Key points

Introduction

Idiopathic normal pressure hydrocephalus (iNPH) is a treatable cause of dementia, clinically defined by the triad of gait disturbances, cognitive decline, and urinary incontinence. Epidemiologic studies have reported iNPH prevalence rates of 1.5% in individuals aged 70 to 79 years and 5.9% among those 80 years and older. ^, Despite the potential for symptom reversal through shunt surgery, iNPH is frequently underdiagnosed and often mistaken for Alzheimer’s disease (AD) or Parkinsonian syndromes, emphasizing the critical need for reliable and specific diagnostic biomarkers. ^,

This narrative review aims to address the knowledge gap by examining all biomarkers investigated in the context of iNPH, including those traditionally associated with AD as well as other emerging biomarkers.

Discussion

We conducted a literature search on PubMed and Embase using medical subject heading keywords. Our focus was on studies quantifying diagnostic or prognostic biomarkers in the cerebrospinal fluid (CSF) or blood. We included papers that investigated probable iNPH based on widely used criteria, such as Relkin and colleagues or Nakajima and colleagues, which included healthy controls or AD or were iNPH cohorts to document shunt responsiveness. ^, Papers with secondary normal pressure hydrocephalus (NPH) included or a lack of control groups were excluded. In total 1547 papers were screened, and all included papers are summarized in Table 1 .

Table 1

A review of all papers investigating CSF or blood biomarkers in iNPH

Author, Year	Study Design	Sample Type	Participants	Diagnostic	Biomarkers Measured	Main Outcome
Said et al, 2022	Case-control	CSF	iNPH = 80, AD = 48, FTD = 34, LBD = 30	Relkin et al. 2005	Aβ1–42, Aβ1–40, t-tau, p-tau181	Aβ1–42 ↑ in iNPH compared to AD/LBD. P-tau181 ↓ in iNPH compared to AD and LBD. T-tau ↓ in iNPH compared to all other groups. Aβ1–40 and Aβ1–42/Aβ1–40 not significantly different between groups. Aβ1-42/t-tau ↑ in iNPH.
Mutoh et al, 2022	Case-control	CSF	iNPH = 19, PD = 49, control = 17	Nakajima et al. 2021	galactosylceramide, glucosylceramide, lactosylceramide subspecies	Decrease of galactosylceramide but no other glycolipids in iNPH.
Futakawa et al, 2012	Case-control	CSF	iNPH = 29, non-iNPH = 19, AD = 19	Definite iNPH: Ishiwaka 2004. Non-iNPH were shunt non-responders.	Transferrin isoforms	The Tf-2/Tf-1 index ↑ in iNPH compared to non-iNPH and AD.
Jeppsson et al, 2016	Case-control	CSF	Improved iNPH = 10, unimproved iNPH = 10, control = 20	Relkin et al. 2005. Shunt response according to iNPH scale.	Aβ1-38, Aβ1-40, Aβ1-42, APLP1-derived peptides, APL1β25, APL1β27, APL1β28, NfL, YKL-40	sAPPα, sAPPβ, Aβ1-38, Aβ1-40, Aβ1-42, and APL1β28 ↓ and APL1β25 and 27 ↑ in iNPH compared with controls. NfL and YKL-40 did not differ between groups. APL1β28/total APL1β ratio and the Aβ1-42/total Aβ ratio ↓ in iNPH compared with controls. No differences between improved and unimproved iNPH.
Li et al, 2006	Case-control	CSF	iNPH = 15, control = 12	Clinical symptoms and CT/MRI findings. Tap test performed to determine the indications for shunt surgery.	LRG, ACT, apoD, apoJ, haptoglobin-1, albumin, AMBP	LRG, ACT, apoD, apoJ, haptoglobin-1, albumin, and AMBP ↑ in iNPH.
Gastaldi et al, 2020	Case-control	CSF, serum	iNPH = 43, AD = 17, atypical parkinsonisms = 12, PSP = 6, LBD = 4, CBS = 2, FTD = 4, amyloid angiopathy = 2. Serum 43 controls.	Relkin et al. 2005 and Todisco 2020	AQP4 antibody	AQP4 IgG and IgA in serum and CSF were negative in all iNPH and controls, as well as in serum of all healthy subjects.
Taghdiri et al, 2020	Case-control	CSF	Probable iNPH = 38, Unlikely iNPH = 34, AD = 30, control = 29	Relkin et al. 2005	Aβ1–42, t-tau, p-tau181	Aβ1-42, t-tau, and p-tau were not significantly different in the probable and unlikely NPH. Aβ1-42 and p-tau were ↓ in probable NPH compared with controls. P-tau181 and t-tau were ↓ in the probable NPH compared to AD.
Grønning et al, 2023	Case-control	CSF	Improved iNPH = 81, unimproved iNPH = 38	Relkin et al. 2005. The iNPH scale Hellström used to determine shunt response	Aβ1-40, Aβ1-42, sAPPα, sAPPβ, MCP-1, NfL, neurogranin, GAP43, GFAP, YKL-40, t-tau, p-tau181	Relative increase in neurogranin is associated with postoperative improvement.
Kapaki et al, 2007	Case-control	CSF	AD = 67, iNPH = 18, control = 72	iNPH: classic triad, ventricular dilation, Evan’s index >0.3	t-tau, p-tau181, Aβ1-42	T-tau increased in iNPH and AD vs controls, Aβ1-42 decreased in both AD and iNPH vs controls, P-tau181 increased only in AD, P-tau181 (cut-off 47.4 pg/mL) most effective for discriminating iNPH from AD.
Akiba et al, 2018	Case-control	CSF	First cohort: AD = 17, iNPH = 17, control = 12, Second cohort: iNPH = 51	Definite iNPH: Mori 2012	p-tau181, Aβ1-42, Aβ1-42 toxic conformer	First cohort: P-tau higher in AD compared with iNPH and controls. Aβ1-42 was significantly lower in both AD and iNPH compared with controls. Aβ1-42 toxic conformer higher in AD compared with both iNPH and controls, with no significant difference between iNPH and controls. Change in Aβ1-42 toxic conformer ratio after shunting predicts long-term cognitive outcomes in iNPH, even in patients with low p-tau levels. Second cohort: Low-p-tau group showed significant improvement in MMSE a y postshunt, but varied outcomes at 2 y. High-p-tau181 group showed significant decline in MMSE at 2 y postshunt. In the low-p-tau181 group, the decreased-conformer subgroup maintained cognitive improvement at 2 y, while the increased-conformer subgroup showed cognitive decline.
Nagata et al, 2018	Case-control	CSF	Metabolomics = AD = 39, iNPH = 19, validation = AD = 42, iNPH = 38	Definite iNPH: Mori 2012	Comprehensive metabolomics analysis by CE-TOFMS	iNPH vs AD: 9 metabolites significant. 2 higher in AD (glycerate, N-acetylneuraminate). After regression, 4 metabolites significant: glycerate, N-acetylneuraminate higher in AD; serine, 2-hydroxybutyrate lower in AD.
Jeppsson et al, 2019	Case-control	CSF	iNPH = 82, non-iNPH disorders including AD = 295, control = 54	Relkin et al. 2005	T-tau, p-tau181, NfL, Aβ1-38, Aβ1-40, Aβ1-42, sAPPα, sAPPβ, MCP-1	iNPH vs controls: Lower P-tau181, APP-derived proteins; higher MCP-1. iNPH vs non-iNPH: Lower T-tau, P-tau181, APP-derived proteins; higher MCP-1. iNPH vs cognitive disorders: Lower T-tau, P-tau181, Aβ1-38, Aβ1-40, sAPPα, sAPPβ; similar Aβ1-42 to AD. iNPH vs movement disorders: Similar t-tau, lower p-tau181 and APP-derived proteins. Combination of T-tau, Aβ1-40, MCP-1: AUC 0.86 for iNPH vs non-iNPH, 0.92 for iNPH vs cognitive disorders.
Ray et al, 2011	Case-control	CSF	iNPH = 23, Non-NPH controls = 13	Modified Ishikawa 2004 plus elevated CSF cerebral aqueductal flow by MRI and gait improvement after large volume spinal tap.	T-tau, p-tau181, Aβ1-40, Aβ1-42, sAPPα	Decrease in total sAPP, sAPPα and Aβ1-42 in NPH vs controls. No change in t-tau or p-tau in NPH vs controls. Disease severity associated with increased p-tau181 and p-tau181/Aβ1-42.
Hoshi et al, 2023	Case-control	CSF	Depression = 52, Schizophrenia = 54, SIH = 199, Non-SIH = 20, iNPH = 60, Non-iNPH = 27, iNPH shunt-responders = 48	Nakajima et al. 2021. Comorbid AD excluded. Non-iNPH were patients who did not respond to a tap test.	Man-Tf, GlcNAc-Tf, L-PGDS, Sia-Tf	GlcNAc-Tf and L-PGDS lower in iNPH compared to non-iNPH. Despite lower levels, brain-derived markers (Man-Tf, GlcNAc-Tf, and L-PGDS) were highly correlated with each other in iNPH. Brain-derived markers increased after shunt surgery.
Mao et al, 2020	Case-control	CSF	iNPH = 27, AD = 27, Control = 18	Relkin et al. 2005	T-tau, p-tau181, NfL, Aβ1-42	AD had higher t-tau, p-tau181, and t-tau/Aβ1-42 and lower Aβ1-42 compared with controls, while iNPH had similar levels of t-tau, p-tau181, and t-tau/Aβ1-42 to controls, but reduced Aβ1-42. NfL higher in both iNPH and AD compared with controls, but was lower in iNPH than in AD.
Santangelo et al, 2017	Case-control	CSF	AD = 165, iNPH = 34, FTD = 43, LBD = 22, PSP/CBS = 19, VAD = 11, control = 32	Relkin et al. 2005	T-tau, p-tau181, Aβ1-42	Aβ1-42 was lower in NPH compared with controls, but no difference in Aβ1-42 between NPH and AD. t-tau and p-tau were lower in NPH compared to AD, and there was no difference in t-tau and p-tau181 between NPH and controls.
Kawamura et al, 2021	Case-control,cohort	CSF	iNPH Evaluation Cohort = 32, iNPH Validation Cohort = 13, AD = 16, PD = 15, PSP = 14, control = 27	Mori 2012	Aβ1-42 Toxic Conformer, AβO10–20, t-tau, p-tau181, Aβ1-38, Aβ1-40, Aβ1-42	AβO10–20 (amyloid-β oligomer containing 10–20 monomers) was higher in iNPH than in the controls, PD, and PSP groups. AβO10–20 decreased in iNPH after shunt placement and decreases in AβO10–20 were associated with better cognitive outcomes.
Pyykkö et al, 2014	Case-control	CSF	iNPH Shunt-responders = 48, iNPH nonresponders = 5, Mixed iNPH + AD = 10, AD = 16, Other Diagnoses = 23	Relkin et al. 2005	T-tau, p-tau181, NfL, Aβ1-38, Aβ1-40, Aβ1-42, sAPPα, sAPPβ, MCP-1, TNF-α, MBP, IL-8	sAPPα was lower in iNPH than in other groups independent of the presence of the brain amyloid in the brain. IL-8, MCP-1, and TNF-α not different between iNPH and AD.
Nakajima et al, 2015	Cohort	CSF	iNPH = 36	Definite iNPH: Mori 2012	p-tau181, Aβ1-38, Aβ1-42, sAPP, sAPPα, sAPPβ, L-PGDS, Cystatin-C	Preoperative levels of p-tau181, Aβ1–38/Aβ1–42, and Aβ1–42/p-tau181 could determine the cognitive prognosis of iNPH 2 y after shunt treatment.
Vanninen et al, 2023	Case-control	CSF	iNPH AD– = 98, iNPH A+ = 90, iNPH A+/τ+ = 28, iNPH τ+ = 6	Relkin et al. 2005	Aβ1-42, t-tau, p-tau181	Aβ1-42, t-tau, and p-tau181 differed between the groups, except for t-tau levels, which did not show a significant difference between the control group and the iNPH with AD pathology (iNPH A+/τ+). Using standard cutoff values for CSF biomarkers to diagnose AD in the general population proved ineffective for diagnosing AD in iNPH. P-tau181/Aβ1-42 demonstrated some value in identifying AD.
Arighi et al, 2019	Case-control	CSF	iNPH = 10, AD = 11, control = 9	Nakajima et al. 2021	Aβ1-42, t-tau, p-tau181, AQP4	Significantly reduced AQP4 in AD compared with controls. A trend of AQP4 reduction in NPH vs controls, but not statistically significant. Aβ1-42 lower in NPH vs controls.
Kim et al, 2019	Case-control	CSF	Probable iNPH = 10, Probable AD = 10, control = 8	Relkin et al. 2005	T-tau, p-tau181, Aβ1-40, Aβ1-42	Aβ1-42 lower in AD vs iNPH and controls. No difference in Aβ1-42 between iNPH and controls. Aβ1-42/Aβ1-40 was similar in iNPH and controls but was lower in AD. t-tau and p-tau181 not different between the groups.
Castaneyra-Ruiz et al, 2015	Case-control	CSF	iNPH = 6, MCI = 7, control = 11	1 to 3 neurologic symptoms suggestive of iNPH, Evan’s ratio> 0.3, no obstruction of CSF flow	TNF-α, AQP1, total protein	Total protein lower in iNPH vs controls. Total protein in MCI also lower than controls, but to a lesser degree. AQP1 and TNF-α in MCI were similar to controls. TNF-α in iNPH was higher vs controls. AQP1 in iNPH was insignificantly higher vs controls.
Tarnaris et al, 2011	Case-control	CSF	iNPH = 22 (17 favorable and 4 unfavorable outcomes)	Probable iNPH: Relkin et al. 2005.	T-tau, Aβ1-42	Both Aβ1–42 and t-tau lower in the favorable outcome group. Aβ1–42 and t-tau predicted favorable surgical outcomes at 6 mo.
Jingami et al, 2019	Case-control	CSF	iNPH = 27, AD = 27, control = 18	Probable iNPH: Relkin et al. 2005	Aβ1-42, t-tau, p-tau181, NfL	Aβ1-42 in iNPH lower than controls but higher than AD. NfL higher in iNPH and AD, but levels in iNPH were lower than AD. No differences in t-tau, p-tau181, and t-tau/Aβ1-42 between iNPH and controls.
Hoshi et al, 2021	Case-control	CSF	iNPH = 52, MCI = 42, AD = 61, PSP = 7, PD = 34, FTD = 10, DLB = 9	iNPH: Mori 2012	T-tau, p-tau181, Aβ1-40, Aβ1-42, Man-Tf	Man-Tf increased in AD and MCI vs other neurologic diseases, including iNPH. Man-Tf correlated with p-tau181.
Craven et al, 2017	Case-control	CSF	Probable iNPH = 79, 30 Lumbar (23 shunt-responsive, 7 unresponsive), 57 ventricular (38 shunt-responsive, 19 unresponsive)	Relkin et al. 2005	T-tau, Aβ1-42, total protein	Lumbar t-tau predicts postoperative improvement in mobility. t-tau lower in iNPH.
Laitera et al, 2015	Case-control	CSF	iNPH = 102	Relkin et al. 2005	sAPPα, sAPPβ, TTR	Ventricular and lumbar TTR were lower in iNPH vs controls. sAPPα and sAPPβ did not differ from controls. Alterations in TTR and APP processing are present in iNPH.
Santangeloa et al, 2019	Case-control	CSF	AD = 277, iNPH = 65, FTD = 123, LBD = 34, PSP/CBS = 19, VaD = 27	Relkin et al. 2005	Aβ1-42, t-tau, p-tau181	p-tau181/Aβ1-42 was the most accurate in differentiating AD and OTD (including iNPH). FDG-PET partially agreed with the p-tau181/Aβ1-42 in patients with a mismatch between clinical diagnoses and CSF findings.
Sosvorova et al, 2015	Case-control	CSF	iNPH = 30, control = 10	iNPH was diagnosed based on clinical symptoms, NMR, and results of a lumbar drainage test.	Cortisol, Cortisone, Dehydroepirosterone (DHEA), 7α-OH-DHEA, 7β-OH-DHEA, 7-oxo-DHEA, 16α-OH-DHEA, Aldosterone	Decreased 7α-OH-DHEA, 7β-OH-DHEA, and 7-oxo-DHEA in NPH. Reduced cortisone and increased cortisol levels could reflect altered activity of the enzyme HSD11B1. Increased aldosterone in NPH could be due to increased synthesis of aldosterone in the CNS.
Molin et al, 1990	Case-control	CSF	iNPH = 5, control = 10, probable AD = 7, multiinfarct dementia = 5	Clinical triad, occasional parkinsonism unresponsive to levodopa and not explained by other diseases, and an Evans ratio ≥ 0.30. All patients improved after placement of shunts.	Somatostatin	Somatostatin lower in iNPH.
Miyajima et al, 2013	Case-control	CSF	iNPH = 46,AD = 10,control = 8	Probable iNPH: Ishiwaka 2008	p-tau181, t-tau, Aβ1-42, sAPP, sAPPα, sAPPβ	P-tau181, t-tau, sAPP, sAPPα, sAPPβ lower in iNPH vs controls. Aβ1-42 not different between the groups. sAPPa had the highest accuracy in differentiating iNPH from AD and controls.
Yang et al, 2015	Case-control	Serum	iNPH = 104, control = 146	Relkin et al. 2005	Free T4, TSH, prolactin, FSH, LH, testosterone, estradiol, ACTH, IGF-1	iNPH had higher serum IGF-1 vs controls. iNPH men had a positive correlation between serum IGF-1 and gait, cognition, and balance scores. iNPH women had lower serum TSH vs controls.
Torretta et al, 2021	Case-control	CSF	iNPH = 24, AD = 18, control = 18	Probable iNPH: Relkin et al. 2005. MMSE score <20/30 or gait disorders secondary to other evident causes were excluded.	CSF Aβ, t-tau, p-tau181 proteins, ceramides, hexosylceramides, sphingomyelins dihydrosphingomyelins	Very long chains Cer C22:0, Cer C24:0 and Cer C24:1 and acute phase proteins, immunoglobulins and complement component fragments ↑ in iNPH. Synaptic proteins (BACE1, APP, SEZ6L and SEZ6L2); secretory proteins (CHGA, SCG3 and VGF); glycosylation proteins (POMGNT1 and DAG1); and proteins involved in lipid metabolism (APOH and LCAT) ↓ in iNPH. t-tau and p-tau181 ↑ in AD compared with controls and iNPH. Aβ levels, in iNPH slightly ↓ vs controls; Aβ ↓ in AD
Torretta et al, 2018	Case-control	CSF,serum	iNPH = 10, AD = 16, control = 10	Relkin et al. 2005	high-performance thin-layer chromatography (HPTLC) in serum MALDI mass spectrometry LC-MS in CSF	Ceramides and sphingomyelins (SMs) similar in serum of iNPH and AD vs controls. SM C24:1 ↓ in AD vs iNPH and controls; phosphatidylcholine (PC) 36:2 is ↑ in iNPH. ↑ Cer C24:0 and glucosylceramide (GlcCer) C24:0 and ↓ of sphingosine-1-phosphate (S1P) in AD vs iNPH. Aβ1-42 were pathologic in AD and normal for controls and iNPH. The same was observed for t-tau and for p-tau181.
Bissacco et al, 2024	Case-control	CSF,blood	iNPH = 38, control = 38	Nakajima et al. 2021	Blood analyzed using automated hematological analyzer Method of CSF analysis not reported	iNPH vs controls had ↑ neutrophil-to-lymphocyte ratio and neutrophils, and ↓ lymphocytes and CSF Aβ1-42. CSF t-tau and p-tau181 slightly ↓ in iNPH although not significantly.
Kuroda et al, 2022	Case-control	CSF	iNPH = 12, AD = 20, control = 10	Mori 2012	Aβ1-42, Aβ1-40, Aβ1-38, t-tau, p-tau181	Negative correlation between the lateral ventricular volume and Aβ1-38. Deep WM lesion volume was more predominant than periventricular WM lesion volume in iNPH, may indicate decreased fluid and Aβ clearance.
Yang et al, 2023	Case-control,cohort	CSF	iNPH = 48, control = 20	Nakajima 2021. Patients followed for 1 y and categorized into a gait disorder improvement and no-improvement group based on the 3-m round-trip test improvement >10%	Aβ (species not specified),t-tau,p-tau181,NfL	Lower Aβ, t-tau, and p-tau in iNPH vs controls. iNPH had higher NfL vs controls. The gait + iNPH had higher NfL vs gait- iNPH and no differences in Aβ, t-tau, and p-tau181. One y after shunting, the gait + group who showed improvement had lower NfL compared to those who did not improve.
Porru et al, 2022	Case-control	CSF	iNPH = 17 (Repeated LP postop in 10), control = 28	Probable iNPH: Relkin 2005 and tap test. A positive response defined as a 5-point increase on the Hellstrom scale.	Oxysterols including 7HOCA, 24-OH, 27-hydroxycholesterol (27-OH)	Before surgery, lower oxysterols in iNPH vs controls. After surgery, 24-OH and 7HOCA increased in iNPH.
Tullberg et al, 2007	Case-control	CSF	iNPH = 35	Gait disturbance, mental deterioration, or urinary incontinence. Enlarged ventricles on CT/MRI with Evan’s index>0.30. A lumbar CSF pressure <20 cm H2O and ventricular filling and block of convexity flow on radionuclide cisternography. In some patients with signs of other disorders the CSF tap test and rCBF measurement were performed and only patients with improvement at the tap test and a characteristic pattern on rCBF were included.	Albumin, IgG, NfL, t-tau, p-tau181, Aβ1-42,S100 B, NSE, GFAP, Sulfatide	Three months after shunt surgery, ventricular but not lumbar NfL and tau decreased, and ventricular NfL and tau correlated with improvement in gait and wakefulness. Ventricular NfL higher in patients with pathologic tau levels.
Hong et al, 2018	Case-control	CSF	iNPH = 31 (17 shunt-responsive, 14 unresponsive)	Relkin et al. 2005	Aβ(species not specified), t-tau, p-tau181	Patients who responded favorably to shunt surgery had lower preoperative p-tau/Aβ vs patients who did not.
Nakajima et al, 2018	Case-control	CSF	iNPH = 40	Mori 2012	Aβ1-42, total tau, p-tau181	Improvement in MMSE and FAB 3 y after shunt surgery in low-p-tau group (<30 pg/mL). High-p-Tau group showed limited improvement.
Nakajima et al, 2021	Case-control	CSF	Cohort 1 = iNPH = 30, AD = 12, PD = 12, control = 10 Cohort 2 = iNPH = 30, control = 27	Mori 2012	PTPRQ, p-tau181, t-tau, Aβ1-42	PTPRQ higher in both the Japanese and Finnish iNPH groups vs controls. PTPRQ elevated in patients with nonidiopathic NPH vs iNPH. No difference in PTPRQ between patients who responded to shunting and those who did not. No difference in PTPRQ between iNPH with and without AD. No difference in Aβ1-42 between groups. p-tau181 and t-tau elevated in AD vs iNPH and controls.
Migliorati et al, 2020	Case-control	CSF	iNPH = 117 (58 tap test nonresponders, 35 Shunt-responders, 15 shunt nonresponders)	Relkin et al. 2005	Aβ1-42, t-tau, p-tau181	Low t-tau, p-tau181 and Aβ1-42 in favorable surgery outcome group. Low presurgical p-tau predicts positive clinical outcomes in iNPH 2 y after shunt surgery.
Gloeckner et al, 2008	Case-control	CSF	iNPH = 13, AD = 23, CJD = 18, DLB = 23, FTD = 10, control = 19	Clinical symptoms, neuroimaging studies, and clinical improvement in the MMSE and gait after spinal tap.	Total tau, Aβ1-42, Aβ1-40, TTR	TTR decreased in AD and NPH vs controls and other dementias. Tau increased in AD, DLB, CJD, and FTD vs controls, but within the normal range in NPH. Aβ1−40 and Aβ1−42 decreased in all dementia vs controls.
Murakami et al, 2018	Case-control	CSF	iNPH = 34, non-iNPH = 15	Ishiwika 2004	Brain-type Tf, serum-type Tf, sAPP	Brain-type Tf reduced in iNPH. Brain-type Tf increased after both continuous lumbar drainage and shunt surgery in iNPH and correlate with cognitive improvement.
Abu-Rumeileh et al, 2019	Case-control	CSF	iNPH = 71, control = 50, AD = 60, VaD = 30, DLB = 35, FTD = 80	Relkin et al. 2005	Aβ1-42, Aβ1-40, t-tau, p-tau181, NfL, t-PrP	Low Aβ and tau in iNPH vs controls. Aβ1-42 lower in iNPH and AD, but the Aβ1-42/Aβ1-40 had better diagnostic accuracy in differentiating iNPH from AD. NfL elevated in iNPH.
Ågren-Wilsson et al, 2007	Case-control	CSF	iNPH = 62, SAE = 26, control = 23	Clinical picture, imaging, CSF samples available preoperatively and postoperatively.	NfL, t-tau, p-tau181, Aβ1-42	Elevated NFL in iNPH and SAE vs controls. Lower T-tau, p-tau181, Aβ1-42 in INPH vs SAE and controls. No difference in sulfatide between groups. CSF biomarkers not predictive of shunt response in iNPH.
Brettschneider et al, 2004	Case-control	CSF,serum	AD = 30, VaD = 13, FTD = 6, depression = 13, iNPH = 19, control = 15	Clinical triad, neuroimaging, positive tap test.	β trace protein, β2 microglobulin, cystatin- C	Lower β trace protein in NPH vs AD, depression, and controls. No differences in β2 microglobulin and cystatin-C levels among groups. Lower β trace protein in NPH may indicate meningeal dysfunction. No differences in serum biomarkers among groups.
Catalan et al, 1994	Case-control	CSF	iNPH = 7, controls = 10	Clinical triad, occasional parkinsonism unresponsive to levodopa and not explained by other diseases, and an Evans ratio ≥ 0.30. All patients went through ICP monitoring.	NPY	NPY reduced in INPH vs controls. No correlation between NPY and MMSE or Blessed Dementia Scale scores.
Darrow et al, 2022	Cohort	CSF	Suspected iNPH = 402 (121 underwent shunt surgery)	Suspected iNPH referred for CSF tap test. TUG 3 m used to asses improvement after tap test.	NfL, Aβ1-42, Aβ1-40, t-tau, p-tau181, LRG-1	Lower NfL, p-tau181, t-tau, and Aβ1-40 predicted long-term improvement after shunt surgery; t-tau, pTau181 and Aβ1-40 were lower in those who improved after tap test.
Jeppsson et al, 2013	Case-control	CSF	iNPH = 28, control = 20	Relkin et al. 2005	NfL, MBP, Aβ1-38, Aβ1-40, Aβ1-42, sAPPα, sAPPβ, t-tau, p-tau181, IL-8, IL-10, MCP-1	NfL and MCP-1 higher in iNPH vs controls. Aβ1-38, Aβ1-40, Aβ1-42, sAPPα, sAPPβ, t-tau, p-tau181 lower in iNPH vs controls. Postshunt (6 mo) increases in NfL, Aβ peptides, sAPP, p-tau181, albumin; decreases in MBP and t-tau. Patients improved after shunt showed greater increase in APP-derived proteins postshunt.
Jingami et al, 2015	Case-control	CSF	iNPH = 55 (46 tap test responders,9 nonresponders),AD = 20,CBS = 11,SCD = 7	Relkin et al. 2005	t-tau, p-tau181, Aβ1-42, Aβ1-40, LRG	t-tau and p-tau181 lower in iNPH vs AD, and Aβ1-42/Aβ1-40 higher in iNPH vs AD, but not significant after MMSE adjustment. iNPH tap test responders had lower t-tau than nonresponders. LRG levels not different between groups.
Jurjević et al, 2017	Case-control	CSF	iNPH = 31, PS = 28, AD = 16, control = 6	Mori 2012	miRNAs (particularly hsa-miR-4274), sAPPβ, Aβ1-42, p-tau181, α-synuclein	hsa-miR-4274 decreased in PS compared to iNPH and controls and showed high accuracy in distinguishing PS from iNPH. sAPPβ and p-tau181 higher in AD compared to iNPH and PS. Aβ1-42 lower in PS and AD compared to iNPH. α-synuclein lower in PS compared to AD.
Kamalian et al, 2024	Case-control	CSF	iNPH = 28, MCI = 38, control = 49	Relkin 2005 and improvement in the TUG 3m test 12 mo postoperatively of at least 30%.	Proteomic analysis of 3000 proteins using Olink Explore 3072 panel	13 proteins identified as potential diagnostic biomarkers for iNPH: GBP2, SPRR1B, CRYM, PODXL2, TAP1, RTN4R, RNF5, JMJD1C, B4GAT1, GAD1, CD99L2, ZNRF4, L1CAM. Most were downregulated except GBP2 and JMJD1C.
Li et al, 2007	Case-control	CSF	iNPH = 21, control = 14	Ishiwika 2004	TGF-β1, TGF-β2, TGF-β3, TGF-β type II receptor (TβR-II), LRG	TGF-β1, TβR-II, and LRG higher in iNPH vs controls. No difference in TGF-β2, but TGF-β3 not detected in either group. TβR-II correlated with LRG and TGF-β1.
Lolansen et al, 2021	Case-control	CSF	iNPH = 20 (10 shunt-responders, 10 nonresponders),control = 20	Relkin et al. 2005	92 inflammatory markers using PEA technique	11 inflammatory markers elevated in iNPH vs controls: CCL28, CCL23, CCL3, OPG, CXCL1, IL-18, IL-8, OSM, 4E-BP1, CXCL6, Flt3L but CDCP1 decreased in iNPH vs controls. No significant differences between shunt responders and nonresponders.
Madelene Braun et al, 2023	Case-control	CSF	iNPH = 72, AD = 21, MCI/AD = 21, MCI = 22, FTD = 13, control = 21	iNPH: international. AD. MCI/AD. MCI: NIA-AA. FTD: clinical with neuroimaging	56 proteins studied using Olink inflammation panel	Higher CCL4, MCP-1, CCL11 in iNPH vs controls. Lower PD-L1 in iNPH vs controls. MCP-1 higher in iNPH than all other groups. CCL4 higher in iNPH than all groups except MCI/AD. PD-L1 lower in iNPH than all groups except MCI. MCP-1, CCL4, PD-L1, and CCL11 could discriminate iNPH from other groups. MCP-1 had the highest variable importance in the model.
Markianos et al, 2009	Case-control	CSF	NPH = 19, control = 19	Relkin et al. 2005	MHPG, 5-HIAA, HVA	HVA higher in NPH. HVA/5-HIAA higher in NPH. No differences in MHPG or 5-HIAA.
Mataró et al, 2003	Cohort	CSF	iNPH = 8	Gait disturbance, cognitive deficits, or sphincter dysfunction. Evan’s index > 0.30, continuous intracranial pressure monitoring, and CSF dynamics	Galanin	Decrease in galanin after shunt surgery. Decrease in galanin correlated with improvements in attention, visuomotor speed, visuoconstructive and frontal functioning, and clinical status.
De Geus et al, 2023	Cohort	CSF	iNPH = 57, control = 68, MCI-AD = 95, DEM-AD = 72, MCI-other = 77, DEM-other = 23	Clinical symptoms and positive tap-test gait outcome after large volume lumbar puncture	Aβ1-42/Aβ1-40 ratio, p-tau181, t-tau, and peptide abundance analysis	NPH had normal Aβ1-42/40 similar to controls and non-AD, but higher than AD. p-tau181/t-tau in NPH similar to cognitively unimpaired and non-AD, but lower than AD.
Nakajima et al, 2011	Cohort	CSF	Suspected iNPH = 90 (52 underwent shunt surgery)	Mori 2001	LRG, t-tau	LRG higher in shunt responders vs nonresponders. Tau not different between groups. Patients with high LRG and low tau showed greatest cognitive improvement after shunting.
Patel et al, 2024	Cohort	CSF	Nonshunted = 245, Shunted = 109	Clinical triad, neuroimaging, positive tap test.	NPTX2, Aβ1–42, Aβ1–40, p-tau181, NfL	NPTX2 positively correlated with p-tau181 and weakly negatively correlated with gait performance and functional activities in iNPH. NPTX2 did not correlate with cognition, age, or ventriculomegaly, nor predict treatment response.
Rota et al, 2006	Case-control	CSF, serum	Probable AD = 30, Probable VaD = 19, iNPH = 14, PD = 24, control = 25	Clinical triad, enlarged ventricles, low CSF pressure, positive tap test	IL-12 (p70 heterodimer total IL-12 p40 chain), IFN-γ, IL-10, TGF-β1	No differences in IL-12, IFN-γ, and IL-10 among groups. TGF-β1 in NPH was not different from Probable AD or controls, unlike probable vascular dementia which had lower levels than probable AD. No differences in serum levels of biomarkers among groups.
Scollato et al, 2010	Cohort	CSF	iNPH = 17 (13 improved after shunt, 4 not improved)	Clinical triad, ventriculomegaly (Evan’s index>0.3) with mean ICP >9 mm Hg and/or presence of “high waves” on ICP monitoring	Proteome analysis	Overexpressed in improved group: α2HS glycoprotein, α1 antichymotrypsin, α1beta glycoprotein, Underexpressed in improved group: GFAP, apolipoproteins (AIV, J, E), complement C3c, antithrombin, α2 antiplasmin, albumin
Vanninen et al, 2021	Case-control	CSF	iNPH = 119 (No-AD = 48, Aβ = 52, Aβ+Tau = 16), control = 33	Relkin et al. 2005. Mori 2012.	LRG, Aβ1-42, t-tau, p-tau181	LRG increased in iNPH vs controls, Aβ1-42, t-tau, and p-tau181 lower in iNPH vs controls. LRG not different among iNPH subgroups (No-AD, Aβ, Aβ+Tau). Aβ1-42 lower in Aβ and Aβ+Tau groups vs No-AD group. Tau and p-tau181 increased with increasing AD pathology. CSF biomarkers did not correlate with short-term shunt response.
Weiner et al, 2023	Cohort	CSF	iNPH = 68 (55 without and 13 with comorbid neurodegenerative conditions)	Relkin et al. 2005. Nakajima et al. 2021.	Aβ1–42, t-tau, p-tau181, comprehensive proteomic analysis	Aβ1–42, p-tau181, t-tau, p-tau/Aβ1–42 showed no difference between responsive and unresponsive; Top biomarker based on iNPHGS score: FABP3, MIF, ANXA4, and B3GAT2. Top biomarker based on gait speed: ITGB1, YWHAG, OLFM2, TGFBI, and DSG2; Most promising biomarker: DSG2 correlated significantly with improvements in iNPHGS, gait speed, and cognitive measures; B3GAT2 showed the highest positive correlation and predictive value with iNPHGS improvement. MIF had the strongest negative correlation with iNPHGS improvement; DSG2 was the only biomarker showing significant correlations with both cognitive measures and iNPHGS.
Yang et al, 2023	Cohort	CSF	iNPH = 63, control = 20	Nakajima et al. 2021	Aβ1-42, t-tau, p-tau181, sTREM2, YKL-40	Lower Aβ1-42, p-tau, and t-tau and higher sTREM2 in iNPH vs controls. Higher p-tau, t-tau, and YKL-40 in nonresponders vs responders. Lower p-tau associated with gait improvement and higher Aβ1-42 and lower sTREM2 associated with cognitive improvement after shunt surgery. No difference in YKL-40 between iNPH and control groups. sTREM2 correlated with Aβ1-42 in the controls, but not in iNPH.

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