Skip to main content

Cerebrospinal fluid biomarkers and genetic factors associated with normal pressure hydrocephalus and Alzheimer’s disease: a narrative review

Abstract

Background

Normal pressure hydrocephalus is a neurologic disease leading to enlargement of ventricles which is presented with gait and balance disturbance, cognitive decline, and urinary incontinence. Diagnosis of normal pressure hydrocephalus is challenging due to the late onset of signs and symptoms. In this review, we summarize the cerebrospinal fluid, plasma, pathology, and genetic biomarkers of normal pressure hydrocephalus and related disorders.

Body

Recently, cerebrospinal fluid and serum biomarkers analysis alongside gene analysis has received a lot of attention. Interpreting a set of serum and cerebrospinal fluid biomarkers along with genetic testing for candidate genes could differentiate NPH from other neurological diseases such as Alzheimer's disease, Parkinson's disease with dementia, and other types of dementia.

Conclusion

Better understanding the pathophysiology of normal pressure hydrocephalus through genetic studies can aid in evolving preventative measures and the early treatment of normal pressure hydrocephalus patients.

Background

Pathological enlargement of the ventricles leads to hydrocephalus. The most common form of hydrocephalus involving adults is idiopathic normal pressure hydrocephalus (iNPH) in which brain imaging shows ventriculomegaly, while the intracranial pressure remains within normal range with no determined secondary cause [1]. Patients with iNPH develop gait and balance disturbance as the most dominant symptom, often accompanied by cognitive decline and/or urinary incontinence. iNPH is diagnosed based on medical history, neurologic examination, and brain imaging with CT or MRI. The international iNPH guidelines and the Japanese iNPH guidelines described the diagnostic criteria for iNPH [2,3,4]. Neuroimaging, either CT or MRI, is an essential step in iNPH diagnosis. In iNPH, the lateral and third ventricles are enlarged with no obstruction. The Evans ratio or index is used to describe hydrocephalus and an Evans ratio greater than 0.3 indicates large ventricles. The annual incidence of iNPH is estimated to be 5.5/100.000. The iNPH prevalence among a population aged 65 is 3.7% and there is even a higher chance for people aged 80 years and above [5, 6].

The standard treatment for iNPH is through the cerebrospinal fluid (CSF) diversion from the craniospinal space to another anatomic space so the CSF can be reabsorbed [7]. Although patients with iNPH are characterized by impaired CSF dynamics, the specific etiology of iNPH is still unclear. Understanding the genetic-based pathways of iNPH provides valuable insight into the pathophysiology of the disease and could benefit us with further effective treatments and preventative measures. Diagnostic workup of iNPH can be challenging due to an overlap in symptoms and neuroimaging features with other differential diagnoses. Despite extensive investigations, a CSF biomarker profile in iNPH has not yet been identified [8]. This survey aims to summarize the main findings in this field which may help the better understanding of the etiology, diagnosis, and prevention of iNPH.

Main text

CSF, plasma and pathology biomarkers

Common biomarkers of Alzheimer's disease and NPH

The hallmark pathology of Alzheimer’s disease (AD) is characterized by the lesions of amyloid-β (Aβ) plaques, tau proteins, and neurofibrillary tangles within the brain of patients [9]. These plaques accumulate in the brain and cause low levels of amyloid-β1–42 (Aβ 42) and an increase in neurofibrillary tangle formation, total tau (t-tau), and phosphorylated tau (p-tau) concentration in CSF. Whereas Aβ 42 had a lower concentration in CSF of AD patients, soluble amyloid-precursor proteins α and β (sAPPa, sAPPb), amyloid-β1–38 (Aβ 38), and amyloid-β1–40 (Aβ 40) were increased. Amyloid positron emission tomography (PET) tracers has high specificity for the detection of Aβ plaques. All of the amyloid peptides (Aβ 42, Aβ 38, and Aβ 40), sAPPa, sAPPb, p-tau, and total-tau protein were reduced in CSF of NPH patients compared to healthy controls and non-NPH patients [10,11,12,13,14,15]. We can use this comparison to differentiate between the two diseases but we must also pay attention to the comorbidity of these two diseases in interpreting these results. Improvement after surgical therapy in NPH patients may be associated with different AD-related biomarkers and this is inconsistent in studies. However, NPH patients who did not respond to therapy had positive PET results, lower Aβ 42 and higher t-tau level in CSF in a study conducted by Jang et al., but Müller‐Schmitz et al. reported that patients who had NPH and AD-related CSF changes (high tau protein, high p-tau, low beta-amyloid) improved cognitive or gait functions after the spinal tap [16, 17]. The postoperative level of Aβ42 was similar in responder and non-responder patients to shunt surgery but non-responders had a high cortical level of Aβ42 [18]. The regional cerebral blood flow in the brain of NPH patients was significantly reduced compared to normal people, and it was improved after surgery. The patients who had AD and NPH showed less improvement of regional cerebral blood flow after surgery compared to NPH only [19]. NPH Patients who had Aβ and tau protein in brain biopsy, CSF ventricular Aβ42 was lower and lumbar p-Tau was higher compared to those whom had not. Lumbar p-Tau was able to predict biopsy results for beta-Amyloid and tau protein. Patients with different biopsy profiles had not any difference in postoperative cognitive tests [20]. Reduction in Aβ42 level was seen in both AD and NPH but did not differ between NPH and AD [8]. Indeed, the diagnostic value of Aβ42/Aβ40 ratio was higher than Aβ42 and it was reduced only in AD, while it was within the normal range in the sample of NPH and vascular dementia [21].

NFL

Neurofilaments are intermediate filaments that consist of light (NF-L), medium (NF-M), and heavy (NF-H) neuron-specific cytoskeletal components. NFs have an important role in axonal structural integrity. Neurofilament light chains are non-specific biomarkers in neurodegenerative and inflammatory diseases such as multiple sclerosis (MS) [22]. Neurofilament protein release in cerebrospinal fluid (CSF) and blood circulation occurs after Axonal damage [23]. Although Patients with NPH exhibited higher levels of NFL in the CSF compared to controls in numerous studies [24,25,26,27], it was not seen in the study by Jeppsson.A et al. [28]. In line with previous studies, it has been shown that NPH patients with more extensive periventricular white matter hyperintensities in MRI exhibited a high level of NFL in CSF before and after therapeutic surgery. It was shown that the greater reduction in NFL after surgery was correlated with better results on postoperative MRI and cognitive tests [24]. NFL can be used for differentiation of NPH from subcortical ischemic vascular disease along with other CSF biomarkers such as Aβ42, t-tau, and synaptic protein neurogranin (NG). These biomarkers were lower in the CSF of NPH patients compared to the CSF of patients with subcortical ischemic vascular disease [29]. The level of NFL in the CSF of the patients who only had NPH had no significant difference compared to the patients with NPH and AD or vascular diseases [21].

MBP

Myelin basic protein (MBP) is abundant in the central nervous system and has multiple functions such as binding to cytoskeleton proteins, myelination, and transmission of extracellular signaling [30]. Patients with NPH, neurovascular diseases, MS, and other neurometabolic disorders had high levels of MBP in CSF and blood samples [26, 31, 32].

LRG

Leucine-rich alpha-2-glycoprotein is localized within the extracellular matrix which binds to collagen, fibronectin, and TGF β. LRG has a membrane-binding component and can potentially bind to transforming growth factor βI type II receptor (TGF βR-II) on the cell membrane. In the brain, LRG is expressed in astrocytes and pericapillary regions also, its expression is more in elderly than young patients [33]. According to this association, NPH patients exhibited higher levels of TGF βR-II, TGF β, and LRG than healthy ones [34]. NPH patients had a higher level of LRG in CSF than healthy controls, but patients with Parkinson's disease with dementia (PDD) and progressive supranuclear palsy (PSP) exhibited a higher level of LRG than NPH and AD patients [35]. So far, studies have shown an increase in LRG in the CSF of NPH patients. LRG could be used as a potential biomarker for diagnosis and forecasting NPH improvement in patients after shunt surgery [36, 37].

Neuro-inflammatory biomarkers

Transforming growth factor β1 (TGF-β1) is a pleiotropic cytokine with multiple roles such as immunosuppression, anti-inflammatory effects, and synaptic plasticity. During an injury, TGF-β1 causes neurodegenerative neuroinflammation, vascular hypertrophy, and neural death [38]. Although TGF-β1 can trigger neuroinflammation, it is a known agent in neuroprotection in AD patients [39, 40]. As mentioned earlier, patients with NPH had high levels of βR-II, TGF β and LRG. The CSF level of TGF-β, and IL-1β is lower in NPH than AD [41, 42]. It has been shown that the CFS content of TGF-β1 in NPH was higher than patients with chronic obstructive hydrocephalus but not as significant as those with subarachnoid hemorrhage-induced hydrocephalus [43].

IL-1β, IL-6, IL-10 (anti-inflammatory cytokine) levels in CSF of NPH patients were significantly increased compared to healthy elderly but there was not any significance in serum levels [44]. These cytokines also increased in AD and Parkinson's disease (PD) and they were not disease-specific biomarkers [45].

Tumor necrosis factor-alpha (TNF-alpha) is probably linked to white matter. As its CSF level in NPH patients before shunt surgery was high and its reduction after surgery was correlated with cognitive improvement [46]. NPH patients had also an increased level of TNF-α compared to chronic obstructive hydrocephalus [44]. However, this relationship was not seen in further studies or was lower than the control group [45, 47]. Monocyte chemoattractant protein 1 (MCP-1) is a monocyte chemotaxis factor plays an important role in inflammation and its CFS level increases during NPH disease [10, 48]. Another inflammatory biomarker is Chitinase-3-like protein-1 (YKL-40) which is an astrocyte activation marker and increases in neuroinflammatory diseases like MS and AD. Previously, YKL-40 was used as a potential biomarker for discrimination of healthy persons and those with mild cognitive impairment and AD [49]. YKL-40 level did not differ in NPH patients from patients with subcortical ischemic vascular disease [29]. However it could be a novel suggesting biomarker for differentiation of NPH from other mimics, but little is known about it [49, 50].

Other suggested biomarkers

Aquaporin 4 (AQ4) is a water channel in the CNS which is located on astrocytes to ease the CSF flow to the parenchyma of the brain [51]. Although it has recently been hypothesized that perivascular inflammation and decreased AQ4 levels in astrocytes may be involved in the pathophysiology of NPH, these changes were not due to CSF and serum level of AQP4-IgG/IgA/IgM auto-antibodies [52].

Protein tyrosine phosphatase receptor type Q (PTPRQ) is a protein associated with hearing loss. PTPRQ component of the CSF was higher in NPH patients than AD, especially in shunt responder patients [53]. Analysis of NPH CSF metabolites showed a low level of glycerate and a high level of N-acetylneuraminate, serine, and 2-hydroxybutyrate compared to AD patients. Metabolite profile could be among novel markers for discrimination of these diseases [54]. The list of important CFS, plasma, and pathology biomarkers described is given in Table 1.

Table 1 List of CSF, pathology and plasma biomarkers of NPH

Genetic factors

CFAP43

Mutations in the gene encoding cilia and flagella associated with protein 43 (CFAP43) are connected to male infertility with various morphologic abnormalities of the sperm flagella. Studies have reported a strong association between the CFAP43 gene and the function and morphology of flagella [55, 56]. Primary cilia dyskinesia (PCD), is a disorder characterized by recurrent infection, hydrocephalus, and infertility [57]. The genetic evaluation of Japanese family members with NPH showed a nonsense gene mutation in CFAP43. The Cfap43−/− mice showed third and lateral ventricles dilation, disfigured sperm flagella, and excess cytoplasm in testis and epididymal cells. Also, a decrease in the number of acetylated tubulins (as a marker of cilium mortality) was found in the choroid plexus of Cfap43−/− mice. There was a defect of Spef2 (as a marker of the axoneme central pair) and Rsph4a (as a marker of radial spokes) in some of the epithelial cells of the lateral ventricle and trachea of the Cfap43−/− mice. Moreover, transmission electron microscopy analyses showed normal 9 + 2 axonemes in the cross section of wild-type tracheal cilia mice but abnormal 8 or 10 + 2 peripheral microtubules in Cfap43-/-. Also, compound cilia were observed only in Cfap43−/− mice. In summary, mutations in the gene CFAP43 are responsible for ciliary dysfunction in different tissues such as the testis, epithelial cells lining the ventricles of the brain, choroid plexus, and also trachea [58].

Adenosine A1 and A2A receptors

The purine ribonucleoside adenosine (Ado) is produced extracellularly through catabolism of excreted ATP and intracellularly from AMP and then released by its transporter. Ado is a metabolite with vastly distributed throughout the body. Both extracellular and intracellular Ado levels increases in response to different physiological stimuli and inflammatory status and tissue injuries. Ado and G-protein are connected in contrary pathways: A1 receptor (A1R) connected to inhibitory Gi-protein and A2A receptor (A2AR) connected to excitatory Gs-protein, therefore decreasing and increasing cAMP levels, respectively. Ado receptors have a major role in brain vasculature dynamics [59]. Aside from brain perfusion, Ado receptors have a part in the control of brain inflammation and microglial activity [60]. Results from analysis of A1R and A2AR mRNA levels in peripheral blood mononuclear cells (PBMCs) from iNPH and control samples showed that the gene expression of A1R and A2AR in PBMCs was significantly lower in iNPH than control samples. The downregulation of A1R and A2AR gene and protein expressions in PBMCs from iNPH compared to healthy samples supports the involvement of the Ado system in the pathophysiology of iNPH disease [61].

Transthyterin and Amyloid precursor

AB peptide is a product of several cleavages of amyloid protein precursor (ABPP). ABPP is processed through cleavage by a secretase (ADAM9, ADAM10, or ADAM17) [62]. All pieces produced from AB processing have different participations in neural system activities [63]. Results from the genome expression profile from 22 iNPH patients and 8 non-demented control subjects showed a 17-fold decrease in Transthyretin expression in iNPH samples. Contrarily, ABPP was expressed three times higher in iNPH samples, and also ADAM10 expression was increased [64].

SFMBT1

SFMBT1 gene is placed on the region of chromosome 3p21.1 which encodes a protein consisting of 866 amino acid residues, containing 4 malignant brain tumor (MBT) repeat domains [65, 66]. The physiologic role of the SFMBT1 protein is poorly understood but relates to histone binding and it is involved in different transcription corepressor activities [65, 67]. The SFMBT1 locus is related to elevated serum urate levels, fasting glucose, and high blood pressure [68,69,70].

Immunohistochemical examination of the normal human brain showed that SFMBT1 protein is localized mainly in smooth muscle and endothelial cells of blood vessels, ependymal cells lining the ventricles, and epithelial cells of the choroid plexus, which play a significant role in secretion, flow, and absorption of CSF. Therefore, it looks like that SFMBT1 gene mutations may affect the normal circulation of CSF in the brain. Patients with iNPH had SFMBT1 gene copy loss compared with healthy controls. The copy number loss was heterozygous and occurred at the 12 kb region within intron 2 of the SFMBT1 gene [71]. There was a strong relationship between the copy number loss in SFMBT1 and iNPH leading to this idea that the copy number loss in SFMBT1 was a risk gene for iNPH [72, 73]. As the gene copy loss prevalence was similar between shunt responder and non-responder patient groups, SFMBT1 seems to be linked with enlargement of brain ventricles but not with shunt response [72].

C9ORF72

C9ORF72 gene is at 9p21.2, encoding C9ORF72 protein is found in many tissues including brain structures. Hexanucleotide repeat expansion in the C9ORF72 gene leads to behavioral variant frontotemporal dementia [74, 75], amyotrophic lateral sclerosis (as the common motor symptom in a patient with the C9ORF72 expansion), and extrapyramidal symptoms [76, 77]. Furthermore, the full or an intermediate (20–30 repeats) C9ORF72 expansion was associated with PD [78]. Atypical Parkinsonian disorders that potentially cause problems with gait could be connected to intermediate number of repeats in the C9ORF72 gene [79,80,81,82,83]. There was also an association between C9ORF72 expansion and iNPH and most of the carriers showed gait disabilities. Also, the mean age at onset of symptoms in patients with C9ORF72 expansion was lower than non-carriers (59 vs 70 years) [84].

APOE4

There are three different apolipoprotein E (APOE) alleles that encode three different ApoE isoproteins [85,86,87]. APOE4 allele is the most significant independent genetic risk factor for late-onset AD [88,89,90] APOE4 is also correlated with other neurological diseases [91, 92]. Studies showed that homozygous ApoE3/3 genotype was slightly associated with gait improvement in patients with iNPH but there was no other evidence for the correlation of APOE4 genotype, iNPH disease, and response to shunt [93,94,95].

Chromosome 19q12–13.31

Studies on five generations of a family suggested possible genetic relation between Essential tremor (ET) and Idiopathic normal pressure hydrocephalus (iNPH). This new autosomal dominant genetic disorder known as essential tremor-idiopathic normal pressure hydrocephalus (ETINPH) was detected in a family with 15 members affected with ET, of whom 3 of them in the second generation developed iNPH. Genetic analyses showed that neither of the three genes that are related to ET is involved in this family. This data raise the genetic link between iNPH and ET [96].

Several loci on chromosome 19q12–13.31, are suspected to be in association with ETINPH. Among loci in this part of the chromosome, some are more possible candidates as they are related to the nervous system functions [97]. One of these genes is the ATP1A3 which codes an isoform of the alpha subunit of N,K-ATPase which is expressed in nervous system. A mutation in the ATP1A3 gene can cause an autosomal dominant disorder called rapid-onset dystonia-parkinsonism [98]. This disease can affect patients between the ages of 15 and 45 years leading to involuntary spasms of the extremities, bradykinesia, dysarthria, dysphagia, and postural instability [99,100,101]. There is a chance that various mutations in the ATP1A3 gene can lead to various loss of function and various clinical manifestations from Parkinsonism to ETINPH.

Another gene is the Presenilin enhancer 2 (PSENEN) gene which encodes a protein that enhances the Presenilin production, a constituent of gamma-secretase. Gamma-secretase is one of the proteins involved in breaking down ABPP and inappropriate breaking of AMPP that leads to Alzheimer’s disease [102]. Amyloid-beta A4 precursor-like protein 1 (APLP1) is structurally homologous to APP and located on chromosome 19 [103]. The list of important genes in pathophysiology of NPH is discussed in Table 2.

Table 2 List of candidate genes involved in NPH

Conclusion

Here, we reviewed the studies that examined the biomarkers of NPH and other related neurologic disorders. There are different categories of markers such as inflammatory markers, markers related to Alzheimer's disease, and various CNS proteins. Also, the genotype results of NPH patients show that some genes in these patients have been altered, which seems to be involved in the pathophysiology of NPH and can be used as a biomarker.

Differentiation of NPH from other similar neurological diseases is possible through CSF, plasma, pathology and genetic biomarkers. However, more studies are needed to provide accurate and comprehensive profiles for these diseases so that we can understand the clinical characteristics of different patients.

Availability of data and materials

Not applicable.

Abbreviations

NPH:

Normal pressure hydrocephalus

iNPH:

Idiopathic normal pressure hydrocephalus

CSF:

Cerebrospinal fluid

AD:

Alzheimer’s disease

PSP:

Supranuclear palsy

MS:

Multiple sclerosis

Aβ:

Amyloid-β

t-tau:

Total tau

SAPP:

Soluble amyloid-precursor proteins

NFL:

Neurofilaments

NG:

Neurogranin

MBP:

Myelin basic protein

LRG:

Leucine-rich alpha-2-glycoprotein

TGF-β1:

Transforming growth factor β1

TGF βR-II:

Transforming growth factor βI type II receptor

PDD:

Parkinson's disease with dementia

PD:

Parkinson's disease

TNF-alpha:

Tumor necrosis factor-alpha

MCP-1:

Monocyte chemoattractant protein 1

YKL-40:

Chitinase-3-like protein-1

PTPRQ:

Protein tyrosine phosphatase receptor type Q

AQ4:

Aquaporin 4

CFAP43:

Cilia and flagella associated with protein 43

PCD:

Primary cilia dyskinesia

Ado:

Adenosine

A2AR:

A2A receptor

A1R:

A1 receptor

PBMCs:

Peripheral blood mononuclear cells

SFMBT:

SFMBT1 gene

C9ORF72:

C9ORF72 gene

ABPP:

Amyloid protein precursor

MBT:

Malignant brain tumor

APOE:

Apolipoprotein E

ET:

Essential tremor

ETINPH:

Essential tremor-idiopathic normal pressure hydrocephalus

PSENEN:

Presenilin enhancer 2

APLP1:

Amyloid beta A4 precursor-like protein 1

References

  1. Adams RD, Fisher CM, Hakim S, Ojemann RG, Sweet WH (1965) Symptomatic occult hydrocephalus with “Normal” cerebrospinal-fluid pressure: a treatable syndrome. N Engl J Med. 273:117–26

    CAS  PubMed  Google Scholar 

  2. Relkin N, Marmarou A, Klinge P, Bergsneider M, Black PM (2005) Diagnosing idiopathic normal-pressure hydrocephalus. Neurosurgery 57(3 Suppl):S4–16; discussion ii–v

  3. Marmarou A, Bergsneider M, Klinge P, Relkin N, Black PM (2005) The value of supplemental prognostic tests for the preoperative assessment of idiopathic normal-pressure hydrocephalus. Neurosurgery 57(3 Suppl):S17–28; discussion ii–v

  4. Mori E, Ishikawa M, Kato T, Kazui H, Miyake H, Miyajima M, et al (2012) Guidelines for management of idiopathic normal pressure hydrocephalus: second edition. Neurol Med Chir (Tokyo) 52(11):775–809

  5. Brean A, Eide PK (2008) Prevalence of probable idiopathic normal pressure hydrocephalus in a Norwegian population. Acta Neurol Scand 118(1):48–53

    CAS  PubMed  Google Scholar 

  6. Andersson J, Rosell M, Kockum K, Lilja-Lund O, Soderstrom L, Laurell K (2019) Prevalence of idiopathic normal pressure hydrocephalus: a prospective, population-based study. PLoS One 14(5):e0217705

  7. Williams MA, Malm J (2016) Diagnosis and treatment of idiopathic normal pressure hydrocephalus. Continuum (Minneap Minn). 22(2 Dementia):579–99

  8. Manniche C, Hejl AM, Hasselbalch SG, Simonsen AH (2019) Cerebrospinal fluid biomarkers in idiopathic normal pressure hydrocephalus versus Alzheimer’s disease and subcortical ischemic vascular disease: a systematic review. J Alzheimers Dis 68(1):267–279

    PubMed  Google Scholar 

  9. Scheltens P, Blennow K, Breteler MM, de Strooper B, Frisoni GB, Salloway S et al (2016) Alzheimer’s disease. Lancet 388(10043):505–517

    CAS  PubMed  Google Scholar 

  10. Jeppsson A, Wikkelso C, Blennow K, Zetterberg H, Constantinescu R, Remes AM et al (2019) CSF biomarkers distinguish idiopathic normal pressure hydrocephalus from its mimics. J Neurol Neurosurg Psychiatry 90(10):1117–1123

    PubMed  Google Scholar 

  11. Schirinzi T, Sancesario GM, Ialongo C, Imbriani P, Madeo G, Toniolo S et al (2015) A clinical and biochemical analysis in the differential diagnosis of idiopathic normal pressure hydrocephalus. Front Neurol 6:86

    PubMed  PubMed Central  Google Scholar 

  12. Picascia M, Zangaglia R, Bernini S, Minafra B, Sinforiani E, Pacchetti C (2015) A review of cognitive impairment and differential diagnosis in idiopathic normal pressure hydrocephalus. Funct Neurol 30(4):217–228

    PubMed  Google Scholar 

  13. Jingami N, Asada-Utsugi M, Uemura K, Noto R, Takahashi M, Ozaki A et al (2015) Idiopathic normal pressure hydrocephalus has a different cerebrospinal fluid biomarker profile from Alzheimer’s disease. J Alzheimers Dis 45(1):109–115

    CAS  PubMed  Google Scholar 

  14. Kapaki EN, Paraskevas GP, Tzerakis NG, Sfagos C, Seretis A, Kararizou E et al (2007) Cerebrospinal fluid tau, phospho-tau181 and beta-amyloid1-42 in idiopathic normal pressure hydrocephalus: a discrimination from Alzheimer’s disease. Eur J Neurol 14(2):168–173

    CAS  PubMed  Google Scholar 

  15. Tsai A, Malek-Ahmadi M, Kahlon V, Sabbagh MN (2014) Differences in cerebrospinal fluid biomarkers between clinically diagnosed idiopathic normal pressure hydrocephalus and Alzheimer's Disease. J Alzheimers Dis Parkinsonism 4(4)

  16. Muller-Schmitz K, Krasavina-Loka N, Yardimci T, Lipka T, Kolman AGJ, Robbers S et al (2020) Normal pressure hydrocephalus associated with Alzheimer’s disease. Ann Neurol 88(4):703–711

    PubMed  Google Scholar 

  17. Jang H, Park SB, Kim Y, Kim KW, Lee JI, Kim ST et al (2018) Prognostic value of amyloid PET scan in normal pressure hydrocephalus. J Neurol 265(1):63–73

    PubMed  Google Scholar 

  18. Abu Hamdeh S, Virhammar J, Sehlin D, Alafuzoff I, Cesarini KG, Marklund N (2018) Brain tissue Abeta42 levels are linked to shunt response in idiopathic normal pressure hydrocephalus. J Neurosurg 130(1):121–129

    PubMed  Google Scholar 

  19. Azuma S, Kazui H, Kanemoto H, Suzuki Y, Sato S, Suehiro T et al (2019) Cerebral blood flow and Alzheimer’s disease-related biomarkers in cerebrospinal fluid in idiopathic normal pressure hydrocephalus. Psychogeriatrics 19(6):527–538

    PubMed  Google Scholar 

  20. McGovern RA, Nelp TB, Kelly KM, Chan AK, Mazzoni P, Sheth SA et al (2019) Predicting cognitive improvement in normal pressure hydrocephalus patients using preoperative neuropsychological testing and cerebrospinal fluid biomarkers. Neurosurgery 85(4):E662–E669

    PubMed  Google Scholar 

  21. Abu-Rumeileh S, Giannini G, Polischi B, Albini-Riccioli L, Milletti D, Oppi F et al (2019) Revisiting the cerebrospinal fluid biomarker profile in idiopathic normal pressure hydrocephalus: the bologna pro-hydro study. J Alzheimers Dis 68(2):723–733

    CAS  PubMed  Google Scholar 

  22. Rossi S, Motta C, Studer V, Barbieri F, Buttari F, Bergami A et al (2014) Tumor necrosis factor is elevated in progressive multiple sclerosis and causes excitotoxic neurodegeneration. Mult Scler 20(3):304–312

    PubMed  Google Scholar 

  23. Lee Y, Lee BH, Yip W, Chou P, Yip BS (2020) Neurofilament proteins as prognostic biomarkers in neurological disorders. Curr Pharm Des 25(43):4560–4569

    PubMed  Google Scholar 

  24. Tullberg M, Blennow K, Mansson JE, Fredman P, Tisell M, Wikkelso C (2007) Ventricular cerebrospinal fluid neurofilament protein levels decrease in parallel with white matter pathology after shunt surgery in normal pressure hydrocephalus. Eur J Neurol 14(3):248–254

    CAS  PubMed  Google Scholar 

  25. Agren-Wilsson A, Lekman A, Sjoberg W, Rosengren L, Blennow K, Bergenheim AT et al (2007) CSF biomarkers in the evaluation of idiopathic normal pressure hydrocephalus. Acta Neurol Scand 116(5):333–339

    CAS  PubMed  Google Scholar 

  26. Jeppsson A, Zetterberg H, Blennow K, Wikkelso C (2013) Idiopathic normal-pressure hydrocephalus: pathophysiology and diagnosis by CSF biomarkers. Neurology 80(15):1385–1392

    CAS  PubMed  Google Scholar 

  27. Pyykko OT, Lumela M, Rummukainen J, Nerg O, Seppala TT, Herukka SK, et al (2014) Cerebrospinal fluid biomarker and brain biopsy findings in idiopathic normal pressure hydrocephalus. PLoS One 9(3):e91974

  28. Jeppsson A, Holtta M, Zetterberg H, Blennow K, Wikkelso C, Tullberg M (2016) Amyloid mis-metabolism in idiopathic normal pressure hydrocephalus. Fluids Barriers CNS 13(1):13

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Manniche C, Simonsen AH, Hasselbalch SG, Andreasson U, Zetterberg H, Blennow K et al (2020) Cerebrospinal fluid biomarkers to differentiate idiopathic normal pressure hydrocephalus from subcortical ischemic vascular disease. J Alzheimers Dis 75(3):937–947

    CAS  PubMed  Google Scholar 

  30. Boggs JM (2006) Myelin basic protein: a multifunctional protein. Cell Mol Life Sci 63(17):1945–1961

    CAS  Google Scholar 

  31. Lamers KJ, Vos P, Verbeek MM, Rosmalen F, van Geel WJ, van Engelen BG (2003) Protein S-100B, neuron-specific enolase (NSE), myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP) in cerebrospinal fluid (CSF) and blood of neurological patients. Brain Res Bull 61(3):261–264

    CAS  PubMed  Google Scholar 

  32. Sutton LN, Wood JH, Brooks BR, Barrer SJ, Kline M, Cohen SR (1983) Cerebrospinal fluid myelin basic protein in hydrocephalus. J Neurosurg 59(3):467–470

    CAS  PubMed  Google Scholar 

  33. Nakajima M, Miyajima M, Ogino I, Watanabe M, Hagiwara Y, Segawa T et al (2012) Brain localization of leucine-rich alpha2-glycoprotein and its role. Acta Neurochir Suppl 113:97–101

    PubMed  Google Scholar 

  34. Li X, Miyajima M, Jiang C, Arai H (2007) Expression of TGF-betas and TGF-beta type II receptor in cerebrospinal fluid of patients with idiopathic normal pressure hydrocephalus. Neurosci Lett 413(2):141–144

    CAS  PubMed  Google Scholar 

  35. Miyajima M, Nakajima M, Motoi Y, Moriya M, Sugano H, Ogino I, et al (2013) Leucine-rich alpha2-glycoprotein is a novel biomarker of neurodegenerative disease in human cerebrospinal fluid and causes neurodegeneration in mouse cerebral cortex. PLoS One 8(9):e74453

  36. Li X, Miyajima M, Mineki R, Taka H, Murayama K, Arai H (2006) Analysis of potential diagnostic biomarkers in cerebrospinal fluid of idiopathic normal pressure hydrocephalus by proteomics. Acta Neurochir (Wien) 148(8):859–64; discussion 64

  37. Nakajima M, Miyajima M, Ogino I, Watanabe M, Miyata H, Karagiozov KL, et al (2011) Leucine-rich alpha-2-glycoprotein is a marker for idiopathic normal pressure hydrocephalus. Acta Neurochir (Wien) 153(6):1339–46; discussion 46

  38. Zhang X, Huang WJ, Chen WW (2016) TGF-beta1 factor in the cerebrovascular diseases of Alzheimer’s disease. Eur Rev Med Pharmacol Sci 20(24):5178–5185

    CAS  PubMed  Google Scholar 

  39. Fang XX, Sun GL, Zhou Y, Qiu YH, Peng YP (2018) TGF-beta1 protection against Abeta1-42-induced hippocampal neuronal inflammation and apoptosis by TbetaR-I. NeuroReport 29(2):141–146

    CAS  PubMed  Google Scholar 

  40. Estrada LD, Oliveira-Cruz L, Cabrera D (2018) Transforming growth factor beta type I role in neurodegeneration: implications for Alzheimer s disease. Curr Protein Pept Sci 19(12):1180–1188

    CAS  PubMed  Google Scholar 

  41. Cacabelos R, Barquero M, Garcia P, Alvarez XA, Varela de Seijas E (1991) Cerebrospinal fluid interleukin-1 beta (IL-1 beta) in Alzheimer's disease and neurological disorders. Methods Find Exp Clin Pharmacol 13(7):455–8

  42. Rota E, Bellone G, Rocca P, Bergamasco B, Emanuelli G, Ferrero P (2006) Increased intrathecal TGF-beta1, but not IL-12, IFN-gamma and IL-10 levels in Alzheimer’s disease patients. Neurol Sci 27(1):33–39

    CAS  PubMed  Google Scholar 

  43. Lee JH, Park DH, Back DB, Lee JY, Lee CI, Park KJ, et al (2012) Comparison of cerebrospinal fluid biomarkers between idiopathic normal pressure hydrocephalus and subarachnoid hemorrhage-induced chronic hydrocephalus: a pilot study. Med Sci Monit 18(12):PR19–25

  44. Sosvorova L, Vcelak J, Mohapl M, Vitku J, Bicikova M, Hampl R (2014) Selected pro- and anti-inflammatory cytokines in cerebrospinal fluid in normal pressure hydrocephalus. Neuro Endocrinol Lett 35(7):586–593

    PubMed  Google Scholar 

  45. Sosvorova L, Mohapl M, Vcelak J, Hill M, Vitku J, Hampl R (2015) The impact of selected cytokines in the follow-up of normal pressure hydrocephalus. Physiol Res 64(Suppl 2):S283–S290

    CAS  PubMed  Google Scholar 

  46. Tarkowski E, Tullberg M, Fredman P, Wikkelso C (2003) Normal pressure hydrocephalus triggers intrathecal production of TNF-alpha. Neurobiol Aging 24(5):707–714

    CAS  PubMed  Google Scholar 

  47. Leinonen V, Menon LG, Carroll RS, Dello Iacono D, Grevet J, Jääskeläinen JE, et al (2011) Cerebrospinal fluid biomarkers in idiopathic normal pressure hydrocephalus. Int J Alzheimer’s Dis

  48. Bianconi V, Sahebkar A, Atkin SL, Pirro M (2018) The regulation and importance of monocyte chemoattractant protein-1. Curr Opin Hematol 25(1):44–51

    CAS  PubMed  Google Scholar 

  49. Kester MI, Teunissen CE, Sutphen C, Herries EM, Ladenson JH, Xiong C et al (2015) Cerebrospinal fluid VILIP-1 and YKL-40, candidate biomarkers to diagnose, predict and monitor Alzheimer’s disease in a memory clinic cohort. Alzheimers Res Ther 7(1):59

    PubMed  PubMed Central  Google Scholar 

  50. Schirinzi T, Sancesario GM, Di Lazzaro G, D’Elia A, Imbriani P, Scalise S et al (2018) Cerebrospinal fluid biomarkers profile of idiopathic normal pressure hydrocephalus. J Neural Transm (Vienna) 125(4):673–679

    CAS  Google Scholar 

  51. Nagelhus EA, Ottersen OP (2013) Physiological roles of aquaporin-4 in brain. Physiol Rev 93(4):1543–1562

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Gastaldi M, Todisco M, Carlin G, Scaranzin S, Zardini E, Minafra B, et al (2020) AQP4 autoantibodies in patients with idiopathic normal pressure hydrocephalus. J Neuroimmunol 349:577407

  53. Nagata Y, Bundo M, Sugiura S, Kamita M, Ono M, Hattori K et al (2017) PTPRQ as a potential biomarker for idiopathic normal pressure hydrocephalus. Mol Med Rep 16(3):3034–3040

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Nagata Y, Hirayama A, Ikeda S, Shirahata A, Shoji F, Maruyama M et al (2018) Comparative analysis of cerebrospinal fluid metabolites in Alzheimer’s disease and idiopathic normal pressure hydrocephalus in a Japanese cohort. Biomark Res 6:5

    PubMed  PubMed Central  Google Scholar 

  55. Tang S, Wang X, Li W, Yang X, Li Z, Liu W et al (2017) Biallelic mutations in CFAP43 and CFAP44 cause male infertility with multiple morphological abnormalities of the sperm flagella. Am J Hum Genet 100(6):854–864

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Coutton C, Vargas AS, Amiri-Yekta A, Kherraf ZE, Ben Mustapha SF, Le Tanno P et al (2018) Mutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in Trypanosoma and human. Nat Commun 9(1):686

    PubMed  PubMed Central  Google Scholar 

  57. Lee L (2011) Mechanisms of mammalian ciliary motility: Insights from primary ciliary dyskinesia genetics. Gene 473(2):57–66

    CAS  PubMed  Google Scholar 

  58. Morimoto Y, Yoshida S, Kinoshita A, Satoh C, Mishima H, Yamaguchi N et al (2019) Nonsense mutation in CFAP43 causes normal-pressure hydrocephalus with ciliary abnormalities. Neurology 92(20):e2364–e2374

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Pelligrino DA, Xu HL, Vetri F (2010) Caffeine and the control of cerebral hemodynamics. J Alzheimers Dis 20(Suppl 1):S51-62

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Luongo L, Guida F, Imperatore R, Napolitano F, Gatta L, Cristino L et al (2014) The A1 adenosine receptor as a new player in microglia physiology. Glia 62(1):122–132

    CAS  PubMed  Google Scholar 

  61. Casati M, Arosio B, Gussago C, Ferri E, Magni L, Assolari L et al (2016) Down-regulation of adenosine A1 and A2A receptors in peripheral cells from idiopathic normal-pressure hydrocephalus patients. J Neurol Sci 361:196–199

    CAS  PubMed  Google Scholar 

  62. Asai M, Hattori C, Szabo B, Sasagawa N, Maruyama K, Tanuma S et al (2003) Putative function of ADAM9, ADAM10, and ADAM17 as APP alpha-secretase. Biochem Biophys Res Commun 301(1):231–235

    CAS  PubMed  Google Scholar 

  63. Muller UC, Zheng H (2012) Physiological functions of APP family proteins. Cold Spring Harb Perspect Med 2(2):a006288

  64. Laitera T, Kurki MI, Pursiheimo JP, Zetterberg H, Helisalmi S, Rauramaa T et al (2015) The expression of transthyretin and amyloid-beta protein precursor is altered in the brain of idiopathic normal pressure hydrocephalus patients. J Alzheimers Dis 48(4):959–968

    PubMed  Google Scholar 

  65. Wu S, Trievel RC, Rice JC (2007) Human SFMBT is a transcriptional repressor protein that selectively binds the N-terminal tail of histone H3. FEBS Lett 581(17):3289–3296

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Bonasio R, Lecona E, Reinberg D (2010) MBT domain proteins in development and disease. Semin Cell Dev Biol 21(2):221–230

    CAS  PubMed  Google Scholar 

  67. Zhang J, Bonasio R, Strino F, Kluger Y, Holloway JK, Modzelewski AJ et al (2013) SFMBT1 functions with LSD1 to regulate expression of canonical histone genes and chromatin-related factors. Genes Dev 27(7):749–766

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Kottgen A, Albrecht E, Teumer A, Vitart V, Krumsiek J, Hundertmark C et al (2013) Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat Genet 45(2):145–154

    PubMed  Google Scholar 

  69. Chung RH, Chiu YF, Hung YJ, Lee WJ, Wu KD, Chen HL et al (2017) Genome-wide copy number variation analysis identified deletions in SFMBT1 associated with fasting plasma glucose in a Han Chinese population. BMC Genomics 18(1):591

    PubMed  PubMed Central  Google Scholar 

  70. Yang HC, Liang YJ, Chen JW, Chiang KM, Chung CM, Ho HY, et al (2012) Identification of IGF1, SLC4A4, WWOX, and SFMBT1 as hypertension susceptibility genes in Han Chinese with a genome-wide gene-based association study. PLoS One 7(3):e32907

  71. Kato T, Sato H, Takahashi Y (2015) A genetic risk factor for idiopathic normal pressure hydrocephalus (iNPH). Fluids Barriers CNS 12(1)

  72. Korhonen VE, Helisalmi S, Jokinen A, Jokinen I, Lehtola JM, Oinas M, et al (2018) Copy number loss in SFMBT1 is common among Finnish and Norwegian patients with iNPH. Neurol Genet 4(6):e291

  73. Sato H, Takahashi Y, Kimihira L, Iseki C, Kato H, Suzuki Y, et al. A Segmental Copy Number Loss of the SFMBT1 Gene Is a Genetic Risk for Shunt-Responsive, Idiopathic Normal Pressure Hydrocephalus (iNPH): A Case-Control Study. PLoS One. 2016;11(11):e0166615.

  74. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ et al (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72(2):245–256

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR et al (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72(2):257–268

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Kaivorinne AL, Bode MK, Paavola L, Tuominen H, Kallio M, Renton AE et al (2013) Clinical characteristics of C9ORF72-linked frontotemporal lobar degeneration. Dement Geriatr Cogn Dis Extra 3(1):251–262

    PubMed  PubMed Central  Google Scholar 

  77. Hsiung GY, DeJesus-Hernandez M, Feldman HH, Sengdy P, Bouchard-Kerr P, Dwosh E et al (2012) Clinical and pathological features of familial frontotemporal dementia caused by C9ORF72 mutation on chromosome 9p. Brain 135(Pt 3):709–722

    PubMed  PubMed Central  Google Scholar 

  78. Nuytemans K, Bademci G, Kohli MM, Beecham GW, Wang L, Young JI et al (2013) C9ORF72 intermediate repeat copies are a significant risk factor for Parkinson disease. Ann Hum Genet 77(5):351–363

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Schottlaender LV, Polke JM, Ling H, MacDoanld ND, Tucci A, Nanji T, et al (2015) Analysis of C9orf72 repeat expansions in a large series of clinically and pathologically diagnosed cases with atypical parkinsonism. Neurobiol Aging 36(2):1221

  80. Cannas A, Solla P, Borghero G, Floris GL, Chio A, Mascia MM et al (2015) C9ORF72 intermediate repeat expansion in patients affected by atypical parkinsonian syndromes or Parkinson’s disease complicated by psychosis or dementia in a Sardinian population. J Neurol 262(11):2498–2503

    CAS  PubMed  Google Scholar 

  81. Wilke C, Pomper JK, Biskup S, Puskas C, Berg D, Synofzik M (2016) Atypical parkinsonism in C9orf72 expansions: a case report and systematic review of 45 cases from the literature. J Neurol 263(3):558–574

    PubMed  Google Scholar 

  82. Lesage S, Le Ber I, Condroyer C, Broussolle E, Gabelle A, Thobois S et al (2013) C9orf72 repeat expansions are a rare genetic cause of parkinsonism. Brain 136(Pt 2):385–391

    PubMed  Google Scholar 

  83. Cavallieri F, Mandrioli J, Rosafio F, Contardi S, Fasano A, Menozzi E et al (2017) C9ORF72 and parkinsonism: Weak link, innocent bystander, or central player in neurodegeneration? J Neurol Sci 378:49–51

    CAS  PubMed  Google Scholar 

  84. Korhonen VE, Remes AM, Helisalmi S, Rauramaa T, Sutela A, Vanninen R et al (2019) Prevalence of C9ORF72 expansion in a large series of patients with idiopathic normal-pressure hydrocephalus. Dement Geriatr Cognit Disord 47(1–2):91–103

    CAS  Google Scholar 

  85. Lehtovirta M, Soininen H, Helisalmi S, Mannermaa A, Helkala EL, Hartikainen P et al (1996) Clinical and neuropsychological characteristics in familial and sporadic Alzheimer’s disease: relation to apolipoprotein E polymorphism. Neurology 46(2):413–419

    CAS  PubMed  Google Scholar 

  86. van der Lee SJ, Wolters FJ, Ikram MK, Hofman A, Ikram MA, Amin N et al (2018) The effect of APOE and other common genetic variants on the onset of Alzheimer’s disease and dementia: a community-based cohort study. Lancet Neurol 17(5):434–444

    PubMed  Google Scholar 

  87. Savolainen S, Hurskainen H, Paljarvi L, Alafuzoff I, Vapalahti M (2002) Five-year outcome of normal pressure hydrocephalus with or without a shunt: predictive value of the clinical signs, neuropsychological evaluation and infusion test. Acta Neurochir (Wien) 144(6):515–23; discussion 23

  88. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW et al (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261(5123):921–923

    CAS  PubMed  Google Scholar 

  89. Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS et al (1993) Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A 90(5):1977–1981

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Seshadri S, Fitzpatrick AL, Ikram MA, DeStefano AL, Gudnason V, Boada M et al (2010) Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA 303(18):1832–1840

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Mahley RW, Weisgraber KH, Huang Y (2006) Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer’s disease. Proc Natl Acad Sci USA 103(15):5644–5651

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Verghese PB, Castellano JM, Holtzman DM (2011) Apolipoprotein E in Alzheimer’s disease and other neurological disorders. Lancet Neurol 10(3):241–252

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Gudmundsson G, Kristjansdottir G, Cook E, Olafsson I (2009) Association of ApoE genotype with clinical features and outcome in idiopathic normal pressure hydrocephalus (iNPH): a preliminary report. Acta Neurochir (Wien) 151(11):1511–1512

    Google Scholar 

  94. Huovinen J, Kastinen S, Komulainen S, Oinas M, Avellan C, Frantzen J et al (2016) Familial idiopathic normal pressure hydrocephalus. J Neurol Sci 368:11–18

    PubMed  Google Scholar 

  95. Laitera T, Paananen J, Helisalmi S, Sarajarvi T, Huovinen J, Laitinen M et al (2017) Effects of Alzheimer’s Disease-Associated Risk Loci on amyloid-beta accumulation in the brain of idiopathic normal pressure hydrocephalus patients. J Alzheimers Dis 55(3):995–1003

    PubMed  Google Scholar 

  96. Zhang J, Williams MA, Rigamonti D (2008) Heritable essential tremor-idiopathic normal pressure hydrocephalus (ETINPH). Am J Med Genet A 146A(4):433–439

    CAS  PubMed  Google Scholar 

  97. Zhang J, Carr CW, Rigamonti D, Badr A (2010) Genome-wide linkage scan maps ETINPH gene to chromosome 19q12–13.31. Hum Hered 69(4):262–7

  98. de Carvalho AP, Sweadner KJ, Penniston JT, Zaremba J, Liu L, Caton M et al (2004) Mutations in the Na+/K+ -ATPase alpha3 gene ATP1A3 are associated with rapid-onset dystonia parkinsonism. Neuron 43(2):169–175

    Google Scholar 

  99. Brashear A, DeLeon D, Bressman SB, Thyagarajan D, Farlow MR, Dobyns WB (1997) Rapid-onset dystonia-parkinsonism in a second family. Neurology 48(4):1066–1069

    CAS  PubMed  Google Scholar 

  100. Dobyns WB, Ozelius LJ, Kramer PL, Brashear A, Farlow MR, Perry TR et al (1993) Rapid-onset dystonia-parkinsonism. Neurology 43(12):2596–2602

    CAS  PubMed  Google Scholar 

  101. Zaremba J, Mierzewska H, Lysiak Z, Kramer P, Ozelius LJ, Brashear A (2004) Rapid-onset dystonia-parkinsonism: a fourth family consistent with linkage to chromosome 19q13. Mov Disord 19(12):1506–1510

    PubMed  Google Scholar 

  102. Hutton M, Hardy J (1997) The presenilins and Alzheimer’s disease. Hum Mol Genet 6(10):1639–1646

    CAS  PubMed  Google Scholar 

  103. Wasco W, Brook JD, Tanzi RE (1993) The amyloid precursor-like protein (APLP) gene maps to the long arm of human chromosome 19. Genomics 15(1):237–239

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Not applicable

Funding

None.

Author information

Affiliations

Authors

Contributions

FC analyzed and interpreted the patient data regarding the hematological disease and the transplant. RH performed the histological examination of the kidney, and was a major contributor in writing the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Fatemeh Afrashteh.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Afrashteh, F., Ghafoury, R. & Almasi-Doghaee, M. Cerebrospinal fluid biomarkers and genetic factors associated with normal pressure hydrocephalus and Alzheimer’s disease: a narrative review. Egypt J Med Hum Genet 23, 30 (2022). https://doi.org/10.1186/s43042-022-00247-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s43042-022-00247-3

Keywords

  • Normal pressure hydrocephalus
  • Cerebrospinal fluid biomarkers
  • Genetic biomarkers
  • Alzheimer’s disease
  • Dementia