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Neuropathologic changes of Alzheimer disease (AD) including Aβ accumulation and neuroinflammation are frequently observed in the cerebral cortex of patients with idiopathic normal pressure hydrocephalus (iNPH). We created an automated analysis platform to quantify Aβ load and reactive microglia in the vicinity of Aβ plaques and to evaluate their association with cognitive outcome in cortical biopsies of patients with iNPH obtained at the time of shunting. Aiforia Create deep learning software was used on whole slide images of Iba1/4G8 double immunostained frontal cortical biopsies of 120 shunted iNPH patients to identify Iba1-positive microglia somas and Aβ areas, respectively. Dementia, AD clinical syndrome (ACS), and Clinical Dementia Rating Global score (CDR-GS) were evaluated retrospectively after a median follow-up of 4.4 years. Deep learning artificial intelligence yielded excellent (>95%) precision for tissue, Aβ, and microglia somas. Using an age-adjusted model, higher Aβ coverage predicted the development of dementia, the diagnosis of ACS, and more severe memory impairment by CDR-GS whereas measured microglial densities and Aβ-related microglia did not correlate with cognitive outcome in these patients. Therefore, cognitive outcome seems to be hampered by higher Aβ coverage in cortical biopsies in shunted iNPH patients but is not correlated with densities of surrounding microglia., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc.)

Introduction: Normal pressure hydrocephalus (NPH) patients undergoing cortical shunting frequently show early Alzheimer's disease (AD) pathology on cortical biopsy, which is predictive of progression to clinical AD. The objective of this study was to use samples from this cohort to identify cerebrospinal fluid  (CSF) biomarkers for AD-related central nervous system (CNS) pathophysiologic changes using tissue and fluids with early pathology, free of post mortem artifact., Methods: We analyzed Simoa, proteomic, and metabolomic CSF data from 81 patients with previously documented pathologic and transcriptomic changes., Results: AD pathology on biopsy correlates with CSF β-amyloid-42/40, neurofilament light chain (NfL), and phospho-tau-181(p-tau181)/β-amyloid-42, while several gene expression modules correlate with NfL. Proteomic analysis highlights seven core proteins that correlate with pathology and gene expression changes on biopsy, and metabolomic analysis of CSF identifies disease-relevant groups that correlate with biopsy data., Discussion: As additional biomarkers are added to AD diagnostic panels, our work provides insight into the CNS pathophysiology these markers are tracking., Highlights: AD CSF biomarkers correlate with CNS pathology and transcriptomic changes. Seven proteins correlate with CNS pathology and gene expression changes. Inflammatory and neuronal gene expression changes correlate with YKL-40 and NPTXR, respectively. CSF metabolomic analysis identifies pathways that correlate with biopsy data. Fatty acid metabolic pathways correlate with β-amyloid pathology., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: To investigate the association between white matter changes and ventricular expansion in idiopathic normal pressure hydrocephalus (iNPH) based on diffusion spectrum imaging (DSI)., Methods: We included 32 patients with iNPH who underwent DSI using a 3T MRI scanner. The lateral ventricles were manually segmented, and ventricular volumes were measured. Two methods were utilised in the study: manual region-of-interest (ROI) delineation and tract diffusion profile analysis. General fractional anisotropy (GFA) and fractional anisotropy (FA) were extracted in different white matter regions, including the bilateral internal capsule (anterior and posterior limbs) and corpus callosum (body, genu, and splenium) with manual ROI delineation. The 18 main tracts in the brain of each patient were extracted; the diffusion metrics of 100 equidistant nodes on each fibre were calculated, and Spearman's correlation coefficient was used to determine the correlation between diffusion measures and ventricular volume of iNPH patients., Results: The GFA and FA of all ROI showed no significant correlation with lateral ventricular volume. However, in the tract diffusion profile analysis, lateral ventricular volume was positively correlated with part of the cingulum bundle, left corticospinal tract, and bilateral thalamic radiation posterior, whereas it was negatively correlated with the bilateral cingulum parahippocampal (all p < 0.05)., Conclusions: The effect of ventricular enlargement in iNPH on some white matter fibre tracts around the ventricles was limited and polarizing, and most white matter fibre tract integrity changes were not associated with ventricular enlargement; this reflects that multiple pathological mechanisms may have been combined to cause white matter alterations in iNPH., (© 2024. The Author(s).)

Clinical improvement following neurosurgical cerebrospinal fluid shunting for presumed idiopathic normal pressure hydrocephalus is variable. Idiopathic normal pressure hydrocephalus patients may have undetected Alzheimer's disease-related cortical pathology that confounds diagnosis and clinical outcomes. In this study, we sought to determine the utility of cortical tissue immuno-analysis in predicting shunting outcomes in idiopathic normal pressure hydrocephalus patients. We performed a pooled analysis using a systematic review as well as analysis of a new, original patient cohort. Of the 2707 screened studies, 3 studies with a total of 229 idiopathic normal pressure hydrocephalus patients were selected for inclusion in this meta-analysis alongside our original cohort. Pooled statistics of shunting outcomes for the 229 idiopathic normal pressure hydrocephalus patients and our new cohort of 36 idiopathic normal pressure hydrocephalus patients revealed that patients with Aβ + pathology were significantly more likely to exhibit shunt nonresponsiveness than patients with negative pathology. Idiopathic normal pressure hydrocephalus patients with Alzheimer's disease -related cortical pathology may be at a higher risk of treatment facing unfavorable outcomes following cerebrospinal fluid shunting. Thus, cortical tissue analysis from living patients may be a useful diagnostic and prognostic adjunct for patients with presumed idiopathic normal pressure hydrocephalus and potentially other neurodegenerative conditions affecting the cerebral cortex., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Determination of the ventricle size in idiopathic normal pressure hydrocephalus (iNPH) is essential for diagnosis and follow-up of shunt results. Fully automated segmentation methods are anticipated to optimize the accuracy and time efficiency of ventricular volume measurements. We evaluated the accuracy of preoperative and postoperative ventricular volume measurements in iNPH by a magnetic resonance imaging (MRI)-based licensed software for fully automated quantitative assessment., Methods: Forty-eight patients diagnosed with iNPH were retrospectively analyzed. All patients received a ventriculoperitoneal shunt and had symptom grading and routine MRI preoperatively and 3-6 months postoperatively. Ventricular volumes, generated by fully automated T1-weighted imaging volume sequence segmentation, were compared with semiautomatic measurements and routine radiologic reports. The relation of postoperative ventricular size change to clinical response was evaluated., Results: Fully automated segmentation was achieved in 95% of the MRIs, but showed various rates of 8 minor segmentation errors. The correlation between both segmentation methods was very strong (r >0.9) and the agreement very good using Bland-Altman analyses. The ventricular volumes differed significantly between semiautomated and fully automated segmentations and between preoperative and postoperative MRI. The fully automated method systematically overestimated the ventricles by a median 15 mL preoperatively and 14 mL postoperatively; hence, the magnitudes of volume changes were equivalent. Routine radiologic reports of ventricular size changes were inaccurate in 51% and lacked association with treatment response. Objectively measured ventricular volume changes correlated moderately with postoperative clinical improvement., Conclusions: A fully automated volumetric method permits reliable evaluation of preoperative ventriculomegaly and postoperative ventricular volume change in idiopathic normal pressure hydrocephalus., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Amyloid-β (Aβ) is one of the hallmark lesions of Alzheimer's disease (AD). During the disease process, Aβ undergoes biochemical changes, producing toxic Aβ variants, proposed to be detected within the neurons. Idiopathic normal pressure hydrocephalus (iNPH) causes cognitive impairment, gait, and urinary symptoms in elderly, that can be reversed by a ventriculo-peritoneal shunt. Majority of iNPH subjects display different Aβ variants in their brain biopsies, obtained during shunting., Objective: To study the cellular compartmentalization of different Aβ variants in brain biopsies from iNPH subjects., Methods: We studied the cellular localization of different proteoforms of Aβ using antibodies towards different amino acid sequences or post-translational modifications of Aβ, including clones 4G8, 6F/3D, unmodified- (7H3D6), pyroglutamylated- (N3pE), phosphorylated-(1E4E11) Aβ and Aβ protein precursor (AβPP), in brain biopsies from 3 iNPH subjects, using immunohistochemistry and light microscopy (LM), light microscopy on semi-thin sections (LMst), and electron microscopy (EM)., Results: In LM all Aβ variants were detected. In LMst and EM, the Aβ 4G8, 6F/3D, and the pyroglutamylated Aβ were detected. The AβPP was visualized by all methods. The Aβ labelling was located extracellularly with no specific signal within the intracellular compartment, whereas the AβPP was seen both intra- and extracellularly., Conclusions: The Aβ markers displayed extracellular localization when visualized by three assessment techniques, reflecting the pathological extracellular accumulation of Aβ in the human brain. No intracellular Aβ pathology was seen. AβPP was visualized in intra- and extracellularly, which corresponds to the localization of the protein in the membranes of cells and organelles.

Introduction: The relationship between neurochemical changes and outcome after shunt surgery in idiopathic normal pressure hydrocephalus (iNPH), a treatable dementia and gait disorder, is unclear. We used baseline ventricular CSF to explore associations to outcome, after shunting, of biomarkers selected to reflect a range of pathophysiological processes., Methods: In 119 consecutive patients with iNPH, the iNPH scale was used before and after shunt surgery to quantify outcome. Ventricular CSF was collected perioperatively and analyzed for biomarkers of astrogliosis, axonal, amyloid and tau pathology, and synaptic dysfunction: glial fibrillary acidic protein (GFAP), chitinase-3-like protein 1 (YKL40/CHI3L1), monocyte chemoattractant protein-1 (MCP-1) neurofilament light (NfL), amyloid beta 38 (Aβ38), Aβ40, Aβ42, amyloid beta 42/40 ratio (Aβ42/40), soluble amyloid precursor protein alfa (sAPPα), sAPPβ, total tau (T-tau), phosphorylated tau (P-tau), growth-associated protein 43 (GAP43), and neurogranin., Results: The neurogranin concentration was higher in improved (68%) compared to unimproved patients (median 365 ng/L (IQR 186-544) vs 330 (205-456); p = 0.046). A linear regression model controlled for age, sex and vascular risk factors including neurogranin, T-tau, and GFAP, resulted in adjusted R 2  = 0.06, p = 0.047. The Aβ42/40 ratio was bimodally distributed across all samples, as well as in the subgroups of improved and unimproved patients but did not contribute to outcome prediction. The preoperative MMSE score was lower within the low Aβ ratio group (median 25, IQR 23-28) compared to the high subgroup (26, 24-29) (p = 0.028). The T-Tau x Aβ40/42 ratio and P-tau x Aβ40/42 ratio did not contribute to shunt response prediction. The prevalence of vascular risk factors did not affect shunt response., Discussion: A higher preoperative ventricular CSF level of neurogranin, which is a postsynaptic marker, may signal a favorable postoperative outcome. Concentrations of a panel of ventricular CSF biomarkers explained only 6% of the variability in outcome. Evidence of amyloid or tau pathology did not affect the outcome., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objective: The presence of tightened sulci in the high-convexities (THC) is a key morphological feature for the diagnosis of idiopathic normal pressure hydrocephalus (iNPH), but the exact localization of THC has yet to be defined. The purpose of this study was to define THC and compare its volume, percentage, and index between iNPH patients and healthy controls., Methods: According to the THC definition, the high-convexity part of the subarachnoid space was segmented and measured the volume and percentage from the 3D T1-weighted and T2-weighted magnetic resonance images in 43 patients with iNPH and 138 healthy controls., Results: THC was defined as a decrease in the high-convexity part of the subarachnoid space located above the body of the lateral ventricles, with anterior end on the coronal plane perpendicular to the anterior commissure-posterior commissure (AC-PC) line passing through the front edge of the genu of corpus callosum, the posterior end in the bilateral posterior parts of the callosomarginal sulci, and the lateral end at 3 cm from the midline on the coronal plane perpendicular to the AC-PC line passing through the midpoint between AC and PC. Compared to the volume and volume percentage, the high-convexity part of the subarachnoid space volume per ventricular volume ratio < 0.6 was the most detectable index of THC on both 3D T1-weighted and T2-weighted magnetic resonance images., Conclusions: To improve the diagnostic accuracy of iNPH, the definition of THC was clarified, and high-convexity part of the subarachnoid space volume per ventricular volume ratio <0.6 proposed as the best index for THC detection in this study., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Focally enlarged sulci (FES) are areas of proposed extraventricular fluid entrapment that may occur within idiopathic normal pressure hydrocephalus (iNPH) with radiographic evidence of disproportionately enlarged subarachnoid-space hydrocephalus (DESH), and should be differentiated from atrophy., Purpose: To evaluate for change in FES size and pituitary height after shunt placement in iNPH., Study Type: Retrospective., Subjects: A total of 125 iNPH patients who underwent shunt surgery and 40 age-matched controls., Field Strength/sequence: 1.5 T and 3 T. Axial T2w FLAIR, 3D T1w MPRAGE, 2D sagittal T1w., Assessment: FES were measured in three dimensions and volume was estimated by assuming an ellipsoid shape. Pituitary gland height was measured in the mid third of the gland in iNPH patients and controls., Statistical Tests: Wilcoxon signed-rank test for comparisons between MRI measurements; Wilcoxon rank sum test for comparison of cases/controls. Significance level was P < 0.05., Results: Fifty percent of the patients had FES. FES volume significantly decreased between the pre and first postshunt MRI by a median of 303 mm 3 or 30.0%. Pituitary gland size significantly increased by 0.48 mm or 14.4%. FES decreased significantly by 190 mm 3 or 23.1% and pituitary gland size increased significantly by 0.25 mm or 6% between the first and last postshunt MRI., Data Conclusion: Decrease in size of FES after shunt placement provides further evidence that these regions are due to disordered cerebrospinal fluid (CSF) dynamics and should not be misinterpreted as atrophy. A relatively smaller pituitary gland in iNPH patients that normalizes after shunt is a less-well recognized feature of altered CSF dynamics., Evidence Level: 3 TECHNICAL EFFICACY: Stage 2., (© 2022 International Society for Magnetic Resonance in Medicine.)

Abstract: Idiopathic normal pressure hydrocephalus (NPH) is a syndrome that affects elderly people and is characterized by excessive accumulation of cerebrospinal fluid in the brain ventricles. Diagnosis is based on the evaluation of clinical symptoms, which consists of a classic triad (Hakim triad), gait disturbances, cognitive impairment, and urinary incontinence. However, this complete triad is not always seen; therefore, it is difficult to make the diagnosis. NPH can be divided into primary or idiopathic NPH and secondary NPH. Diagnostic criteria for NPH remain a topic of discussion; however, the development of diagnostic techniques has brought new opportunities for diagnosis. The aim of this review is to present an overview of neurophysiological and neuropsychological approaches to support the clinical evaluation of patients with NPH and contribute to the differential diagnosis of NPH and dementia, as the clinical symptoms of NPH may resemble other neurodegenerative disorders., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

There are a variety of neurodegenerative diseases that require differentiation from idiopathic normal pressure hydrocephalus(iNPH), including Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, frontotemporal dementia, progressive supranuclear palsy, and corticobasal degeneration. As the clinical features and structural imaging findings of these diseases may overlap with iNPH, biomarkers reflecting disease-specific pathology are necessary for differential diagnosis. In addition, these diseases often coexist with iNPH in elderly patients, and it is important to confirm the coexistence of their pathology even in cases clinically diagnosed as iNPH. This review provides an overview of established and emerging biomarkers for neurodegenerative diseases.

Background: Alzheimer's disease (AD) and normal pressure hydrocephalus (NPH) commonly coexist., Objective: We aimed to characterize an overlapping syndrome of AD and NPH that presents with gait disturbance, ventriculomegaly on magnetic resonance imaging, and significant amyloid deposition on positron emission tomography (PET)., Methods: Of 114 patients who underwent cerebrospinal fluid (CSF) drainage for a possible diagnosis of NPH between 2015 and 2020 in Samsung Medical Center, we identified 24 patients (21.1%) with the NPH patients with amyloid deposition on PET, which we referred to as hydrocephalic AD in this study. We compared their clinical and imaging findings with those of 123 typical AD without hydrocephalic signs/symptoms. We also investigated the frequency and potential predictors of the tap test response in hydrocephalic AD., Results: Evans' index was 0.36±0.03, and a disproportionately enlarged subarachnoid space was present in 54.2% of the hydrocephalic AD patients. The mean age (75.2±7.3 years) and the APOE4 frequency (68.2%) did not differ from those of AD controls. However, the hydrocephalic AD patients showed better memory and language performance, and a thinner cingulate cortex. About 42% of the hydrocephalic AD patients responded to the tap test, of whom seven underwent shunt surgery. Cognition did not improve, whereas gait improved after shunt surgery in all., Conclusion: Hydrocephalic AD has different neuropsychological and imaging characteristics from typical AD. Future studies are warranted to further investigate the effect of CSF removal on their clinical course and to elucidate the pathophysiological interaction between amyloid and NPH.

Background: Idiopathic normal pressure hydrocephalus (iNPH) is often misdiagnosed as Alzheimer's disease (AD) due to overlapping pathophysiology and similar imaging characteristics, including ventricular enlargement and increased white matter lesions (WMLs)., Objective: To compare the extent and distribution of WMLs directly between iNPH and AD and examine the association with underlying pathophysiology., Methods: Twelve patients with iNPH (mean age: 78.08 years; 5 females), 20 with AD (mean age: 75.40 years; 13 females), and 10 normal cognition (NC) participants (mean age: 76.60 years; 7 females) were recruited. The extent and distribution of WMLs and the lateral ventricular volume (LV-V) were evaluated on MRI using voxel-based morphometry analysis. Concentrations of cerebrospinal fluid biomarkers, such as amyloid-β protein (Aβ)42, Aβ40, Aβ38, and tau species, were also measured. Risk factors for small vessel disease (SVD) were assessed by blood examination and medical records., Results: The periventricular WML volume (PWML-V) and deep WML volume (DWML-V) were significantly larger in iNPH than in AD and NC. The DWML-V was dominant in iNPH, while the PWML-V was dominant in AD and NC. GM-V was significantly smaller in AD than in iNPH and NC. The LV-V positively correlated with WML-V in all participants. There was a significant negative correlation between LV-V and Aβ38 in iNPH. Furthermore, there was no significant difference in SVD risk factors between the groups., Conclusion: The differences in the extent and distribution of WMLs between iNPH and AD, especially predominance of DWML-V over PWML-V in iNPH, may reflect decreased fluid and Aβ clearance.

Background and Purpose: While changes in ventricular and extraventricular CSF spaces have been studied following shunt placement in patients with idiopathic normal pressure hydrocephalus, regional changes in cortical volumes have not. These changes are important to better inform disease pathophysiology and evaluation for copathology. The purpose of this work is to investigate changes in ventricular and cortical volumes in patients with idiopathic normal pressure hydrocephalus following ventriculoperitoneal shunt placement., Materials and Methods: This is a retrospective cohort study of patients with idiopathic normal pressure hydrocephalus who underwent 3D T1-weighted MR imaging before and after ventriculoperitoneal shunt placement. Images were analyzed using tensor-based morphometry with symmetric normalization to determine the percentage change in ventricular and regional cortical volumes. Ventricular volume changes were assessed using the Wilcoxon signed rank test, and cortical volume changes, using a linear mixed-effects model ( P  < .05)., Results: The study included 22 patients (5 women/17 men; mean age, 73 [SD, 6] years). Ventricular volume decreased after shunt placement with a mean change of -15.4% ( P  < .001). Measured cortical volume across all participants and cortical ROIs showed a mean percentage increase of 1.4% ( P  < .001). ROIs near the vertex showed the greatest percentage increase in volume after shunt placement, with smaller decreases in volume in the medial temporal lobes., Conclusions: Overall, cortical volumes mildly increased after shunt placement in patients with idiopathic normal pressure hydrocephalus with the greatest increases in regions near the vertex, indicating postshunt decompression of the cortex and sulci. Ventricular volumes showed an expected decrease after shunt placement., (© 2021 by American Journal of Neuroradiology.)

Periventricular white matter changes are common in patients with idiopathic normal pressure hydrocephalus (iNPH) and considered to represent focally elevated interstitial fluid. We compared diffusion measures in periventricular hyperintensities in patients with imaging features of iNPH to patients without. The hypothesis is that periventricular hyperintensities in patients with presumed iNPH show higher water content than in patients without imaging features of iNPH. 21 patients with iNPH Radscale 7-12 ("high probability of iNPH") and 10 patients with iNPH Radscale 2-4 ("low probability of iNPH") were examined with a neurodegeneration imaging protocol including a diffusion microstructure imaging sequence. Periventricular hyperintensities and deep white matter hyperintensities were segmented and diffusion measures were compared. In patients with imaging features of iNPH, the free water content in periventricular hyperintensities was significantly higher compared to the control group (p = 0.005). This effect was also detectable in deep white matter hyperintensities (p = 0.024). Total brain volumes and total gray or white matter volumes did not differ between the groups. Periventricular cap free water fraction was highly discriminative regarding patients with presumed iNPH and controls with an ROC AUC of 0.933. Quantitative diffusion microstructure imaging shows elevated water content in periventricular hyperintensities in patients with imaging features of iNPH, which could be the imaging correlate for pathologic fluid accumulation and may be used as an imaging biomarker in the future., (© 2021. The Author(s).)

Brain aquaporin 1 (AQP1) and AQP4 are involved in cerebrospinal fluid (CSF) homeostasis and might participate in the origin of hydrocephalus. Studies have shown alterations of perivascular AQP4 expression in idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer's disease (AD). Due to the overlapping of clinical signs between iNPH and certain neurological conditions, mainly AD, specific biomarkers might improve the diagnostic accuracy for iNPH. The goal of the present study was to analyze and quantify the presence of AQP1 and AQP4 in the CSF of patients with iNPH and AD to determine whether these proteins can be used as biomarkers of iNPH. We examined AQP1 and AQP4 protein levels in the CSF of 179 participants (88 women) classified into 5 groups: possible iNPH (81 participants), hydrocephalus associated with other neurological disorders (13 participants), AD (41 participants), non-AD dementia (32 participants) and healthy controls (12 participants). We recorded each participant's demographic and clinical variables and indicated, when available in the clinical history, the record of cardiovascular and respiratory complications. An ELISA showed virtually no AQP content in the CSF. Information on the vascular risk factors (available for 61 patients) confirmed some type of vascular risk factor in 86% of the patients with possible iNPH and 58% of the patients with AD. In conclusion, the ELISA analysis showed insufficient sensitivity to detect the presence of AQP1 and AQP4 in CSF, ruling out the possible use of these proteins as biomarkers for diagnosing iNPH., Competing Interests: The authors have declared that no competing interests exist.

Early Alzheimer's disease (AD) pathology can be found in cortical biopsies taken during shunt placement for Normal Pressure Hydrocephalus. This represents an opportunity to study early AD pathology in living patients. Here we report RNA-seq data on 106 cortical biopsies from this patient population. A restricted set of genes correlate with AD pathology in these biopsies, and co-expression network analysis demonstrates an evolution from microglial homeostasis to a disease-associated microglial phenotype in conjunction with increasing AD pathologic burden, along with a subset of additional astrocytic and neuronal genes that accompany these changes. Further analysis demonstrates that these correlations are driven by patients that report mild cognitive symptoms, despite similar levels of biopsy β-amyloid and tau pathology in comparison to patients who report no cognitive symptoms. Taken together, these findings highlight a restricted set of microglial and non-microglial genes that correlate with early AD pathology in the setting of subjective cognitive decline., (© 2021. The Author(s).)

Aim: To investigate changes in olfactory bulb (OB) volume in patients with idiopathic normal-pressure hydrocephalus (NPH)., Materials and Methods: This multicentric retrospective study included a test group of 23 patients with NPH (10 male and 13 female patients) and a control group of 27 healthy participants without hydrocephalus. The OB volume in all participants had been measured using cranial magnetic resonance imaging (MRI). In the NPH group, positivity for disproportionately enlarged subarachnoid space hydrocephalus (DESH) was also evaluated., Results: The OB volumes of the NPH group (R 38.29 ± 9.34 mm 3 and L37.52 ± 9.59 mm 3 ) were significantly lower than those of the control group (R 45.87 ± 7.33 mm 3 and L48.41 ± 7.62 mm 3 ) bilaterally. There were no significant differences between right and left OB volumes in the NPH group. Nine of the 23 patients were DESH positive and 14 were DESH negative. There were no significant differences between OB volumes of the DESH positive and DESH vpatients in the NPH group. In both groups, there was a positive correlation between right and left OB volumes. There were no significant correlations between OB volumes and age or gender. In the NPH group, there were no significant correlations between DESH positivity and OB volumes., Conclusion: OB volume decrease and olfactory problems should be taken into account in idiopathic NPH patients. When expanded ventricles and decreased OB volume are observed at cranial MRI, a diagnosis of idiopathic NPH should be considered., (Copyright © 2021 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Background: Although there may theoretically be a disturbance in the eye or the visual pathways due to abnormal cerebrospinal fluid (CSF) dynamics in idiopathic normal pressure hydrocephalus (iNPH), it has not been studied systemically. Optical coherence tomography (OCT) is a noninvasive, reproducible procedure for quantitative and qualitative analysis of retinal morphology., Methods: OCT was used to study the eye fundus before and after a CSF tap test in patients with iNPH compared with healthy individuals (HIs). Twelve patients with iNPH (6 females and 6 males) with a median age of 76 years (64-84 years) and 21 HIs (11 females and 10 males) with a median age of 73 years (64-79 years) were included. The patients underwent neurological, cognitive, and physiotherapeutic evaluation. Brain magnetic resonance imaging, CSF tap test via lumbar puncture, and subsequently CSF analysis were performed. OCT was performed before and after CSF removal. HIs underwent OCT once., Results: The patients had significantly reduced retinal ganglion cell layer thickness 71 μm (56-81 μm) compared with the HIs, 79.5 μm (72-90 μm) (P = 0.001), but no significant changes were observed before or after the CSF tap test. All patients improved in motor function in a 10-m walk test after the CSF tap test. The median CSF pressure was 15 and 1 cm H 2 O, respectively, before and after lumbar puncture with removal of median 43.5 mL CSF., Conclusions: This pilot study shows OCT findings that differ from HIs and implies a rational for becoming a valuable tool in the diagnosis of iNPH. Further studies are warranted to elucidate the pathology of the retina in iNPH., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Stepwise occurrence of biochemically modified amyloid-β (Aβ) in the brain of subjects with Alzheimer's disease (AD) has been suggested to be of significance for cognitive impairment. Our previous reports have shown that Aβ is observed in 63% of all subjects with idiopathic normal pressure hydrocephalus (iNPH) suggesting that the majority of iNPH subjects with Aβ are indeed also suffering from AD., Objective: We assessed the occurrence of biochemically modified Aβ variants, in vivo, in subjects with iNPH and in a cohort of postmortem brain samples from patients with dementia., Methods: We assessed Aβ proteins in 127 diagnostic brain biopsies obtained from subjects with iNPH and in a cohort of subjects with dementia by means of immunohistochemistry., Results: The pyroglutamylated Aβ (pyAβ) precedes the aggregation of phosphorylated Aβ (pAβ) during the AD neuropathological change progression; moreover, these modified variants of Aβ correlate with hyperphosphorylated tau in the frontal cortical area of human brain. Our results confirm the existence of the suggested biochemical stages of Aβ aggregation that might be of significance for neurodegeneration leading to cognitive impairment., Conclusion: The observation that both pyAβ and pAβ are seen in vivo in iNPH subjects is intriguing. It has been reported that most of the iNPH subjects with Aβ in the brain biopsy indeed develop AD with time. Based on our current and previous results, it is clinically merited to obtain a diagnostic biopsy from a subject with iNPH. When Aβ is observed in the biopsy, the biochemical characterization is of interest.

Primary endpoint of this single-centre, prospective consecutive cohort study was to evaluate DESH score, CA, CSS and Evans index of suspected iNPH patients against the reference standard of lumbar infusion test (LIT) and external lumbar drainage (ELD) in prediction of gait response after VP shunt implantation in patients with idiopathic normal pressure hydrocephalus (iNPH). Patients were assigned to NPH and non-NPH groups based on LIT and ELD results. Age-matched controls were added for group comparison. 32 NPH, 46 non-NPH and 15 control subjects were enrolled in the study. There were significant differences in mean preoperative DESH scores of NPH, non-NPH and control groups (6.3 ± 2.3 ([±SD]) (range 2-10) vs 4.5 ± 2.4 (range 0-10) vs 1.0 ± 1.2 (range 0-4)). Differences in mean CA and Evans index were not significant between NPH and non-NPH groups. CSS showed 62.5% sensitivity, 60.87% specificity, 52.63% PPV and 70% NPV for differentiation of NPH and non-NPH groups. A CA of 68 degrees had 48.49% sensitivity, 76.09% specificity, 59.26% PPV 67.31% NPV and DESH score of 4 had 93.75% sensitivity, 41.30% specificity, 52.63% PPV and 90.48% NPV for differentiation between NPH and non-NPH groups. The groups of probable iNPH patients with gait impairment diagnosed by high DESH score or positive functional testing did not overlap and DESH score did not correlate with gait improvement after ELD. DESH score should not be used as a simple diagnostic or prognostic marker of iNPH and we could not confirm the benefit of measurement of callosal angle and cingulate sulcus sign., Competing Interests: Conflicts of interests All authors certify that they have no affiliations with or involvement in any organisation or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Longitudinal changes in cerebrospinal fluid (CSF) biomarkers are seldom studied. Furthermore, data on biomarker gradient between lumbar (L-) and ventricular (V-) compartments seems to be discordant., Objective: To examine alteration of CSF biomarkers reflecting Alzheimer's disease (AD)-related amyloid-β (Aβ) aggregation, tau pathology, neurodegeneration, and early synaptic degeneration by CSF shunt surgery in idiopathic normal pressure hydrocephalus (iNPH) in relation to AD-related changes in brain biopsy. In addition, biomarker levels in L- and V-CSF were compared., Methods: L-CSF was collected prior to shunt placement and, together with V-CSF, 3-73 months after surgery. Thereafter, additional CSF sampling took place at 3, 6, and 18 months after the baseline sample from 26 iNPH patients with confirmed Aβ plaques in frontal cortical brain biopsy and 13 iNPH patients without Aβ pathology. CSF Amyloid-β42 (Aβ42), total tau (T-tau), phosphorylated tau (P-tau181), neurofilament light (NFL), and neurogranin (NRGN) were analyzed with customized ELISAs., Results: All biomarkers but Aβ42 increased notably by 140-810% in L-CSF after CSF diversion and then stabilized. Aβ42 instead showed divergent longitudinal decrease between Aβ-positive and -negative patients in L-CSF, and thereafter increase in Aβ-negative iNPH patients in both L- and V-CSF. All five biomarkers correlated highly between V-CSF and L-CSF (Aβ42 R = 0.87, T-tau R = 0.83, P-tau R = 0.92, NFL R = 0.94, NRGN R = 0.9; all p < 0.0001) but were systematically lower in V-CSF (Aβ42 14 %, T-tau 22%, P-tau 20%, NFL 32%, NRGN 19%). With APOE genotype-grouping, only Aβ42 showed higher concentration in non-carriers of allele ɛ4., Conclusion: Longitudinal follow up shows that after an initial post-surgery increase, T-tau, P-tau, and NRGN are stable in iNPH patients regardless of brain biopsy Aβ pathology, while NFL normalized toward its pre-shunt levels. Aβ42 as biomarker seems to be the least affected by the surgical procedure or shunt and may be the best predictor of AD risk in iNPH patients. All biomarker concentrations were lower in V- than L-CSF yet showing strong correlations.

We investigated differences in cortical thickness between idiopathic normal-pressure hydrocephalus (INPH) patients and healthy controls. We also explored whether a relationship exists between cortical thinning and gait disturbance in INPH patients. Forty-nine INPH patients and 26 healthy controls were imaged with MRI, including 3-dimensional volumetric images, for automated surface-based cortical thickness analysis across the entire brain. Compared with age- and gender-matched healthy controls, unexpectedly, INPH patients showed statistically significant cortical thickening mainly in areas located in the high convexity of the frontal, parietal, and occipital regions. Additionally, cortical thinning mainly in temporal and orbitofrontal regions was observed in the INPH group relative to the control group. The Gait Status Scale (GSS) scores were negatively correlated with cortical thickness in the medial orbital part of the superior frontal gyrus, gyrus rectus, superior temporal gyrus, temporal pole, and insula. A distinctive pattern of cortical thickness changes was found in INPH patients. We cautiously suggest that cortical thickening in INPH can result from reactive gliosis. Further, our results support the hypothesis that cortical thinning in INPH can result from neuronal degeneration. In addition, cortical thinning can play an important role in gait disturbances in INPH patients.

Background: Primary ciliary dyskinesia (PCD) is a highly heterogeneous genetic disorder caused by defects in motile cilia. The hallmark features of PCD are the chronic infections of the respiratory tract, moreover, clinical manifestations include also laterality defects and risk of male infertility. Clinical phenotypes of PCD are the result of mutations in genes encoding components of axonema or factors involved in axonemal assembly. Recent studies have identified over 45 PCD-associated genes, therefore, molecular analysis represents a powerful diagnostic tool to confirm and uncover new genetic causes of this rare disease., Case Presentation: Here, we describe a female infant of Moroccan origin with normal pressure hydrocephalus (NPH) in addition to most common PCD symptoms. Transmission Electron Microscopy (TEM) and molecular tests, such as a Next generation Sequencing panel and a custom array CGH, were performed for diagnosis of PCD. TEM revealed outer dynein arm (ODA) defects, whilst molecular analyses detected a novel 6,9 kb microdeletion in DNAI2 gene., Conclusions: Since DNAI2 mutations are very rare, this case report contributes to better delineate the important role of DNAI2 as causative of PCD phenotype, suggesting, furthermore, that the variations in DNAI2 may be as a new genetic risk factor for NPH. Indeed, although the association of hydrocephalus with PCD has been well documented, however, only a small number of human patients show this defect. Furthermore, this study highlights the importance of high-throughput technologies in advancing our understanding of heterogeneous genetic disorders.

The association between morphology of the brain and symptoms of suspected idiopathic normal pressure hydrocephalus (iNPH) is largely unknown. We investigated how ventricular expansion (width of the temporal horns [TH], callosal angle [CA], and Evans' index [EI]) related to symptom severity in suspected iNPH. Participants (n = 168; 74.9 years ± SD 6.7; 55% females) from the general population underwent neurological examination, computed tomography, and neuropsychological testing. Multiple linear regression analysis revealed that wide TH was independently associated with all examined iNPH symptoms (p < 0.01) except for fine-motor performance, whereas a narrow CA only was associated to specific motor and cognitive functions (p < 0.05). TH and EI correlated significantly with incontinence (r s 0.17 and r s 0.16; p < 0.05). In conclusion, wide TH was significantly associated with most iNPH-symptoms. This finding potentially reflects the complex nature of the hippocampus, however further studies are needed to demonstrate functional connectivity.

Introduction: Core symptomatology in idiopathic normal pressure hydrocephalus (iNPH) points at dysfunction in the mesencephalon and pons indicating pathological changes in these regions, but only a few studies have addressed the issue. The aim of this study was to investigate diffusion (ADC) and perfusion patterns pre- and postoperatively in these areas in iNPH., Methods: Twenty iNPH patients and 15 healthy controls were included. Patients underwent a clinical examination and brain MRI pre- and 3-6 months postoperatively. The MRI-scan included diffusion and dynamic susceptibility contrast perfusion weighted sequences. Regions of interest in the mesencephalon and pons were drawn on a FLAIR sequence and co-registered to ADC maps and perfusion data., Results: There were no significant differences in pre or postoperative ADC compared to the control group, however postoperative ADC increased by 10% (p = 0.026) in the mesencephalon and 6% (p = 0.016) in the pons in all patients and also in the subgroup of shunt responders by 11% (p = 0.021) and 4% (p = 0.020), respectively. Preoperative relative cerebral blood flow (rCBF) was similar in iNPH patients and controls. Postoperatively, rCBF increased in shunt responders by 6% (p = 0.02) in the mesencephalon and 11% (p = 0.004) in the pons. This increase correlated with the degree of clinical improvement (rs = 0.80, p = 0.031 and rs = 0.66, p = 0.021, respectively)., Conclusion: The postoperative increase in ADC and the correlation between postoperative increase in rCBF and clinical improvement in the mesencephalon and pons shown in this study point at an involvement of these areas in the core pathophysiology and its reversibility in iNPH., Competing Interests: The authors have declared that no competing interests exist.

Recently, age-related timing dissociation between the superficial and deep venous systems has been observed; this was particularly pronounced in patients with normal pressure hydrocephalus, suggesting a common mechanism of ventriculomegaly. Establishing the relationship between venous drainage and ventricular enlargement would be clinically relevant and could provide insight into the mechanisms underlying brain ageing. To investigate a possible link between venous drainage and ventriculomegaly in both normal ageing and pathological conditions, we compared 225 healthy subjects (137 males and 88 females) and 71 traumatic brain injury patients of varying ages (53 males and 18 females) using MRI-based volumetry and a novel perfusion-timing analysis. Volumetry, focusing on the CSF space, revealed that the sulcal space and ventricular size presented different lifespan profiles with age; the latter presented a quadratic, rather than linear, pattern of increase. The venous timing shift slightly preceded this change, supporting a role for venous drainage in ventriculomegaly. In traumatic brain injury, a small but significant disease effect, similar to idiopathic normal pressure hydrocephalus, was found in venous timing, but it tended to decrease with age at injury, suggesting an overlapping mechanism with normal ageing. Structural bias due to, or a direct causative role of ventriculomegaly was unlikely to play a dominant role, because of the low correlation between venous timing and ventricular size after adjustment for age in both patients and controls. Since post-traumatic hydrocephalus can be asymptomatic and occasionally overlooked, the observation suggested a link between venous drainage and CSF accumulation. Thus, hydrocephalus, involving venous insufficiency, may be a part of normal ageing, can be detected non-invasively, and is potentially treatable. Further investigation into the clinical application of this new marker of venous function is therefore warranted., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Purpose: The pathophysiology of idiopathic normal pressure hydrocephalus (iNPH) has not been completely clarified. We investigated the brain structure in iNPH using automatic ventricular volumetry, single-tensor diffusion tensor imaging (DTI) and bi-tensor free-water (FW) imaging analyses while focusing on cognitive impairments before and after lumboperitoneal shunt surgery., Materials and Methods: This retrospective study included 12 iNPH patients with structural magnetic resonance imaging (MRI) and diffusion MRI (dMRI) on a 3T-MRI scanner who underwent neuropsychological assessments before and after shunting and 8 healthy controls. Ventricular volumetry was conducted on structural MRI datasets using FreeSurfer. Ventricular volume was compared pre- and postoperatively. Correlation analyses were performed between ventricular volume or volume change and neuropsychological scores or score change. Tract-based spatial statistics were performed using dMRI datasets for group analyses between iNPH and controls and between pre- and post-surgery iNPH patients and for correlation analyses using neuropsychological scores. Tract-specific analyses were performed in the anterior thalamic radiation (ATR), followed by comparison and correlation analyses., Results: The third ventricular volume was significantly decreased after shunting; its volume reduction negatively correlated with a neuropsychological improvement. Compared with controls, iNPH patients had lower fractional anisotropy and higher axial, radial, and mean diffusivities, and FW in the periventricular white matter including ATR, resulting in no difference in FW-corrected indices. Single-tensor DTI indices partially correlated with neuropsychological improvements, while FW-corrected indices had no correlations., Conclusion: Third ventricle enlargement is possibly linked to cognitive impairment and FW imaging possibly provides better white matter characterization in iNPH., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Idiopathic normal pressure hydrocephalus (iNPH) is a prevalent reversible neurological disorder characterized by impaired locomotion, cognition and urinary control with ventriculomegaly. Symptoms can be relieved with cerebrospinal fluid drainage, which makes iNPH the leading cause of reversible dementia. Because of a limited understanding of pathophysiological mechanisms, unspecific symptoms and the high prevalence of comorbidity (i.e. Alzheimer's disease), iNPH is largely underdiagnosed. For these reasons, there is an urgent need for developing noninvasive quantitative biomarkers for iNPH diagnosis and prognosis. Structural and functional changes of brain circuits in relation to symptoms and treatment response are expected to deliver major advances in this direction. We review structural and functional brain connectivity findings in iNPH and complement those findings with iNPH symptom meta-analyses in healthy populations. Our goal is to reinforce our conceptualization of iNPH as to brain network mechanisms and foster the development of new hypotheses for future research and treatment options., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Various MRI markers have been applied to support the diagnosis of progressive supranuclear palsy (PSP), such as midbrain diameter and surface, superior cerebellar peduncle (SCP) width, midbrain to pons (m/p) diameter and surface ratio and the Magnetic Resonance Parkinsonism Index (MRPI). These markers provide excellent diagnostic accuracy in discriminating Richardson's syndrome from other causes of Parkinsonism. Idiopathic normal pressure hydrocephalus (iNPH) may mimic Richardson's syndrome, particularly in cases of subtle opthalmokinetic abnormalities. The aim of this study was to compare these MRI markers in PSP and iNPH and examine their diagnostic accuracy., Materials and Methods: Forty-three patients with probable PSP, 17 patients with iNPH, and 29 controls were included. Midbrain diameter and surface, SCP width, m/p diameter and surface ratio and the MRPI were recorded. The "hummingbird sign," "morning glory sign" and "mickey mouse sign" were also evaluated. Analysis of covariance, chi-squared test, and ROC curve analysis were used as appropriate., Results: All MRI measurements differed significantly among the three study groups. Comparison of PSP and iNPH patients produced the following significant differences: midbrain diameter (P < .0001), m/p diameter ratio (P < .0001), SCP width (P = .050), and MRPI (P = .049). None of these markers produced combined high (>80%) specificity and sensitivity. Qualitative MRI signs were specific, but lacked sensitivity., Discussion: Midbrain morphology in iNPH may resemble that of PSP. Established MRI markers of midbrain and SCP atrophy cannot confidently differentiate PSP from iNPH. MRI markers do not provide combined high sensitivity and specificity for the differential diagnosis of PSP from iNPH., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Approximately 10% of dementia patients have idiopathic normal pressure hydrocephalus (iNPH), an expansion of the cerebrospinal fluid (CSF)-filled brain ventricles. iNPH and Alzheimer's disease (AD) both exhibit sleep disturbances, build-up of brain metabolic wastes and amyloid-β (Aβ) plaques, perivascular reactive astrogliosis, and mislocalization of astrocyte aquaporin-4 (AQP4). The glia-lymphatic (glymphatic) system facilitates brain fluid clearance and waste removal during sleep via glia-supported perivascular channels. Human studies have implicated impaired glymphatic function in both AD and iNPH. Continued investigation into the role of glymphatic system biology in AD and iNPH models could lead to new strategies to improve brain health by restoring homeostatic brain metabolism and CSF dynamics., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Aim: Idiopathic normal pressure hydrocephalus (iNPH) is one subtype of dementia characterized by cerebrospinal fluid (CSF) disturbance, but with unknown cause. We recently reported that frontal cortex biopsies of iNPH patients disclosed degenerative alterations of the capillary basement membrane, including degenerated pericyte processes. Given that pericyte degeneration is associated with blood-brain barrier (BBB) dysfunction, the present study was undertaken to examine whether BBB leakage of blood proteins can be revealed by light microscopy (LM) immunohistochemistry in iNPH., Methods: The study included cortical brain tissue specimens from 14 reference (REF) subjects undergoing neurosurgery for epilepsy, aneurysm or tumor, and 45 iNPH patients. Dysfunction of the BBB was measured semi-quantitatively as area percentage extravasated fibrin(ogen) in cerebral cortical layers I, II and III. The degree of fibrin(ogen) extravasation was also correlated with expression of glial fibrillary acidic protein (GFAP), aquaporin-4 (AQP4), dystrophin 71 (Dp71) and Cluster of Differentiation 68 (CD68)., Results: The study disclosed extravasation of fibrin(ogen) in 4/14 REF subjects and in 45/45 iNPH patients, the percentage area of fibrin(ogen) was significantly higher in iNPH than REF cortical specimens. Diffuse, less prominent fibrin(ogen) extravasation was seen in the subcortical white matter of one iNPH individual. Increasing degree of fibrinogen extravasation in cerebral cortex was significantly associated with increasing degree of astrogliosis and with reduced expression of perivascular AQP4 and Dp71., Conclusions: The present results provide evidence of BBB dysfunction in iNPH. The BBB leakage of blood proteins may render for impaired neurovascular units in iNPH patients., (Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: A growing body of evidence suggests that the accumulation of amyloid-β and tau (HPτ) in the brain of patients with the dementia subtype idiopathic normal pressure hydrocephalus (iNPH) is associated with delayed extravascular clearance of metabolic waste. Whether also clearance of intracellular debris is affected in these patients needs to be examined. Hypothetically, defective extra- and intra-cellular clearance of metabolites may be instrumental in the neurodegeneration and dementia characterizing iNPH. This study explores whether iNPH is associated with altered mitochondria phenotype in neurons and astrocytes., Methods: Cortical brain biopsies of 9 reference (REF) individuals and 30 iNPH patients were analyzed for subcellular distribution and morphology of mitochondria using transmission electron microscopy. In neuronal soma of REF and iNPH patients, we identified normal, pathological and clustered mitochondria, mitochondria-endoplasmic reticulum contact sites and autophagic vacuoles. We also differentiated normal and pathological mitochondria in pre- and post-synaptic nerve terminals, as well as in astrocytic endfoot processes towards vessels., Results: We found a high prevalence of pathological mitochondria in neuronal soma and pre- and post-synaptic terminals, as well as increased mitochondrial clustering, and altered number of mitochondria-endoplasmic reticulum contact sites in iNPH. Non-fused autophagic vacuoles were more abundant in neuronal soma of iNPH patients, suggestive of cellular clearance failure. Moreover, the length of postsynaptic densities was reduced in iNPH, potentially related to reduced synaptic activity. In astrocytic endfoot processes, we also found increased number, area and area fraction of pathological mitochondria in iNPH patients. The proportion of pathological mitochondria correlated significantly with increasing degree of astrogliosis and reduced perivascular expression of aquaporin-4 (AQP4), assessed by light microscopy immunohistochemistry., Conclusion: Our results provide evidence of mitochondrial pathology and signs of impaired cellular clearance in iNPH patients. The results indicate that iNPH is a neurodegenerative disease with close similarity to Alzheimer's disease.

Disproportionately enlarged subarachnoid-space hydrocephalus (DESH), a feature of normal pressure hydrocephalus (NPH), is often misinterpreted as cortical atrophy. We report a 67-year-old man with features of NPH but not diagnosed because radiographic findings were interpreted as cortical atrophy. Autopsy showed findings consistent with NPH and no neurodegenerative disease. The second patient with DESH underwent shunt surgery. Entrapped fluid diminished after the surgery, confirming this is not atrophy, but due to a CSF dynamic process. Patients with DESH have tight sulci adjacent to the entrapped fluid pockets, distinguishing it from cortical atrophy. 18F-Fluorodeoxyglucose PET can help differentiate DESH from cortical atrophy.

Here, we assessed unique brain tissue samples, obtained from living subjects with idiopathic Normal Pressure Hydrocephalus (iNPH). Our cohort of 95 subjects with age ranging from 75 to 79 years, displayed a high prevalence of β-amyloid (Aβ) and hyperphosphorylated τ (HPτ) pathology (63 and 61%, respectively) in a frontal cortex biopsy obtained during shunt operation. These lesions, i.e., Alzheimer's Disease Neuropathologic Change (ADNC), increased within 5 years and were more frequent in females. The extent of HPτ pathology was sparse, primarily seen as neurites and stained dots. Noteworthy, concomitant pathology was seen in 49% of the whole cohort, indicating a severity of ADNC corresponding to a low/intermediate level following the current recommendations. This observation is predictable as based on previous publications a substantial number of subjects with iNPH over time develop AD. Thus, iNPH can be considered as a model of AD. We noted a surprisingly remarkable neuronal preservation assessing Neuronal Nuclei (NeuN) in parallel with a substantial depletion of matrix/neuropil. This finding is intriguing as it suggests that loss of matrix/neuropil might be one of the first lesion of ADNC but also a hallmark lesion of iNPH. The latter observation is in line with the enlarged ventricles, a cardinal feature of iNPH. Furthermore, a positive correlation was observed between the extent of Aβ and NeuN but only in females indicating a neuronal preservation even when Aβ pathology is present. The assessment of a surgical biopsy as described here is certainly informative and thus it is surprising that a neuropathologic assessment in the setting of iNPH, while inserting a shunt, is seldom performed. Here, we observed ADNC and surprisingly remarkable neuronal preservation in a substantial number of iNPH subjects. Thus, these subjects allow us to observe the natural course of the disease and give us an opportunity for intervention at the earliest stages of AD, prior to severe neuronal damage.

Objective: To identify genes related to normal-pressure hydrocephalus (NPH) in one Japanese family with several members with NPH., Methods: We performed whole-exome sequencing (WES) on a Japanese family with multiple individuals with NPH and identified a candidate gene. Then we generated knockout mouse using CRISPR/Cas9 to confirm the effect of the candidate gene on the pathogenesis of hydrocephalus., Results: In WES, we identified a loss-of-function variant in CFAP43 that segregated with the disease. CFAP43 encoding cilia- and flagella-associated protein is preferentially expressed in the testis. Recent studies have revealed that mutations in this gene cause male infertility owing to morphologic abnormalities of sperm flagella. We knocked out mouse ortholog Cfap43 using CRISPR/Cas9 technology, resulting in Cfap43 -deficient mice that exhibited a hydrocephalus phenotype with morphologic abnormality of motile cilia., Conclusion: Our results strongly suggest that CFAP43 is responsible for morphologic or movement abnormalities of cilia in the brain that result in NPH., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background and Purpose: Ventricular enlargement in elderly raises a challenging differential diagnosis to physicians. While Alzheimer's disease is the most common form of dementia, idiopathic normal pressure hydrocephalus (iNPH) constitutes a potentially reversible syndrome. iNPH has a unique pathophysiology pertaining to cerebrospinal fluid (CSF) dynamics and periventricular white matter. We aimed to determine the effects of iNPH on periventricular white matter bundles and to further characterize its ventricular and sulcal CSF distribution by using diffusion tensor tractography (DTT) and CSF volumetrics on high resolution T1-weighted magnetic resonance imaging data., Methods: Deterministic DTT and validated volumetric parcellation were performed on 20 healthy elderly, 13 Alzheimer's disease (AD), and 9 iNPH patients. The superior thalamic radiation, corticospinal tract, and dentatorubrothalamic tract were traced and quantified using DTI studio software. Cloud-based volumetric parcellation was also performed on 138 healthy subjects across the lifespan, 13 AD, and 9 iNPH-patients. Ventricular and sulcal CSF volumes in the three groups were compared., Results: Combining increased mean diffusivity of the superior thalamic radiation with ventricular volume resulted in clear separation of iNPH from the AD and age-matched healthy subject groups. Additionally, ventricular to sulcal CSF ratio, utilizing fully automated methods, was significantly greater in the iNPH patients compared to AD and healthy age-matched controls., Conclusions: Combined microstructural (DTT) and macrostructural (ventricular volume) changes is a promising radiological approach in studying ventriculomegaly. Automated estimation of the disproportionate ventricular and sulcal CSF ratio in patients presenting with ventriculomegaly may be important as radiologic markers in differentiating iNPH from other causes of ventriculomegaly., (© 2018 by the American Society of Neuroimaging.)

Objectives: The pathological bases for the cognitive and neuropsychiatric symptoms in normal pressure hydrocephalus (NPH) have not been elucidated. However, the symptoms may indicate dysfunction of subcortical regions. Previously, volume reductions of subcortical deep grey matter (SDGM) structures have been observed in NPH patients. The present study used automated segmentation methods to investigate whether SDGM structure volumes are associated with cognitive and neuropsychiatric measures., Methods: Fourteen NPH patients and eight healthy controls were included in the study. Patients completed neuropsychological tests of general cognition, verbal learning and memory, verbal fluency and measures of apathy and depression pre- and postshunt surgery. Additionally, patients underwent 3 Tesla T1-weighted magnetic resonance imaging at baseline and 6 months postoperatively. Controls were scanned once. SDGM structure volumes were estimated using automated segmentation (FSL FIRST). Since displacement of the caudate nuclei occurred for some patients due to ventriculomegaly, patient caudate volumes were also estimated using manual tracing. Group differences in SDGM structure volumes were investigated, as well as associations between volumes and cognitive and neuropsychiatric measures in patients., Results: Volumes of the caudate, thalamus, putamen, pallidum, hippocampus and nucleus accumbens (NAcc) were significantly reduced in the NPH patients compared to controls. In the NPH group, smaller caudate and NAcc volumes were associated with poorer performance on neuropsychological tests and increased severity of neuropsychiatric symptoms, while reduced volume of the pallidum was associated with better performance on the MMSE and reduced apathy., Conclusions: Striatal volume loss appears to be associated with cognitive and neuropsychiatric changes in NPH., (© 2018 The Authors. Acta Neurologica Scandinavica Published by John Wiley & Sons Ltd.)

We examined the potential association of idiopathic normal pressure hydrocephalus (iNPH) with the generation of normal-tension glaucoma (NTG), to explore possible relationships between intracranial pressure (ICP) and the presence of glaucoma, and to compare disc morphology of NTG patients with or without iNPH. We investigated 20 iNPH patients, examined the prevalence of glaucoma, and compared the optic discs of NTG patients with iNPH (n = 11) and age-matched NTG patients without iNPH (n = 16). All data were collected prior to the treatment of iNPH, to eliminate the possibility that the treatment may have contributed to the progression of NTG. The diagnoses of NTG were made using visual field data, intraocular pressure measurements, fundoscopy, and optical coherence tomography (OCT). Using OCT, the optic nerve disc depth was also measured. The ICP was higher in the iNPH with NTG compared to iNPH without NTG (p = 0.0425), and the cupping depths of the discs of NTG patients with iNPH were significantly shallower compared with those of NTG patients without iNPH (p = 0.0097). Based on the difference in cupping depth, NTG patients with iNPH may have a different morphology from typical glaucoma patients, which could in turn reflect a different pathogenesis compared to NTG patients without iNPH.

Background and Purpose: Several studies have evaluated the use of MR imaging markers for the prediction of outcome after shunt surgery in idiopathic normal pressure hydrocephalus with conflicting results. Our aim was to investigate the predictive value of a number of earlier proposed morphologic MR imaging markers in a large group of patients with idiopathic normal pressure hydrocephalus., Materials and Methods: One hundred sixty-eight patients (mean age, 70 ± 9.3 years) with idiopathic normal pressure hydrocephalus, subjected to standardized quantification of clinical symptoms before and after shunt surgery, were included in the study. Outcome was calculated using a composite score. Preoperative T1, FLAIR, and flow-sensitive images were analyzed regarding the presence of 13 different morphologic MR imaging markers., Results: The median Evans index was 0.41 (interquartile range, 0.37-0.44). All patients had an aqueductal flow void sign present and white matter hyperintensities. The median callosal angle was 68.8° (interquartile range, 57.7°-80.8°). Dilated Sylvian fissures were found in 69%; focally dilated sulci, in 25%; and widening of the interhemispheric fissure, in 55%. Obliteration of the sulci at the convexity was found in 36%, and 36% of patients were characterized as having disproportionately enlarged subarachnoid space hydrocephalus. Sixty-eight percent of patients improved after surgery. None of the investigated MR imaging markers were significant predictors of improvement after shunt surgery., Conclusions: Disproportionately enlarged subarachnoid space hydrocephalus, a small callosal angle, and the other MR imaging markers evaluated in this study should not be used to exclude patients from shunt surgery. These markers, though they may be indicative of idiopathic normal pressure hydrocephalus, do not seem to be a part of the mechanisms connected to the reversibility of the syndrome., (© 2019 by American Journal of Neuroradiology.)

Aim: To analyze specific changes in brain tissue of patients with idiopathic normal pressure hydrocephalus at cellular and subcellular levels., Material and Methods: Brain biopsies from 32 patients with idiopathic normal pressure hydrocephalus were investigated by light and electron microscopy. Biopsies were made in 3 points (the cortex, subcortical and periventricular white matter during ventricular catheter positioning)., Results: A number of pathological features of idiopathic normal pressure hydrocephalus were identified. Most frequent were the exhaustion of brain tissue, enlargement of perivascular spaces, aseptic necrosis, and amyloid and Lewy body's formation., Conclusion: The changes in brain tissue of patients with idiopathic normal pressure hydrocephalus transform our views on its mechanisms. It becomes clear that idiopathic normal pressure hydrocephalus is part of common neurodegenerative process that has characteristic features affecting clinical manifestations of the disease.

Idiopathic normal pressure hydrocephalus (iNPH) is a subtype of dementia that may be successfully treated with cerebrospinal fluid (CSF) diversion. Recently, magnetic resonance imaging (MRI) using a MRI contrast agent as a CSF tracer revealed impaired clearance of the CSF tracer from various brain regions such as the entorhinal cortex of iNPH patients. Hampered clearance of waste solutes, for example, soluble amyloid-β, may underlie neurodegeneration and dementia in iNPH. The goal of the present study was to explore whether iNPH is associated with altered subcellular distribution of aquaporin-4 (AQP4) water channels, which is reported to facilitate CSF circulation and paravascular glymphatic drainage of metabolites from the brain parenchyma. Cortical brain biopsies of 30 iNPH patients and 12 reference individuals were subjected to AQP4 immunogold cytochemistry. Electron microscopy revealed significantly reduced density of AQP4 water channels in astrocytic endfoot membranes along cortical microvessels in patients with iNPH versus reference subjects. There was a significant positive correlation between density of AQP4 toward endothelial cells (perivascular) and toward parenchyma, but the reduced density of AQP4 toward parenchyma was not significant in iNPH. We conclude that perivascular AQP4 expression is attenuated in iNPH, potentially contributing to impaired glymphatic circulation, and waste clearance, and subsequent neurodegeneration. Hence, restoring normal perivascular AQP4 distribution may emerge as a novel treatment strategy for iNPH., (© 2018 Wiley Periodicals, Inc.)

Background: Idiopathic normal pressure hydrocephalus (iNPH) is frequently associated with concomitant amyloid-β (Aβ) pathology., Objective: To compare the [11C]PIB PET uptake in the patients with suspected iNPH to Aβ and hyperphosphorylated-tau (HPτ) in the right frontal cortical biopsy, the cerebrospinal fluid (CSF) Aβ, the response to a CSF shunt, and the final clinical diagnosis of Alzheimer's disease (AD)., Methods: Patients (n = 21) from Kuopio NPH Registry (http://www.uef.fi/nph) with intraventricular pressure monitoring, immunostaining for Aβ and HPτ in the right frontal cortical biopsies, and a Mini-Mental State Examination and a Clinical Dementia Rating underwent [11C]PIB PET. Aβ, total tau, and Pτ181 were measured by ELISA from the ventricular (n = 15) and the lumbar (n = 9) CSF. Response to the shunt was seen in 13 out of the 15 shunted patients. AD was diagnosed in 8 patients during a median follow-up of 6 years (mean 7.3±2.4 years, range 3-1)., Results: [11C]PIB uptake in the right frontal cortex (ρ= 0.60, p < 0.01) and the combined neocortical [11C]PIB uptake score (ρ= 0.61, p < 0.01) were associated with a higher Aβ load in the right frontal cortical biopsy. Excluding one (1/15) outlier, [11C]PIB uptake was also associated with the ventricular CSF Aβ (ρ= -0.58, p = 0.03)., Conclusions: The findings show that [11C]PIB PET can reliably detect simultaneous amyloid pathology among the iNPH patients. Further studies will show whether amyloid PET could predict a clinical response to the shunt operation. In addition, the presence of Aβ pathology in the patients with iNPH might also warrant treatment with current AD drugs.

Numerous brain disorders are associated with ventriculomegaly, including both neuro-degenerative diseases and cerebrospinal fluid disorders. Detailed evaluation of the ventricular system is important for these conditions to help understand the pathogenesis of ventricular enlargement and elucidate novel patterns of ventriculomegaly that can be associated with different diseases. One such disease is normal pressure hydrocephalus (NPH), a chronic form of hydrocephalus in older adults that causes dementia. Automatic parcellation of the ventricular system into its sub-compartments in patients with ventriculomegaly is quite challenging due to the large variation of the ventricle shape and size. Conventional brain labeling methods are time-consuming and often fail to identify the boundaries of the enlarged ventricles. We propose a modified 3D U-Net method to perform accurate ventricular parcellation, even with grossly enlarged ventricles, from magnetic resonance images (MRIs). We validated our method on a data set of healthy controls as well as a cohort of 95 patients with NPH with mild to severe ventriculomegaly and compared with several state-of-the-art segmentation methods. On the healthy data set, the proposed network achieved mean Dice similarity coefficient (DSC) of 0.895 ± 0.03 for the ventricular system. On the NPH data set, we achieved mean DSC of 0.973 ± 0.02, which is significantly (p < 0.005) higher than four state-of-the-art segmentation methods we compared with. Furthermore, the typical processing time on CPU-base implementation of the proposed method is 2 min, which is much lower than the several hours required by the other methods. Results indicate that our method provides: 1) highly robust parcellation of the ventricular system that is comparable in accuracy to state-of-the-art methods on healthy controls; 2) greater robustness and significantly more accurate results on cases of ventricular enlargement; and 3) a tool that enables computation of novel imaging biomarkers for dilated ventricular spaces that characterize the ventricular system., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

OBJECTIVE Postoperative decrease in ventricle size is usually not detectable either by visual assessment or by measuring the Evans index in patients with idiopathic normal pressure hydrocephalus (iNPH). The aim of the present study was to investigate whether the angle between the lateral ventricles (the callosal angle [CA]) increases and ventricular volume decreases after shunt surgery in patients with iNPH. METHODS Magnetic resonance imaging of the brain was performed before and 3 months after shunt surgery in 18 patients with iNPH. The CA and Evans index were measured on T1-weighted 3D MR images, and ventricular volume contralateral to the shunt valve was measured with quantitative MRI. RESULTS The CA was larger postoperatively (mean 78°, 95% CI 69°-87°) than preoperatively (mean 67°, 95% CI 60°-73°; p < 0.001). The volume of the lateral ventricle contralateral to the shunt valve decreased from 73 ml (95% CI 66-80 ml) preoperatively to 63 ml (95% CI 54-72 ml) postoperatively (p < 0.001). The Evans index was 0.365 (95% CI 0.35-0.38) preoperatively and 0.358 (95% CI 0.34-0.38) postoperatively (p < 0.05). Postoperative change of CA showed a negative correlation with change of ventricular volume (r = -0.76, p < 0.01). CONCLUSIONS In this sample of patients with iNPH, the CA increased and ventricular volume decreased after shunt surgery. The relative difference was most pronounced for the CA, indicating that this accessible, noninvasive radiological marker should be evaluated further as an indirect method to determine shunt function in patients with iNPH.

Objective: The authors conducted a study to test if the cortical brain tissue levels of soluble amyloid beta (Aβ) reflect the propensity of cortical Aβ aggregate formation and may be an additional factor predicting surgical outcome following idiopathic normal pressure hydrocephalus (iNPH) treatment., Methods: Highly selective ELISAs (enzyme-linked immunosorbent assays) were used to quantify soluble Aβ40, Aβ42, and neurotoxic Aβ oligomers/protofibrils, associated with Aβ aggregation, in cortical biopsy samples obtained in patients with iNPH (n = 20), sampled during ventriculoperitoneal (VP) shunt surgery. Patients underwent pre- and postoperative (3-month) clinical assessment with a modified iNPH scale. The preoperative CSF biomarkers and the levels of soluble and insoluble Aβ species in cortical biopsy samples were analyzed for their association with a favorable outcome following the VP shunt procedure, defined as a ≥ 5-point increase in the iNPH scale., Results: The brain tissue levels of Aβ42 were negatively correlated with CSF Aβ42 (Spearman’s r = -0.53, p < 0.05). The Aβ40, Aβ42, and Aβ oligomer/protofibril levels in cortical biopsy samples were higher in patients with insoluble cortical Aβ aggregates (p < 0.05). The preoperative CSF Aβ42 levels were similar in patients responding (n = 11) and not responding (n = 9) to VP shunt treatment at 3 months postsurgery. In contrast, the presence of cortical Aβ aggregates and high brain tissue Aβ42 levels were associated with a poor outcome following VP shunt treatment (p < 0.05)., Conclusions: Brain tissue measurements of soluble Aβ species are feasible. Since high Aβ42 levels in cortical biopsy samples obtained in patients with iNPH indicated a poor surgical outcome, tissue levels of Aβ species may be associated with the clinical response to shunt treatment.

Purpose: The purpose of this study was to elucidate the specific regional cerebral blood flow (rCBF) alterations for idiopathic normal pressure hydrocephalus (iNPH) by comparing the proportional rCBF and gray matter change from those of a normal database at the same point of SPECT and MRI examinations., Methods: Thirty subjects with iNPH underwent both CBF SPECT and MRI. After normalization, voxel-wise two-sample t tests between patients and 11 normal controls were conducted to compare the regional alteration in the gray matter density and rCBF., Results: The rCBF reduction and the gray matter decrease were seen in almost similar regions surrounding Sylvian fissure, the left parietotemporal region and frontal lobes, whereas we did not find rCBF increase at the top of the high convexity, where the increase of the gray matter density was the highest (p < 0.05)., Conclusion: Our study showed regional associations and dissociations between the relative gray matter density and rCBF in patients with iNPH.

Background: In patients suspected of having idiopathic normal-pressure hydrocephalus (iNPH), improvement in impaired cognition is common after a diagnostic cerebrospinal fluid tap test (CSFTT). Measures used to evaluate cognitive function before and after a CSFTT include the Mini-Mental State Examination (MMSE), Frontal Assessment Battery (FAB), and Trail Making Test (TMT). However, the time point at which cognitive function should be reevaluated after a CSFTT remains controversial., Objective: To investigate differences in cognitive function 1 day and 1 week after a CSFTT (versus baseline) in patients with suspected iNPH., Methods: This retrospective study, conducted between October 2012 and January 2017, involved 39 patients with suspected iNPH. We analyzed their MMSE, FAB, and TMT scores on tests conducted before and 1 day and 1 week after the CSFTT., Results: Changes in MMSE scores were negligible 1 day after the CSFTT but began to appear 1 week later. Changes in FAB scores were observed from 1 day to 1 week after the CSFTT. Although no statistically significant differences in TMT scores were observed at either time point, the execution time for the test tended to be shorter on the day after the CSFTT. Changes in cognitive function were not associated with demographic or morphological parameters. More severe impairments at baseline, however, were associated with greater changes in cognitive function., Conclusions: Performing several reevaluations using each test may enable more accurate assessment of cognitive function in patients with suspected iNPH. Our results highlight the need for long-term follow-up, regardless of the severity of cognitive impairment.