of nonresponders compared with improved patients [55]. The overexpression of alpha-2HS glycoprotein, alpha-1-antichymotrypsin, and alpha-1-beta glycoprotein and the underexpression of glial fibrillary acidic protein, apolipoproteins (AIV, J, and E), complement C3c, antithrombin, alpha-2-antiplasmin, and albumin appeared to be associated with a positive response to surgery [55].
Nakajima et al. assessed the levels of tau protein and leucine-rich α-2-glycoprotein (LGR) in the lumbar CSF of 52 patients and correlated the results with cognitive outcomes at 12 months. A combination of higher LGR and lower tau protein values predicted a positive response in the tap test in over 90% of patients and all shunt responders. Their cut-offs of LRG concentrations of 67 ng/ml or higher gave 81.6% sensitivity and 78.6% specificity [56]. Interestingly tau protein levels in the CSF did not differ significantly between the shunt responders (167.4 ± 105.4 pg/ml) and the nonresponder group (264.9 ± 209.5 pg/ml; p > 0.05).
Summary of current evidence
When neurologists with an interest in dementia assess patients they base their diagnosis of the condition mostly on clinical grounds, and any biomarkers will then serve an auxiliary role. Out of the most studied CSF proteins, Aβ (1–42), is decreased in the CSF of AD patients possibly because of the deposition of fibrillar Aβ (1–42) in senile plaques. Tau protein is increased in the CSF of AD patients as a reflection of the release of tau in CSF with neuronal loss. P-tau stems finally from tangle deposition. The pooled sensitivities and specificities for Aβ (1–42) in AD versus controls is 86% and 89% and for tau 81% and 91%, respectively [57]. There are no exclusive biomarkers for patients with vascular dementia and so the aforementioned have been studied. In the case of vascular dementia versus AD the combination rather than the use of a single biomarker appears useful. Having reviewed the current literature we have seen that none of the studied proteins can fulfill the role of a biomarker for iNPH according to the criteria set by the Consensus Report of the Working Group on Molecular and Biochemical Markers of Alzheimer’s Disease (sensitivity and specificity greater than 80% and validated by two independent studies) [2].
Summary of currently available evidence
No CSF biomarker has fulfilled the criteria required to aid in the diagnosis or differential diagnosis of the condition.
Lower than AD total tau levels and comparable Aβ (1–42) levels to AD may aid in the differential diagnosis from patients with AD.
sAPPa appears in one study as a single marker (cut-off of 234.5 ng/ml), with high sensitivity and specificity to differentiate between iNPH, AD, and normal controls.
A combination of the light chain of neurofilament protein (NFL), p-tau, and Aβ (1–42) has provided high accuracy in distinguishing iNPH from SIVD in one study and again may act as a platform for future prospective studies.
No CSF marker has shown currently any promise to distinguish between NPH and patients with PD.
The evidence for prognostic biomarkers is at present weak since there are too few studies, with small numbers of patients. A combination of p-tau and Aβ (1–42) or t-tau and Aβ (1–42) appears promising and should be replicated in further studies by different groups.
Experimental problems
Any diagnostic biomarkers need to reflect the pathological changes characterizing the condition. In iNPH, because of the small number of autopsy cases, it is impossible to conclude whether anatomicopathological alterations are present in all cases, or differ depending on the severity or the chronicity of the condition. The pathological changes observed have resulted mainly from cortical biopsies and selected autopsy studies from research that predates modern diagnostic criteria and have not been replicated in a cohort of idiopathic NPH. However, it is thought that in NPH changes similar to those found in arteriosclerotic encephalopathy or Alzheimer’s dementia are common. In a prospective study of 56 patients who underwent ventriculoperitoneal shunting for iNPH and cortical biopsy no specimen biopsy showed inflammation, neoplasm, neurons with Lewy bodies, Pick bodies, or glial cells with silver-positive inclusions [58]. Amyloid angiopathy and neuropil threads were detected in only a few specimens and sparse accumulations of neurofibrillary tangles were seen in six (10.7%). Neuritic plaques were found in 23 (41%) biopsies, whereas 12 (21.4%) patients showed only diffuse plaques. A diagnosis of definite Alzheimer’s disease could be made in seven cases (12.5%), probable disease in nine (16%), and possible disease in seven (12.5%) [58].
There are firstly technical details that need to be considered such as the fast transfer of the CSF sample to the lab from theaters or the ward, proper spinning and storage to proper polypropylene tubes and freezing. The CSF volume taken can influence the concentration of biomarkers [59]. If storage is required for later investigation this can be done at 4–8°C (short-term) or at –20°C (long-term). If storage is required, 12 ml of CSF should be partitioned into three to four sterile tubes [60]. Also avoidance of thawing of the CSF, which may affect the accuracy of protein measurement, is paramount. If ventricular CSF is collected, the first few ml need to be discarded as they may “contaminate” the CSF sample. This is because the sample obtained may contain proteins from the cerebral tissue encountered during cannulation, thus not reflecting the ventricular CSF levels. When one measures ventricular or lumbar levels of a biomarker one needs to be aware that there are rostrocaudal variations in the markers and the lumbar levels do not always reflect the ventricular levels and vice versa. It is important to collect matched serum and/or plasma samples for evaluation of CSF biomarkers because the concentration of the marker in blood often influences that in CSF. In addition, serum/plasma pairs are essential to study the intrathecal origin of a biomarker and its central nervous system specificity.
Standardization of laboratory methods and adherence to published guidelines are also of importance. A recent meta-analysis showed considerable differences in absolute concentrations of Aβ (1–42) and tau between laboratories, even when the same test kit was used.
Quo vadis?
It has taken the medical community 40 years to provide internationally accepted and evidence-based guidelines for the diagnosis and treatment of the syndrome [61]. As seen at the beginning of the chapter, it took 20 years from the description of the syndrome for the first studies in CSF markers to be published and almost 40 years until the first study that looked into amyloid beta and tau as potential markers for the condition.
It has been emphasized on many occasions in the past that collaborative studies across multiple centers are needed to ensure a large enough number of participants. This is more feasible in studies that explore diagnostic markers using patients with AD or other forms of neurodegenerative disorders as the control group because these conditions are more common than iNPH. Such studies will require robust diagnostic criteria and inclusion criteria as well as validated outcome scales which at best should be condition specific. The follow-up should also be much longer than the most commonly used period of 12 months. Various studies have shown that the beneficial effects of shunt implantation can last more than 5 years, so it is important to be able to select those patients that will most likely benefit from a surgical procedure. One of these studies is the European multicenter study on iNPH [62], which it is hoped will give us further insight into potential biomarkers of the condition.
Ideally biomarkers should combine findings from multiple disciplines, including neuropsychological testing, blood tests, CSF biochemistry, and brain imaging. It is difficult to evaluate whether diagnostic or prognostic biomarkers would be of most value in the effective treatment of our patients. Currently CSF biomarkers are assessing the “load” of comorbid conditions in a single patient, thus highlighting what we currently know about the unfavorable surgical outcomes in patients who may harbor AD or vascular ischemic pathologies. Researchers should focus on markers that have showed promise so far such as t-tau, p-tau, and Aβ (1–42), reproducing results of previous studies in the hope that some of these proteins will fulfill the definition of a biomarker. No condition-specific biomarker has been so far developed because our insight into the pathology of the syndrome is still at an early stage. It is hoped that once biomarkers have been established, they will form part of any future diagnostic guidelines for the syndrome. Using the noninvasive biomarkers that are being developed and taking into account the heterogeneity of the syndrome, we may then move towards a stratified or personalized approach to treatment of our patients.
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