A role for mutations in AK9 and other genes affecting ependymal cells in idiopathic normal pressure hydrocephalus.

Idiopathic normal pressure hydrocephalus (iNPH) is an enigmatic neurological disorder that develops after age 60 and is characterized by gait difficulty, dementia, and incontinence. Recently, we reported that heterozygous CWH43 deletions may cause iNPH. Here, we identify mutations affecting nine additional genes (AK9, RXFP2, PRKD1, HAVCR1, OTOG, MYO7A, NOTCH1, SPG11, and MYH13) that are statistically enriched among iNPH patients. The encoded proteins are all highly expressed in choroid plexus and ependymal cells, and most have been associated with cilia. Damaging mutations in AK9, which encodes an adenylate kinase, were detected in 9.6% of iNPH patients. Mice homozygous for an iNPH-associated AK9 mutation displayed normal cilia structure and number, but decreased cilia motility and beat frequency, communicating hydrocephalus, and balance impairment. AK9+/- mice displayed normal brain development and behavior until early adulthood, but subsequently developed communicating hydrocephalus. Together, our findings suggest that heterozygous mutations that impair ventricular epithelial function may contribute to iNPH.

Utility of cortical tissue analysis in normal pressure hydrocephalus.

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 Aß + 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.

Peripheral immunity changes are associated with neurodegeneration and worse clinical outcome in idiopathic normal pressure hydrocephalus.

BACKGROUND AND PURPOSE: Idiopathic normal pressure hydrocephalus (iNPH) pathogenesis is multifactorial. Systemic inflammation might have a role in gathering clinical-pathological trajectories. We aimed to shape the peripheral immune profile of iNPH and establish correlations with cerebrospinal fluid (CSF) markers, ventricular enlargement, and clinical outcomes. METHODS: We conducted a single-center retrospective-longitudinal study, including 38 iNPH patients and 38 controls. Baseline iNPH Grading Scale and modified Rankin Scale (mRS) scores were collected with peripheral blood cell count, CSF amyloid-ß42 (Aß42), total tau (t-tau), phosphorylated-181-tau, and Evans index. Depending on 5-year outcome, iNPH patients were grouped into "poor outcome" (PO; mRS ≥ 5) and "favorable outcome" (FO; mRS < 5). Biomarkers were compared and correlated with each other. Receiver operating characteristic analysis was performed. RESULTS: iNPH patients compared to controls had higher neutrophil-to-lymphocyte ratio (NLR; 2.43 ± 1.04 vs. 1.61 ± 0.47, p < 0.001), higher neutrophils (4.22 ± 0.86 1000/mL vs. 3.48 ± 1.34, p = 0.033), and lower lymphocytes (1.45 ± 0.55 1000/mL vs. 2.07 ± 0.86, p = 0.038), with the expected CSF biomarkers signature. In the patients' cohort, NLR was associated directly with t-tau and inversely with Aß42. NLR directly correlated with Evans index. PO patients compared to those with FO had higher NLR (3.25 ± 1.40 vs. 2.01 ± 0.77, p = 0.035) and higher t-tau (274.76 ± 114.39 pg/mL vs. 150.28 ± 72.62, p = 0.017), with an area under the curve of 0.786 and 0.793, respectively. CONCLUSIONS: iNPH patients present a proinflammatory state associated with neurodegeneration and predicting poor clinical outcome. Systemic inflammation represents a factor in the clinical-pathological progression of iNPH, and the NLR emerges as a potential prognostic index.

Normal pressure hydrocephalus and cognitive impairment: The gait phenotype matters too.

BACKGROUND AND PURPOSE: Idiopathic normal pressure hydrocephalus (iNPH) is a chronic neurological disease resulting in progressive gait and cognitive disorders. We investigated whether the gait phenotype is associated with the severity of cognitive deficits in iNPH. METHODS: This retrospective study recruited 88 patients (mean age = 76.18 ± 7.21 years, 42% female). Patients were initially referred for suspicion of iNPH and underwent a comprehensive analysis, including gait analysis and cognitive evaluation. RESULTS: In this cohort (27% normal gait, 25% frontal gait, 16% parkinsonian gait, 27% other gait abnormalities), patients with parkinsonian and frontal gait had the lowest Mini-Mental State Examination (MMSE) scores and the slowest gait speed. Patients with normal gait had the highest MMSE scores and gait speed. Frontal gait was associated with lower MMSE score, even after adjusting for age, gender, comorbidities, white matter lesions, and education level (ß = -0.221 [95% confidence interval (CI) = -3.718 to -0.150], p = 0.034). Normal gait was associated with the best MMSE scores, even after adjusting for the abovementioned variables (ß = 0.231 [95% CI = 0.124-3.639], p = 0.036). CONCLUSIONS: Gait phenotypes among iNPH patients are linked to global cognition as assessed with MMSE.

Gut Microbiome Changes in Patients With Idiopathic Normal Pressure Hydrocephalus.

BACKGROUND: The gut microbiome is a complex system within the human gastrointestinal tract. The bacteria play a significant role in human health, and some can promote inflammation and pathologic processes through chemical interactions or metabolites. Gut microbiome dysbiosis has been linked to some neurological and other diseases. Here we aimed to examine microbiome differences between patients with a progressive neurological disorder, idiopathic normal pressure hydrocephalus (iNPH), compared with healthy controls (CO). METHODS: We recruited 37 neurologically healthy CO and 10 patients with shunted iNPH. We evaluated these participants' cognition using the CERAD-NB test battery and CDR test, and collected a variety of information, including about dietary habits and health. We also collected fecal samples, which were subjected to 16S amplicon sequencing to analyze differences in gut microbiome composition. RESULTS: We found that the iNPH group exhibited significantly different abundances of 10 bacterial genera compared with the CO group. The Escherichia/Shigella and Anaeromassilibacillus genera were most remarkably increased. Other increased genera were Butyrivibrio , Duncaniella , and an unidentified genus. The decreased genera were Agathobaculum , Paramuribaculum , Catenibacterium , and 2 unidentified genera. CONCLUSIONS: Here we report the first identified microbiome differences in iNPH patients compared with healthy controls.

Diffusion spectrum imaging in patients with idiopathic normal pressure hydrocephalus: correlation with ventricular enlargement.

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.

Cases of familial idiopathic normal pressure hydrocephalus implicate genetic factors in disease pathogenesis.

Idiopathic normal pressure hydrocephalus is a disorder of unknown pathophysiology whose diagnosis is paradoxically made by a positive response to its proposed treatment with cerebrospinal fluid diversion. There are currently no idiopathic normal pressure hydrocephalus disease genes or biomarkers. A systematic analysis of familial idiopathic normal pressure hydrocephalus could aid in clinical diagnosis, prognosis, and treatment stratification, and elucidate disease patho-etiology. In this 2-part analysis, we review literature-based evidence for inheritance of idiopathic normal pressure hydrocephalus in 22 pedigrees, and then present a novel case series of 8 familial idiopathic normal pressure hydrocephalus patients. For the case series, demographics, familial history, pre- and post-operative symptoms, and cortical pathology were collected. All novel familial idiopathic normal pressure hydrocephalus patients exhibited improvement following shunt treatment and absence of neurodegenerative cortical pathology (amyloid-beta and hyperphosphorylated tau), in contrast to many sporadic cases of idiopathic normal pressure hydrocephalus with variable clinical responses. Analysis of the 30 total familial idiopathic normal pressure hydrocephalus cases reported herein is highly suggestive of an autosomal dominant mechanism of inheritance. This largest-ever presentation of multiply affected idiopathic normal pressure hydrocephalus pedigrees provides strong evidence for Mendelian inheritance and autosomal dominant transmission of an idiopathic normal pressure hydrocephalus trait in a subset of patients that positively respond to shunting and lack neurodegenerative pathology. Genomic investigation of these families may identify the first bona fide idiopathic normal pressure hydrocephalus disease gene.

Efficacy and safety of shunt surgery in patients with idiopathic normal-pressure hydrocephalus: can we predict shunt response by preoperative magnetic resonance imaging (MRI)?

AIM: The aim of this study was to identify preoperative magnetic resonance imaging (MRI) findings that can predict the shunt responsiveness in idiopathic normal-pressure hydrocephalus (iNPH) patients and to investigate postoperative outcome and complications. MATERIALS AND METHODS: A total of 192 patients with iNPH who underwent shunt at our hospital between 2000 and 2021 were included to investigate complications. Of these, after exclusion, 127 (1-month postoperative follow-up) and 77 (1-year postoperative follow-up) patients were evaluated. The preoperative MRI features (the presence of tightness of the high-convexity subarachnoid space, Sylvian fissure enlargement, Evans' index, and callosal angle) of the shunt-response and nonresponse groups were compared, and a systematic review was conducted to evaluate whether preoperative MRI findings could predict shunt response. RESULTS: Postoperative complications within one month after surgery were observed in 6.8% (13/192), and the most common complication was hemorrhage. Changes in corpus callosum were observed in 4.2% (8/192). The shunt-response rates were 83.5% (106/127) in the 1-month follow-up group and 70.1% (54/77) in 1-year follow-up group. In the logistic regression analysis, only Evans' index measuring >0.4 had a significant negative relationship with shunt response at 1-month follow-up; however, no significant relationship was observed at 1-year follow-up. According to our systematic review, it is still controversial whether preoperative MRI findings could predict shunt response. CONCLUSION: Evans' index measure of >0.4 had a significant relationship with the shunt response in the 1-month follow-up group. In systematic reviews, there is ongoing debate about whether preoperative MRI findings can accurately predict responses to shunt surgery. Postoperative corpus callosal change was observed in 4.2% of iNPH patients.

Comparing the Long-Term Cardiovascular Outcomes of Lumbo-Peritoneal, Ventriculo-Peritoneal, or Non-Shunting Treatment after Idiopathic Normal Pressure Hydrocephalus: A Nationwide Retrospective Cohort Study.

Purpose: With advances in medical technology, the average lifespan has increased, leading to a growing significance of idiopathic normal pressure hydrocephalus (iNPH), particularly in the elderly population. Most patients with iNPH have been treated either with ventriculo-peritoneal shunts (VPS) or conservative measures. However, lumbo-peritoneal shunts (LPS) have emerged as an alternative treatment option for iNPH in recent decades, extensive research still lacks comparing outcomes with LPS to those with VPS or non-surgical treatment. The aim of the resent study is to disclose the long-term therapeutic outcomes of LPS, VPS, and non-shunting in patients with iNPH. Methods: We used the National Health Insurance Research Database in Taiwan to assess the long-term outcomes of these treatment options. We enrolled 5,537 iNPH patients who received shunting surgery, of which 5,254 were VPS and 283 were LPS. To compare the difference between each group, matching was conducted by propensity score matching using a 1:1 ratio based on LPS patients. Primary outcomes included death and major adverse cardiovascular events (MACEs) Results: Our findings show that VPS resulted in significantly more MACEs than non-surgical treatment (Odds ratio: 1.83, 95% confidence interval: 1.16-2.90). In addition, both VPS and LPS groups had significantly lower overall mortality rates than non-shunting group. Moreover, LPS had lower overall mortality but similar MACEs rates to VPS. Conclusions: Based on these findings, we propose that the LPS is preferable to the VPS, and surgical treatment should be considered the primary choice over conservative treatment unless contraindications are present.

Shunting for idiopathic normal pressure hydrocephalus.

BACKGROUND: Normal pressure hydrocephalus (NPH) occurs when the brain ventricles expand, causing a triad of gait, cognitive, and urinary impairment. It can occur after a clear brain injury such as trauma, but can also occur without a clear cause (termed idiopathic, or iNPH). Non-randomised studies have shown a benefit from surgically diverting ventricular fluid to an area of lower pressure by cerebrospinal fluid (CSF)-shunting in iNPH, but historically there have been limited randomised controlled trial (RCT) data to confirm this. OBJECTIVES: To determine the effect of CSF-shunting versus no CSF-shunting in people with iNPH and the frequency of adverse effects of CSF-shunting in iNPH. SEARCH METHODS: We searched the Cochrane Dementia and Cognitive Improvement Group's register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid SP), Embase (Ovid SP), PsycINFO (Ovid SP), CINAHL (EBSCOhost), Web of Science Core Collection (Clarivate), LILACS (BIREME), ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform on 15 February 2023. SELECTION CRITERIA: We included only RCTs of people who had symptoms of gait, cognitive, or urinary impairment with communicating hydrocephalus (Evans index of > 0.3) and normal CSF pressure. Control groups included those with no CSF shunts or those with CSF shunts that were in 'inactive' mode. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. Where necessary, we contacted study authors requesting data not provided in the papers. We assessed the overall certainty of the evidence using GRADE. MAIN RESULTS: We included four RCTs, of which three were combined in a meta-analysis. The four RCTs included 140 participants (73 with immediate CSF-shunting and 67 controls who had delayed CSF-shunting) with an average age of 75 years. Risk of bias was low in all parallel-group outcomes evaluated apart from gait speed, cognitive function (general cognition and Symbol Digit Test) (some concerns) and adverse events, which were not blind-assessed. CSF-shunting probably improves gait speed at less than six months post-surgery (standardised mean difference (SMD) 0.62, 95% confidence interval (CI) 0.24 to 0.99; 3 studies, 116 participants; moderate-certainty evidence). CSF-shunting may improve qualitative gait function at less than six months post-surgery by an uncertain amount (1 study, 88 participants; low-certainty evidence). CSF-shunting probably results in a large reduction of disability at less than six months post-surgery (risk ratio 2.08, 95% CI 1.31 to 3.31; 3 studies, 118 participants; moderate-certainty evidence). The evidence is very uncertain about the effect of CSF-shunting on cognitive function at less than six months post-CSF-shunt surgery (SMD 0.35, 95% CI -0.04 to 0.74; 2 studies, 104 participants; very low-certainty evidence). The evidence is also very uncertain about the effect of CSF-shunt surgery on adverse events (1 study, 88 participants; very low-certainty evidence). There were no data regarding the effect of CSF-shunting on quality of life. AUTHORS' CONCLUSIONS: We found moderate-certainty evidence that CSF-shunting likely improves gait speed and disability in iNPH in the relative short term. The evidence is very uncertain regarding cognition and adverse events. There were no longer-term RCT data for any of our prespecified outcomes. More studies are required to improve the certainty of these findings. In addition, more information is required regarding patient ethnicity and the effect of CSF-shunting on quality of life.

Comparison of decline in different cognitive domain in patients with normal pressure hydrocephalus.

We sought to describe the cognitive profile of patients with Idiopathic Normal Pressure Hydrocephalus (iNPH) using a comprehensive neuropsychological battery. Based on age and education correlated norms, we aimed to compare performance in each measured cognitive domain: executive functions (EFs), verbal memory (VM), non-verbal memory (nVM), visuoconstructional abilities (VA) and attention/psychomotor speed (A/PS). Patients diagnosed with iNPH underwent comprehensive neuropsychological evaluation before shunting. Their performance was compared to the age and education correlated norms. Correlation of different cognitive domains in iNPH profile was performed. A total of 53 iNPH patients (73.21 ± 5.48 years) were included in the study. All of the measured cognitive domains were significantly damaged. The most affected domains were EFs and VM (p<0.001 and p<0.001, respectively). A/PS domain was affected milder than EFs and VM (p<0.001). The least affected domains were nVM (p<0.001) and VA (p<0.001). Patients with iNPH are affected in all cognitive domains and the cognitive decline is uneven across these domains. The impairment of memory was shown to depend on the presented material. VM was shown to be much more severely affected than nVM and along with VM, EFs were shown to be the most affected. A/PS speed was shown to be less affected than VM and EFs and the least affected domains were nVM and VA.

Correlation between GLCM-based texture features of the lateral pterygoid muscle and cognitive function in patients with idiopathic normal pressure hydrocephalus: a preliminary report.

PURPOSE: The potential relationship between mastication ability and cognitive function in idiopathic normal pressure hydrocephalus (iNPH) patients is unclear. This report investigated the association between mastication and cognitive function in iNPH patients using the gray level of the co-occurrence matrix on the lateral pterygoid muscle. METHODS: We analyzed data from 96 unoperated iNPH patients who underwent magnetic resonance imaging (MRI) between December 2016 and February 2023. Radiomic features were extracted from T2 MRI scans of the lateral pterygoid muscle, and muscle texture parameters were correlated with the iNPH grading scale. Subgroup analysis compared the texture parameters of patients with normal cognitive function with those of patients with cognitive impairment. RESULTS: The mini-mental state examination score correlated positively with the angular second moment (P < 0.05) and negatively with entropy (P < 0.05). The dementia scale (Eide's classification) correlated negatively with gray values (P < 0.05). Gray values were higher in the cognitive impairment group (64.7 ± 16.6) when compared with the non-cognitive impairment group (57.4 ± 13.3) (P = 0.005). Entropy was higher in the cognitive impairment group (8.2 ± 0.3) than in the non-cognitive impairment group (8.0 ± 0.3) (P < 0.001). The area under the receiver operating characteristic curve was 0.681 (P = 0.003) and 0.701 (P < 0.001) for gray value and entropy, respectively. CONCLUSION: Our findings suggest an association between heterogeneity of mastication and impaired cognitive function in iNPH patients and highlight muscle texture analysis as a potential tool for predicting cognitive impairment in these patients.

Normal pressure hydrocephalus, or Hakim syndrome: review and update.

This review makes the case that idiopathic normal pressure hydrocephalus (iNPH) is an outdated term because new information indicates that the syndrome is less idiopathic and that the cerebrospinal fluid (CSF) pressure of normal individuals is affected by several factors such as body mass index, age, and sex. Our review updates the epidemiology of iNPH and provides a clinical approach to the management of these patients. All the clinical features of iNPH are common in older individuals, and each has many causes, so the diagnosis is difficult. The first step in reaching an accurate diagnosis is to address the possible contributory factors to the gait abnormality and determine what if any role iNPH may be playing. The two best diagnostic tests are neuroimaging and cerebrospinal fluid (CSF) diversion (large volume lumbar puncture or external lumbar drainage) with pre/post gait evaluation. This review provides an update on the growing evidence that vascular disease, impaired CSF absorption, congenital, and genetic factors all contribute to the pathogenesis of iNPH. We suggest replacing the term iNPH with the term Hakim syndrome (HS) in acknowledgement of the first person to describe this syndrome. Lastly, we discuss the improvements in shunt technology and surgical techniques that have decreased the risks and long-term complications of shunt surgery.

In vivo assessment of the ocular biomechanical properties in patients with idiopathic normal pressure hydrocephalus.

PURPOSE: Idiopathic normal pressure hydrocephalus (iNPH) is associated with an increased prevalence of open-angle glaucoma, attributed to variations of the pressure gradient between intraocular and intracranial compartments at the level of the lamina cribrosa (LC). As ocular biomechanics influence the behavior of the LC, and a lower corneal hysteresis (CH) has been associated to a higher risk of glaucomatous optic nerve damage, in this study we compared ocular biomechanics of iNPH patients with healthy subjects. METHODS:  Twenty-four eyes of 24 non-shunted iNPH patients were prospectively recruited. Ocular biomechanical properties were investigated using the ocular response analyzer (Reichert Instruments) for the calculation of the CH, corneal resistance factor (CRF), Goldmann-correlated intraocular pressure (IOPg), and corneal-compensated intraocular pressure (IOPcc). Results were compared with those of 25 eyes of 25 healthy subjects. RESULTS:  In iNPH eyes, the median CH value and interquartile range (IQR) were 9.7 mmHg (7.8-10) and 10.6 mmHg (9.3-11.3) in healthy controls (p = 0.015). No significant differences were found in IOPcc [18.1 mmHg (14.72-19.92) vs. 16.4 mmHg (13.05-19.6)], IOPg [15.4 mmHg (12.82-19.7) vs. 15.3 mmHg (12.55-17.35)], and CRF [9.65 mmHg (8.07-11.65) vs. 10.3 mmHg (9.3-11.5)] between iNPH patients and controls. CONCLUSIONS:  In iNPH patients, the CH was significantly lower compared to healthy subjects. This result suggests that ocular biomechanical properties may potentially contribute to the risk of development of glaucomatous optic nerve damage in iNPH patients.

Neuronal pentraxin 2 correlates with neurodegeneration but not cognition in idiopathic normal pressure hydrocephalus (iNPH).

AIM OF THE STUDY: Neuronal pentraxin-2 (NPTX2) is a synaptic protein responsible for modulating plasticity at excitatory synapses. While the role of NPTX2 as a novel synaptic biomarker in cognitive disorders has been elucidated recently, its role in idiopathic normal pressure hydrocephalus (iNPH) is not yet understood. CLINICAL RATIONALE FOR STUDY: To determine if NPTX2 predicts cognition in patients with iNPH, and whether it could serve as a predictive marker for shunt outcomes. MATERIAL AND METHODS: 354 iNPH patients underwent cerebrospinal fluid drainage (CSF) as part of the tap test or extended lumbar drainage. Demographic and clinical measures including age, Evans Index (EI), Montreal Cognitive Assessment (MoCA) score, Functional Activities Questionnaire (FAQ) score, and baseline and post-shunt surgery Timed Up and Go (TUG) test scores were ascertained. CSF NPTX2 concentrations were measured using an ELISA. CSF ß-amyloid 1-40 (Aß1-40), ß-amyloid 1-42 (Aß1-42), and phosphorylated tau-181 (pTau-181) were measured by chemiluminescent assays. Spearman's correlation was used to determine the correlation between CSF NPTX2 concentrations and age, EI, MoCA and FAQ, TUG, Aß1-40/Aß1-42 ratio, and pTau-181 concentrations. Logistic regression was used to determine if CSF NPTX2 values were a predictor of short-term improvement post-CSF drainage or long-term improvement post-shunt surgery. RESULTS: There were 225 males and 129 females with a mean age of 77.7 years (± 7.06). Average CSF NPTX2 level in all iNPH patients was 559.97 pg/mL (± 432.87). CSF NPTX2 level in those selected for shunt surgery was 505.61 pg/mL (± 322.38). NPTX2 showed modest correlations with pTau-181 (r = 0.44, p < 0.001) with a trend for Aß42/Aß40 ratio (r = -0.1, p = 0.053). NPTX2 concentrations did not correlate with age (r = -0.012, p = 0.83) or MoCA score (r = 0.001, p = 0.87), but correlated negatively with FAQ (r = -0.15, p = 0.019). CONCLUSIONS: While CSF NPTX2 values correlate with neurodegeneration, they do not correlate with cognitive or functional measures in iNPH. CSF NPTX2 cannot serve as a predictor of either short-term or long-term improvement after CSF drainage. CLINICAL IMPLICATIONS: These results suggest that synaptic degeneration is not a core feature of iNPH pathophysiology.

Distinct cerebral cortical perfusion patterns in idiopathic normal-pressure hydrocephalus.

The aims of the study are to evaluate idiopathic normal-pressure hydrocephalus (INPH)-related cerebral blood flow (CBF) abnormalities and to investigate their relation to cortical thickness in INPH patients. We investigated cortical CBF utilizing surface-based early-phase 18 F-florbetaben (E-FBB) PET analysis in two groups: INPH patients and healthy controls. All 39 INPH patients and 20 healthy controls were imaged with MRI, including three-dimensional volumetric images, for automated surface-based cortical thickness analysis across the entire brain. A subgroup with 37 participants (22 INPH patients and 15 healthy controls) that also underwent 18 F-fluorodeoxyglucose (FDG) PET imaging was further analyzed. Compared with age- and gender-matched healthy controls, INPH patients showed statistically significant hyperperfusion in the high convexity of the frontal and parietal cortical regions. Importantly, within the INPH group, increased perfusion correlated with cortical thickening in these regions. Additionally, significant hypoperfusion mainly in the ventrolateral frontal cortex, supramarginal gyrus, and temporal cortical regions was observed in the INPH group relative to the control group. However, this hypoperfusion was not associated with cortical thinning. A subgroup analysis of participants that also underwent FDG PET imaging showed that increased (or decreased) cerebral perfusion was associated with increased (or decreased) glucose metabolism in INPH. A distinctive regional relationship between cerebral cortical perfusion and cortical thickness was shown in INPH patients. Our findings suggest distinct pathophysiologic mechanisms of hyperperfusion and hypoperfusion in INPH patients.

A pilot study assessing sphingolipids and glycolipids dysmetabolism in idiopathic normal pressure hydrocephalus.

Idiopathic normal pressure hydrocephalus usually exhibits triad of symptoms including gait disturbance, urinary incontinence, and dementia with ventriculomegaly. Currently, its pathogenesis remains to be fully elucidated. To provide a better understanding of this order, we examined whether dysmetabolism of sphingolipids as major lipid components in the brain present in cerebrospinal fluid (CSF) of the patients. Here, we measured various sphingolipidsincluding ceramide and sphingomyelin and glycolipids by electrospray ionization-tandem mass spectrometry in the cerebrospinal fluid of 19 consecutive idiopathic normal pressure hydrocephalus patients, 49 Parkinson's disease patients, and 17 neurologically normal controls. The data showed that there was a significant and specific reduction of all galactosylceramide subspecies levels in idiopathic normal pressure hydrocephalus patients compared with other groups, whereas ceramide and sphingomyelin levels as well as other neutral glycolipids such as glucosylceramide and lactosylceramide were similar in both disease states. Multiple regression analysis of sex and age did not show any correlation with galactosylceramide levels. We also examined whether MMSE scores are correlated with sphingolipid levels in iNPH patients. A specific subspecies of sphingomyelin (d18:1/18:0) only exhibited a statistically significant negative correlation (p = 0.0473, R = -0.4604) with MMSE scores but no other sphingolipids in iNPH patients. These data strongly suggest that myelin-rich galactosylceramide metabolism is severely impaired in idiopathic normal pressure hydrocephalus patients and might serve as the basis of biomarker for this disorder.

Alpha-Synuclein RT-QuIC in Idiopathic Normal Pressure Hydrocephalus.

This study quantified the occurrence of an underlying synucleinopathy in 50 patients with idiopathic normal pressure hydrocephalus by means of real-time quaking-induced conversion, a highly sensitive and specific technique capable of detecting and amplifying misfolded aggregated forms of α-synuclein in the cerebrospinal fluid. Seven patients were positive and they did not differ from negative cases, except for a more frequent L-dopa responsiveness and gait characterized by a wider base. The two groups did not differ in terms of response rate to tap test or shunt surgery, although step length and gait velocity improved by a lesser extent in positive cases. ANN NEUROL 2022;92:985-991.

Change in Morphological Features of Enlarged Subarachnoid Spaces Following Treatment in Idiopathic Normal Pressure Hydrocephalus.

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 mm3 or 30.0%. Pituitary gland size significantly increased by 0.48 mm or 14.4%. FES decreased significantly by 190 mm3 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.

Risk estimation for idiopathic normal-pressure hydrocephalus: development and validation of a brain morphometry-based nomogram.

OBJECTIVES: To develop and validate a nomogram based on MRI features for predicting iNPH. METHODS: Patients aged ≥ 60 years (clinically diagnosed with iNPH, Parkinson's disease, or Alzheimer's disease or healthy controls) who underwent MRI including three-dimensional T1-weighted volumetric MRI were retrospectively identified from two tertiary referral hospitals (one hospital for derivation set and the other for validation set). Clinical and imaging features for iNPH were assessed. Deep learning-based brain segmentation software was used for 3D volumetry. A prediction model was developed using logistic regression and transformed into a nomogram. The performance of the nomogram was assessed with respect to discrimination and calibration abilities. The nomogram was internally and externally validated. RESULTS: A total of 452 patients (mean age ± SD, 73.2 ± 6.5 years; 200 men) were evaluated as the derivation set. One hundred eleven and 341 patients were categorized into the iNPH and non-iNPH groups, respectively. In multivariable analysis, high-convexity tightness (odds ratio [OR], 35.1; 95% CI: 4.5, 275.5), callosal angle < 90° (OR, 12.5; 95% CI: 3.1, 50.0), and normalized lateral ventricle volume (OR, 4.2; 95% CI: 2.7, 6.7) were associated with iNPH. The nomogram combining these three variables showed an area under the curve of 0.995 (95% CI: 0.991, 0.999) in the study sample, 0.994 (95% CI: 0.990, 0.998) in the internal validation sample, and 0.969 (95% CI: 0.940, 0.997) in the external validation sample. CONCLUSION: A brain morphometry-based nomogram including high-convexity tightness, callosal angle < 90°, and normalized lateral ventricle volume can help accurately estimate the probability of iNPH. KEY POINTS: • The nomogram with MRI findings (high-convexity tightness, callosal angle, and normalized lateral ventricle volume) helped in predicting the probability of idiopathic normal-pressure hydrocephalus. • The nomogram may facilitate the prediction of idiopathic normal-pressure hydrocephalus and consequently avoid unnecessary invasive procedures such as the cerebrospinal fluid tap test, drainage test, and cerebrospinal fluid shunt surgery.