Predicting post-surgical outcomes in idiopathic normal pressure hydrocephalus using clinically important changes from the cerebrospinal fluid tap test.

OBJECTIVE: Patients diagnosed with idiopathic Normal Pressure Hydrocephalus (iNPH) typically experience symptom improvements after undergoing a cerebrospinal fluid-tap test (CSF-TT), These improvements are recognized as indicative of potential improvements following surgical intervention. As gait disturbance is the most common iNPH symptom, gait improvements are of predominant interest. The purpose of this study was to examine if clinically important changes in gait and balance from CSF-TT predict meaningful changes following surgery. METHOD: The study involved analysis of data collected in a prospective observational study for 34 iNPH patients who underwent a CSF-TT and subsequent surgery. Linear regression, logistic regression and classification trees were used for predictive modelling comparing changes from CSF-TT with post-surgical changes in Tinetti, Timed Up and Go (TUG) and Berg Balance Scale (BBS) outcomes. RESULTS: Predictive models for minimal clinically important differences (MCIDs) from CSF-TT to surgery were significant for Tinetti (odds ratio = 1.42, p = 0.02) and BBS (odds ratio = 1.57, p < 0.01). Four items on Tinetti and two items on BBS were identified with a predictive accuracy of 79% and 76% respectively. BBS has the highest sensitivity (85%) and negative predictive value (77%). TUG had a 100% specificity and 100% positive predictive value. The predictive model using MCIDs for TUG was not significant (odds ratio = 1.13, p = 0.06). CONCLUSION: Clinically important changes from CSF-TT are useful in predicting post-surgical outcomes in iNPH patients. Tinetti and BBS, both have predictive value using MCID scores as cut off values, of which BBS is a stronger outcome measure for prediction.

Influence of interaction of cerebral fluids on ventricular deformation: A mathematical approach.

This paper describes the effects of the interaction of cerebral fluids (arterial, capillary and venous blood, cerebrospinal fluid) on ventricular wall displacement and periventricular pressure using a mathematical multiphase poroelasticity model for the cerebral parenchyma. The interaction of cerebral fluids is given by a set of four numerical coefficients. A multiple linear regression with interaction is constructed that allows us to quantify the effect of these coefficients on the average ventricular wall displacement. The prevailing influence of an arterial-liquor component was observed. The sets of coefficients associated with such pathological conditions were found: normal pressure hydrocephalus, intracranial hypertension, and replacement ventriculomegaly under a prolonged hypoperfusion.

Comparison of comfortable and maximum walking speed in the 10-meter walk test during the cerebrospinal fluid tap test in iNPH patients: A retrospective study.

BACKGROUND: The 10-meter walking test (10 MWT) is widely used during a cerebrospinal fluid tap test (CSFTT) for idiopathic normal-pressure hydrocephalus (iNPH). However, various previous studies and guidelines do not specify whether to adopt a comfortable walking speed or maximum walking speed when implementing the 10 MWT. In this study, we analyzed the values of comfortable and maximum walking speeds during the CSFTT in patients who underwent shunt surgery to determine which walking form is desirable for evaluation. METHODS: The patients were 29 consecutive cases in which a CSFTT was performed, followed by shunting, between October 2012 and April 2019. Data on the 10 MWT comfortable walking speed and maximum walking speed were collected, as were data on the timed up and go (TUG) test and Mini-Mental State Examination (MMSE). We analyzed the rate of change in comfortable walking speed and maximum walking speed before CSFTT and on the first day after CSFTT, and the amount of improvement compared to baseline ability. In addition, diagnostic performance was compared using a receiver operating characteristic (ROC) analysis. RESULTS: Twenty-eight patients who underwent shunt surgery improved their symptoms and were designated as shunt responders. The remaining patient who underwent surgery was considered a non-responder with no improvement in symptoms. The parameters of the shunt responders that changed were muscle strength, the 10 MWT, and the TUG test, and there was no significant change in cognitive function. The rate of change, amount of change, and sensitivity were large at a comfortable walking speed, but ROC analysis showed that the maximum walking speed had a large area under the curve and excellent specificity. The higher the preoperative gait function, the lower the improvement rate of gait function. DISCUSSION: The comfortable walking speed is easy to measure, but its specificity is inferior to the maximum walking speed. However, the maximum walking speed may be affected by the ceiling effect and measurement errors. Despite this, we concluded that the maximum walking speed had a better diagnostic performance. Because the causes of gait disturbance in iNPH include decreased muscle output, postural instability, and gait rhythm disorder, and maximum walking speed is strongly related to each of these factors, this accounts for the changes in maximum walking speed. CONCLUSION: In conclusion, although comfortable walking speed was easy to measure in terms of changes and had high sensitivity, the maximum walking speed had the highest specificity and comprehensive diagnostic performance. It is recommended that maximum walking speed be evaluated when making a definitive diagnosis of iNPH.

Asymmetry and tuning shift of the cervical vestibular evoked myogenic potential indicate saccular dysfunction in idiopathic normal pressure hydrocephalus.

OBJECTIVE: The purpose of this study was to investigate the effects of excessive cerebrospinal fluid (CSF) retention on the peripheral vestibular function and the inner ear fluid in patients with idiopathic normal pressure hydrocephalus (iNPH). METHODS: In 25 patients with iNPH (14 females, age 65-88 years), cervical vestibular evoked myogenic potential (cVEMP) was measured before the spinal tap test. The asymmetry ratios (ARs) and tuning properties in 500 Hz and 1,000 Hz short-tone burst stimuli of cVEMP were evaluated. Furthermore, cVEMP was measured in an age-matched control group of 12 non-iNPH patients. RESULTS: Seven (28%) iNPH patients exhibited a cVEMP asymmetry (AR > 33%). cVEMP tuning was significantly shifted to a higher frequency in the iNPH group than in the age-matched control group. CONCLUSIONS: One-fourth of patients with iNPH had obvious saccular dysfunction. A high rate of a shift in cVEMP tuning in the iNPH group indicated that excessive CSF accumulation propagated to the endolymph and perilymph. SIGNIFICANCE: Saccular dysfunction might be one of the possible causes of imbalance in iNPH, and the shift in cVEMP tuning may be a determining factor in the diagnosis and treatment strategy.

Gait characteristics and effects of the cerebrospinal fluid tap test in probable idiopathic normal pressure hydrocephalus.

OBJECTIVES: To evaluate gait characteristics and investigate changes pre- and post- cerebrospinal fluid tap test (CSF TT) in gait parameters in patients with probable idiopathic normal pressure hydrocephalus (iNPH). METHODS: Sixty patients were sequential circuited and diagnosed with possible iNPH according to Japanese second iNPH guidelines at our hospital from December 2016 to March 2021. All patients underwent the CSF TT. Gait parameters, cognitive and urinary function were assessed pre- and post-CSF TT. Patients who were unable to ambulate to take the tests or could not walk independently or walked normally were excluded. RESULTS: Twenty-six patients were diagnosed with probable iNPH using the CSF TT. After CSF TT, the Boon sum score improved from 20.0 ± 7.7-16.6 ± 8.0 (p < 0.001), the Boon walking score improved from 8.9 ± 3.5-7.8 ± 4.4 (p = 0.008), the Boon step score improved from 6.3 ± 2.3-5.2 ± 2.1 (p < 0.001), the Boon time score improved from 4.9 ± 2.4-3.7 ± 2.3 (p < 0.001), tandem walking disturbance improved from 1.7 ± 0.7-1.4 ± 0.9 (p = 0.043), tendency toward falling improved from 1.7 ± 0.7-1.3 ± 1(p = 0.022), 3-meter timed up and go test (3-mTUG) improved from 21.9 ± 7.1-17.6 ± 5.1( p < 0.001), 10-meter walking (10-MWT) step improved from 31.1 ± 13.1-24.6 ± 7.5 (p < 0.001), velocity improved from 0.7 ± 0.2-0.8 ± 0.3 (p < 0.001) and stride length improved from 0.4 ± 0.1-0.46 ± 0.1(p < 0.001), compared with before the CSF TT. CONCLUSION: These results suggest that many parameters in the Boon gait test were responsive to the CSF TT, and the Boon gait test may help objectify response to the CSF TT by combining the 10-MWT and 3-mTUG gait assessments.

Cerebral ventriculomegaly in myotonic dystrophy type 1: normal pressure hydrocephalus-like appearances on magnetic resonance imaging.

BACKGROUND: Cerebral ventriculomegaly is an abnormal feature characteristic of myotonic dystrophy type 1 (DM1). This retrospective study investigated the morphologic changes accompanied by ventriculomegaly in DM1 on brain MRI. METHODS: One hundred and twelve adult patients with DM1 and 50 sex- and age-matched controls were assessed. The imaging characteristics for evaluations included the z-Evans Index (ventriculomegaly), callosal angle (CA), enlarged perivascular spaces in the centrum semiovale (CS-EPVS), temporo-polar white matter lesion (WML) on 3D fluid-attenuated inversion recovery (FLAIR), disproportionately enlarged subarachnoid-space hydrocephalus (DESH), and pathological brain atrophy. The "z-Evans Index" was defined as the maximum z-axial length of the frontal horns to the maximum cranial z-axial length. To determine the imaging characteristics and genetic information (CTG repeat numbers) that were associated with the z-Evans Index, we used binominal logistic regression analyses. RESULTS: The z-Evans Index was significantly larger in the patients than in the controls (0.30 ± 0.05 vs. 0.24 ± 0.02; p < 0.01). The z-Evans Index was independently associated with the callosal angle (p < 0.01) and pathological brain atrophy (p < 0.01) but not with age, gender, CTG repeat numbers, or CS-EPVS. Of the 34 patients older than 49 years, 7 (20.6%) were considered to have DESH. CONCLUSIONS: Our MRI study revealed a normal pressure hydrocephalus (NPH)-like appearance as a morphologic finding accompanied by ventriculomegaly in DM1 that tends to occur in elderly patients.

Assessment of neurological symptoms in adult hydrocephalus occlusus. A pilot study.

BACKGROUND: Comprehensively describe and compare (pre/postoperatively) the clinical symptomatology in adult non-communicated hydrocephalus. Associated hydrocephalus signs were analyzed with the idiopathic Normal Pressure Hydrocephalus Scale (iNPH Scale). A standardized clinical scale for non-communicated hydrocephalus is currently not in use. METHODS: Ten patients with hydrocephalus occlusus (HO) were analyzed. Hydrocephalus signs were examined with the iNPH Scale in gait, neuropsychology, continence, and balance before and three months after treatment with shunt operation or third endoscopic ventriculostomy. RESULTS: Patients significantly improved in iNPH total score (25.8%) and gait score (35.4%) three months after neurosurgical intervention. Domain scores in neuropsychology, continence, and balance reached statistical trends (p ≤ 0.066). Most clinical symptoms and signs at baseline improved after surgery (dizziness, lapse of concentration, gait instability, and headache). CONCLUSION: Patients with non-communicated HO also showed classical hydrocephalus symptoms as communicated in iNPH patients. The iNPH Scale allows a structured neurological assessment over the disease's progress and surgical intervention. Further studies with a larger patient samples are necessary to support our results.

Quantitative gait analysis of idiopathic normal pressure hydrocephalus using deep learning algorithms on monocular videos.

A vision-based gait analysis method using monocular videos was proposed to estimate temporo-spatial gait parameters by leveraging deep learning algorithms. This study aimed to validate vision-based gait analysis using GAITRite as the reference system and analyze relationships between Frontal Assessment Battery (FAB) scores and gait variability measured by vision-based gait analysis in idiopathic normal pressure hydrocephalus (INPH) patients. Gait data from 46 patients were simultaneously collected from the vision-based system utilizing deep learning algorithms and the GAITRite system. There was a strong correlation in 11 gait parameters between our vision-based gait analysis method and the GAITRite gait analysis system. Our results also demonstrated excellent agreement between the two measurement systems for all parameters except stride time variability after the cerebrospinal fluid tap test. Our data showed that stride time and stride length variability measured by the vision-based gait analysis system were correlated with FAB scores. Vision-based gait analysis utilizing deep learning algorithms can provide comparable data to GAITRite when assessing gait dysfunction in INPH. Frontal lobe functions may be associated with gait variability measurements using vision-based gait analysis for INPH patients.

Intracranial pressure waveform characteristics in idiopathic normal pressure hydrocephalus and late-onset idiopathic aqueductal stenosis.

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) and late-onset idiopathic aqueductal stenosis (LIAS) are two forms of chronic adult hydrocephalus of different aetiology. We analysed overnight intracranial pressure (ICP) monitoring to elucidate ICP waveform changes characteristic for iNPH and LIAS to better understand pathophysiological processes of both diseases. METHODS: 98 patients with iNPH and 14 patients with LIAS from two neurosurgical centres were included. All patients underwent diagnostic overnight computerised ICP monitoring with calculation of mean ICP, ICP heartbeat related pulse wave amplitude calculated in the frequency domain (AMP) and the time domain (MWA), index of cerebrospinal compensatory reserve (RAP) and power of slow vasogenic waves (SLOW). RESULTS: ICP was higher in LIAS than iNPH patients (9.3 ± 3.0 mmHg versus 5.4 ± 4.2 mmHg, p = 0.001). AMP and MWA were higher in iNPH versus LIAS (2.36 ± 0.91 mmHg versus 1.81 ± 0.59 mmHg for AMP, p = 0.012; 6.0 ± 2.0 mmHg versus 4.9 ± 1.2 mmHg for MWA, p = 0.049). RAP and SLOW indicated impaired reserve capacity and compliance in both diseases, but did not differ between groups. INPH patients were older than LIAS patients (77 ± 6 years versus 54 ± 14 years, p < 0.001). CONCLUSIONS: ICP is higher in LIAS than in iNPH patients, likely due to the chronically obstructed CSF flow through the aqueduct, but still in a range considered normal. Interestingly, AMP/MWA was higher in iNPH patients, suggesting a possible role of high ICP pulse pressure amplitudes in iNPH pathophysiology. Cerebrospinal reserve capacity and intracranial compliance is impaired in both groups and the pressure-volume relationship might be shifted towards lower ICP values in iNPH. The physiological influence of age on ICP and AMP/MWA requires further research.

Exploring mechanisms of ventricular enlargement in idiopathic normal pressure hydrocephalus: a role of cerebrospinal fluid dynamics and motile cilia.

Idiopathic normal pressure hydrocephalus (iNPH) is considered an age-dependent chronic communicating hydrocephalus associated with cerebrospinal fluid (CSF) malabsorption; however, the aetiology of ventricular enlargement in iNPH has not yet been elucidated. There is accumulating evidence that support the hypothesis that various alterations in CSF dynamics contribute to ventricle dilatation in iNPH. This review focuses on CSF dynamics associated with ventriculomegaly and summarises the current literature based on three potential aetiology factors: genetic, environmental and hydrodynamic. The majority of gene mutations that cause communicating hydrocephalus were associated with an abnormal structure or dysfunction of motile cilia on the ventricular ependymal cells. Aging, alcohol consumption, sleep apnoea, diabetes and hypertension are candidates for the risk of developing iNPH, although there is no prospective cohort study to investigate the risk factors for iNPH. Alcohol intake may be associated with the dysfunction of ependymal cilia and sustained high CSF sugar concentration due to uncontrolled diabetes increases the fluid viscosity which in turn increases the shear stress on the ventricular wall surface. Sleep apnoea, diabetes and hypertension are known to be associated with the impairment of CSF and interstitial fluid exchange. Oscillatory shear stress to the ventricle wall surfaces is considerably increased by reciprocating bidirectional CSF movements in iNPH. Increased oscillatory shear stress impedes normal cilia beating, leading to motile cilia shedding from the ependymal cells. At the lack of ciliary protection, the ventricular wall is directly exposed to increased oscillatory shear stress. Additionally, increased oscillatory shear stress may be involved in activating the flow-mediated dilation signalling of the ventricular wall. In conclusion, as the CSF stroke volume at the cerebral aqueduct increases, the oscillatory shear stress increases, promoting motor cilia shedding and loss of ependymal cell coverage. These are considered to be the leading causes of ventricular enlargement in iNPH.

Evaluating the cerebrospinal fluid tap test with the Hellström iNPH scale for patients with idiopathic normal pressure hydrocephalus.

BACKGROUND: The cerebrospinal fluid tap test (CSF TT) is used for selecting shunt surgery candidates among patients with idiopathic normal pressure hydrocephalus (iNPH). We aimed to evaluate the predictive value of the CSF TT, by using the Hellström iNPH scale for shunted iNPH patients with a standardized method. METHODS: One hundred and sixteen shunt-operated iNPH patients were retrospectively included in this study. The gait and balance domains in the iNPH scale were used as outcome measures for the CSF TT and the total iNPH scale score as the postoperative outcome. A positive response to CSF TT was defined as a change of ≥ 5 points in the gait domain and ≥ 16 points in the balance domain. Differences between CSF TT responders and non-responders, sensitivity, specificity, positive and negative predictive values, accuracy, and correlations between changes from baseline to post CSF TT and from baseline to the postoperative follow-up, were calculated. RESULTS: In the CSF TT there were 63.8% responders in the gait domain and correspondingly 44.3% in the balance domain. CSF TT responders had a significantly better postoperative outcome in the total scale score (gait P ≤ 0.001, balance P ≤ 0.012) and gait CSF TT responders improved more in gait (P ≤ 0.001) and balance CSF TT responders in balance (P ≤ 0.001). No differences between CSF TT gait or balance responders could be found in neuropsychological or urinary continence assessments postoperatively. The sensitivity and specificity of the CSF TT and the outcome of the total iNPH scale score postoperatively were 68.1% and 52.0% for gait and 47.8% and 68.0% for balance, respectively. CONCLUSIONS: The CSF TT, with the Hellström iNPH scale as the outcome measure, has clear limitations in predicting postoperative results. The gait domain may be used to predict outcomes for gait, but the balance domain is too insensitive.

Aqueductal CSF stroke volume measurements may drive management of shunted idiopathic normal pressure hydrocephalus patients.

CSF shunting with adjustable valve is the treatment of idiopathic normal pressure hydrocephalus. The opening pressure valve setting is left to the neurosurgeon's experience. Aqueductal CSF stroke volume by phase-contrast magnetic resonance measures the CSF passing through the Sylvian aqueduct and it changes with intracranial hydrodynamics. We sought to identify a window of stroke volume differences associated with the best clinical outcome and lowest rate of complications. The records of 69 patients were reviewed. At every clinical check, stroke volume, opening pressure valve, clinical outcome, and CSF overdrainage were analyzed. The correlation between stroke volume differences and negative outcome was also analyzed. The median follow-up was 2.3 years (range 0.3-10.4 years). The odds of negative outcome between two consecutive checks significantly increased by 16% (95%CI 4-28%, p = 0.006). Taking the lowest risk group as reference, the odds ratio of negative outcome was 1.16 (95%CI 0.51-2.63, p = 0.726) for SV differences less than - 37.6 µL, while it was 1.96 (95%CI 0.97-3.98, p = 0.062) for stroke volume changes above + 23.1 µL. Maintaining stroke volume values within a definite range might help maximize clinical benefit and avoid the risk of CSF overdrainage.

Perceived and actual changes in gait balance after CSF shunting in idiopathic normal pressure hydrocephalus.

OBJECTIVES: We evaluated the perceived and actual changes in gait and balance function immediately after cerebrospinal fluid (CSF) shunting in patients with idiopathic normal pressure hydrocephalus (iNPH), including those with mild cases. MATERIALS AND METHODS: Ninety-nine iNPH patients were assessed using the timed Up and Go (TUG) and Functional Gait Assessment (FGA) before and 1-week after CSF shunting and their perceived changes were assessed on a Global Rate of Change (GRC) scale. Minimal clinically important differences (MCIDs) were calculated using a receiver operating characteristic (ROC) curve method using GRC scores. RESULTS: In all patients (n = 99), the TUG value postoperatively was significantly faster than the preoperative value (difference; 3.1 ± 4.6 s, p < 0.001), and the postoperative FGA score was significantly better than the preoperative score (difference; 3.8 ± 3.3 points, p < 0.001). In the TUG <15 s group (n = 51), the postoperative FGA score was significantly improved (difference; 3.3 ± 2.9 points, p < 0.001), whereas the TUG value was only slightly improved (difference; 0.6 ± 1.6 s, p = 0.008). The ROC curve MCIDs of GRC ≥2 points, which is the recommended level of improvement, were 1.7 s (16.5%) for the TUG and 4 points (20.0%) for the FGA in all patients (n = 99) and the TUG <15 s group (n = 51). CONCLUSIONS: FGA can be used to confirm treatment effects, including perceived and actual changes after CSF shunting, in patients with mild iNPH. Our results can help clinicians to determine the clinical significance of improvements in gait and balance function immediately after CSF shunting in individual patients with iNPH.

The Pathogenesis Based on the Glymphatic System, Diagnosis, and Treatment of Idiopathic Normal Pressure Hydrocephalus.

Idiopathic normal pressure hydrocephalus (iNPH) is a rare neurological disorder with no clear prevalence factors and is a significant danger to the elderly. The intracranial glymphatic system is the internal environment that maintains brain survival and metabolism, and thus fluid exchange changes in the glymphatic system under various pathological conditions can provide important insights into the pathogenesis and differential diagnosis of many neurodegenerative diseases such as iNPH. iNPH can be diagnosed using a combination of clinical symptoms, imaging findings and history, and cerebrospinal fluid biomarkers due to the glymphatic system disorder. However, only few researchers have linked the two. Shunt surgery can improve the glymphatic system disorders in iNPH patients, and the surgical approach is determined using a combination of clinical diagnosis and trials. Therefore, we have composed this review to provide a future opportunity for elucidating the pathogenesis of iNPH based on the glymphatic system, and link the glymphatic system to the diagnosis and treatment of iNPH. The review will provide new insights into the medical research of iNPH.

Structural volumetry in NPH diagnostics and treatment-future or dead end?

To assess automated volumetric analysis as a potential presurgical diagnostic tool or as a method to potentially shed light on normal pressure hydrocephalus (NPH) pathophysiology. MRI imaging according to our protocol was performed in 29 NPH patients, 45 non-NPH (but suspected) patients and 15 controls. Twenty patients underwent a second MRI 3 months after ventriculoperitoneal (VP) shunt surgery. All structures relevant to NPH diagnosis were automatically segmented using commercial software. The results were subsequently tested using ANOVA analysis. Significant differences in the volumes of the corpus callosum, left hippocampus, internal globus pallidus, grey and white matter and ventricular volumes were observed between NPH group and healthy controls. However, the differences between NPH and non-NPH groups were non-significant. Three months after, VP shunt insertion decreased ventricular volume was the only clearly significant result (p value 0.0001). Even though a detailed volumetric study shows several significant differences, volumetric analysis as a standalone method does not provide a simple diagnostic biomarker, nor does it shed a light on an unknown NPH aetiology.

Altered glymphatic system in idiopathic normal pressure hydrocephalus.

OBJECTIVE: To assess the glymphatic activity in patients with idiopathic normal pressure hydrocephalus (NPH) using the "Diffusion Tensor Image-Analysis aLong the Perivascular Space (DTI-ALPS)" method, and determine the feasibility of non-invasive MRI for the evaluation of the glymphatic function. METHODS: Between April 2017 and March 2019, 16 patients diagnosed with NPH and 16 age- and sex-matched controls were included. On 3T DTI-MRI, the diffusivities along x-, y-, and z-axes were measured, and the ALPS-index - a ratio that accentuated water diffusion along the perivascular space - was calculated by two independent readers. The inter-observer agreement was tested using the interclass correlation coefficient. The differences in the diffusivities and the ALPS-index between the NPH and control groups were compared using the Mann-Whitney test. The values were also compared according to the treatment response to the cerebrospinal fluid drainage and correlated with the callosal angle using a correlation coefficient. RESULTS: The inter-observer agreements were excellent for the diffusivities and the ALPS-index. The diffusivity along the x-axis in the projection fibers area and the ALPS-index were significantly lower in patients with NPH (median, 0.556/1.181) than in the controls (0.610/1.540), respectively (P = 0.032/< 0.0001). The ALPS-index was significantly lower in the NPH group who did not show treatment response than those who showed symptomatic relief (0.987/1.329; P < 0.0001). The ALPS-index showed a significant positive correlation with the callosal angle (r = 0.82, P = 0.0001). CONCLUSIONS: The DTI-ALPS method can be a useful imaging tool for identifying glymphatic dysfunction and for individually quantifying glymphatic activity in patients with NPH.

Dynamic functional networks in idiopathic normal pressure hydrocephalus: Alterations and reversibility by CSF tap test.

Idiopathic Normal Pressure Hydrocephalus (iNPH)-the leading cause of reversible dementia in aging-is characterized by ventriculomegaly and gait, cognitive and urinary impairments. Despite its high prevalence estimated at 6% among the elderlies, iNPH remains underdiagnosed and undertreated due to the lack of iNPH-specific diagnostic markers and limited understanding of pathophysiological mechanisms. INPH diagnosis is also complicated by the frequent occurrence of comorbidities, the most common one being Alzheimer's disease (AD). Here we investigate the resting-state functional magnetic resonance imaging dynamics of 26 iNPH patients before and after a CSF tap test, and of 48 normal older adults. Alzheimer's pathology was evaluated by CSF biomarkers. We show that the interactions between the default mode, and the executive-control, salience and attention networks are impaired in iNPH, explain gait and executive disturbances in patients, and are not driven by AD-pathology. In particular, AD molecular biomarkers are associated with functional changes distinct from iNPH functional alterations. Finally, we demonstrate a partial normalization of brain dynamics 24 hr after a CSF tap test, indicating functional plasticity mechanisms. We conclude that functional changes involving the default mode cross-network interactions reflect iNPH pathophysiological mechanisms and track treatment response, possibly contributing to iNPH differential diagnosis and better clinical management.

Acute Presentation of Normal Pressure Hydrocephalus After Transcatheter Aortic Valve Implantation: A Novel Interaction Between the First and Third Circulations.

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) negatively affects gait and cognition abilities and urine continence in the elderly. It is associated with systemic hypertension, although the exact pathophysiology is still unknown. A correlation to increased intracranial pulsatility and decreased compliance was suggested. Transcatheter aortic valve implantation (TAVI) is increasingly used in the treatment of severe AS. New-onset systemic hypertension affects some patients after TAVI. OBJECTIVE: To identify any association between aortic valve replacement and the development of NPH. METHODS: A cohort was created retrospectively of all patients who were evaluated for NPH with cerebrospinal fluid (CSF) tap test at a single institute during 2014-2019. Patients were reviewed for a past medical history of aortic valvular disease or aortic valve replacement. RESULTS: A total of 242 patients underwent evaluations for NPH. Of these patients, 133 were considered to have iNPH. Six patients underwent aortic valve replacement before the initial symptoms of NPH: 1 surgical and 5 TAVI. The time from aortic valve replacement to the initial NPH symptoms was <6 months in 3 patients (as low as 1 month in 2 of them). Two patients had functional improvement after CSF tap test and proceeded to receive a shunt, 4 and 6 months after TAVI, respectively. Two patients developed hypertension after TAVI. Pulse pressure increased by >10 mm Hg in 3 patients after TAVI. CONCLUSIONS: This is the first case series of symptomatic NPH after TAVI. In this unique subgroup, NPH symptoms can develop rapidly. Post-TAVI iNPH represents a novel interaction between the blood and CSF circulations.

Pathogenesis and pathophysiology of idiopathic normal pressure hydrocephalus.

Idiopathic normal pressure hydrocephalus (iNPH), the most common type of adult-onset hydrocephalus, is a potentially reversible neuropsychiatric entity characterized by dilated ventricles, cognitive deficit, gait apraxia, and urinary incontinence. Despite its relatively typical imaging features and clinical symptoms, the pathogenesis and pathophysiology of iNPH remain unclear. In this review, we summarize current pathogenetic conceptions of iNPH and its pathophysiological features that lead to neurological deficits. The common consensus is that ventriculomegaly resulting from cerebrospinal fluid (CSF) dynamics could initiate a vicious cycle of neurological damages in iNPH. Pathophysiological factors including hypoperfusion, glymphatic impairment, disturbance of metabolism, astrogliosis, neuroinflammation, and blood-brain barrier disruption jointly cause white matter and gray matter lesions, and eventually lead to various iNPH symptoms. Also, we review the current treatment options and discuss the prospective treatment strategies for iNPH. CSF diversion with ventriculoperitoneal or lumboperitonealshunts remains as the standard therapy, while its complications prompt attempts to refine shunt insertion and develop new therapeutic procedures. Recent progress on advanced biomaterials and improved understanding of pathogenesis offers new avenues to treat iNPH.

In Vivo Evidence for Impaired Glymphatic Function in the Visual Pathway of Patients With Normal Pressure Hydrocephalus.

Purpose: Impaired ability to remove toxic metabolites from central nervous system may be an important link between cerebral and ophthalmic degenerative diseases. The aim of the present study was to compare the glymphatic function in the visual pathway in patients with idiopathic normal pressure hydrocephalus (iNPH), a neurodegenerative dementia subtype, with a reference group. Methods: We compared 31 subjects with Definite iNPH (i.e., shunt-responsive) with 13 references in a prospective and observational study. After intrathecal injection of the magnetic contrast agent gadobutrol (Gadovist, 0.5 mL, 1.0 mmol/mL, Bayer Pharma AG), serving as a tracer, consecutive magnetic resonance imaging (MRI) scans were obtained (next 24-48 hours). The normalized MRI T1 signal recorded in the cerebrospinal fluid (CSF) and along the visual pathway served as a semi-quantitative measure of tracer enrichment. Gadobutrol does not penetrate the blood-brain barrier and is thus confined to the extravascular space. Overnight measurements of pulsatile intracranial pressure were used as a surrogate marker for the intracranial compliance. Results: The tracer enriched the prechiasmatic cistern similarly in both groups, but clearance was delayed in the iNPH group. Moreover, both delayed enrichment and clearance of the tracer were observed in the visual pathway in the iNPH subjects. The enrichment in the visual pathway and the CSF correlated. Individuals with elevated pulsatile intracranial pressure showed reduced enrichment within the visual pathway. Conclusions: There was delayed enrichment and clearance of a tracer in the visual pathway of iNPH patients, which suggests impaired glymphatic function in the visual pathway in this disease.