Quantifying CSF Dynamics disruption in idiopathic normal pressure hydrocephalus using phase lag between transmantle pressure and volumetric flow rate

BackgroundMagnetic resonance imaging (MRI) does not only ascertain morphological features, but also measures physiological properties such as fluid velocity or pressure gradient. The purpose of this study was to investigate cerebrospinal fluid (CSF) dynamics in patients with morphological abnormalities such as enlarged brain ventricles and subarachnoid spaces. We used a time-resolved three dimensional phase contrast (3D-PC) MRI technique to quantitatively evaluate CSF dynamics in the Sylvian aqueduct of healthy elderly individuals and patients with either idiopathic normal pressure hydrocephalus (iNPH) or Alzheimer’s disease (AD) presenting with ventricular enlargement.MethodsNineteen healthy elderly individuals, ten iNPH patients, and seven AD patients (all subjects ≥ 60 years old) were retrospectively evaluated 3D-PC MRI. The CSF velocity, pressure gradient, and rotation in the Sylvian aqueduct were quantified and compared between the three groups using Kolmogorov–Smirnov and Mann–Whitney U tests.ResultsThere was no statistically significant difference in velocity among the three groups. The pressure gradient was not significantly different between the iNPH and AD groups, but was significantly different between the iNPH group and the healthy controls (p < 0.001), and similarly, between the AD group and the healthy controls (p < 0.001). Rotation was not significantly different between the iNPH and AD groups, but was significantly different between the iNPH group and healthy controls (p < 0.001), and similarly, between the AD group and the healthy controls (p < 0.001).ConclusionsQuantitative analysis of CSF dynamics with time resolved 3D-PC MRI revealed differences and similarities in the Sylvian aqueduct between healthy elderly individuals, iNPH patients, and AD patients. The results showed that CSF motion is in a hyperdynamic state in both iNPH and AD patient groups compared to healthy elderly individuals, and that iNPH patients and AD patients display similar CSF motion profiles.

The aim of the present study was to examine cerebrospinal fluid (CSF) volumetric net flow rate and direction at the cranio-cervical junction (CCJ) and cerebral aqueduct in individuals with idiopathic normal pressure hydrocephalus (iNPH) using cardiac-gated phase-contrast magnetic resonance imaging (PC-MRI). An in-depth, pixel-by-pixel analysis of regions of interest from the CCJ and cerebral aqueduct, respectively, was done in 26 iNPH individuals, and in 4 healthy subjects for validation purposes. Results from patients were compared with over-night measurements of static and pulsatile intracranial pressure (ICP). In iNPH, CSF net flow at CCJ was cranially directed in 17/22 as well as in 4/4 healthy subjects. Estimated daily CSF volumetric net flow rate at CCJ was 6.9 ± 9.9 L/24 hours in iNPH patients and 4.5 ± 5.0 L/24 hours in healthy individuals. Within the cerebral aqueduct, the CSF net flow was antegrade in 7/21 iNPH patients and in 4/4 healthy subjects, while it was retrograde (i.e. towards ventricles) in 14/21 iNPH patients. Estimated daily CSF volumetric net flow rate in cerebral aqueduct was 1.1 ± 2.2 L/24 hours in iNPH while 295 ± 53 ml/24 hours in healthy individuals. Magnitude of cranially directed CSF net flow in cerebral aqueduct was highest in iNPH individuals with signs of impaired intracranial compliance. The study results indicate CSF flow volumes and direction that are profoundly different from previously assumed. We hypothesize that spinal CSF formation may serve to buffer increased demand for CSF flow through the glymphatic system during sleep and during deep inspiration to compensate for venous outflow.

Cerebrospinal fluid volumetric net flow rate and direction in idiopathic normal pressure hydrocephalus

Normal pressure hydrocephalus (NPH) is a disorder found mainly in the elderly (> 60 years) with an increasing prevalence with age and is one of the few treatable causes of dementia. If untreated NPH often leads to severe motor, psychomotor and irreversible cognitive deficits. The pathogenesis is not yet fully understood. Clinical symptoms consist of the (not always complete) classical triad of equilibrium and gait disturbances followed later by incontinence and dementia. Symptoms often show a gradual progression to irreversibility in non-treated patients; therefore, early diagnosis and treatment are mandatory. Important differential diagnoses are Parkinson's disease (similar gait), Alzheimer's disease and vascular dementia, not least due to the high comorbidity of these conditions with NPH. The standard radiological method for evaluation of NPH is conventional cross-sectional imaging that typically shows ventriculomegaly (Evans' index > 0.3 and cella media index < 4) often combined with the so-called disproportionately enlarged subarachnoid space hydrocephalus (DESH) pattern (tight convexity sulci and enlarged sylvian fissure). These findings should be differentiated from ventriculomegaly in atrophy combined with enlarged convexity sulci. Special magnetic resonance imaging (MRI) techniques can be used to evaluate cerebrospinal fluid (CSF) flow but are not yet part of the diagnostic guidelines. Combined with cross-sectional imaging, well-established clinical and invasive diagnostic tests, such as repeated spinal tap or lumbar drainage with re-evaluation of clinical symptoms lead to a diagnosis and help with preoperative patient selection for CSF diversion. Ventriculoperitoneal CSF shunting has proven to be safe and is the only known successful therapy for NPH.

Disturbed cerebrospinal fluid (CSF) dynamics are part of the pathophysiology of normal pressure hydrocephalus (NPH) and can be modified and treated with shunt surgery. This study investigated the contribution of established CSF dynamic parameters to AMP(mean), a prognostic variable defined as mean amplitude of cardiac-related intracranial pressure pulsations during 10 min of lumbar constant infusion, with the aim of clarifying the physiological interpretation of the variable. AMP(mean) and CSF dynamic parameters were determined from infusion tests performed on 18 patients with suspected NPH. Using a mathematical model of CSF dynamics, an expression for AMP(mean) was derived and the influence of the different parameters was assessed. There was high correlation between modelled and measured AMP(mean) (r = 0.98, p < 0.01). Outflow resistance and three parameters relating to compliance were identified from the model. Correlation analysis of patient data confirmed the effect of the parameters on AMP(mean) (Spearman's ρ = 0.58-0.88, p < 0.05). Simulated variations of ±1 standard deviation (SD) of the parameters resulted in AMP(mean) changes of 0.6-2.9 SD, with the elastance coefficient showing the strongest influence. Parameters relating to compliance showed the largest contribution to AMP(mean), which supports the importance of the compliance aspect of CSF dynamics for the understanding of the pathophysiology of NPH.

Objective:Normal pressure hydrocephalus (NPH) is characterized by pathologically enlarged ventricles without elevated cerebrospinal fluid (CSF) pressure along with a triad of clinical symptoms including gait disturbances, urinary incontinence, and cognitive impairment. NPH is evaluated with lumbar drain trials (LDTs) where CSF is removed over several days to determine if patients would benefit from ventricular shunting. Candidate selection and success for these surgeries remains challenging because other diseases such as Alzheimer’s disease (AD) share common features with NPH in cognitive impairment and enlarged ventricles. Prior research has found that 20%-40% of presumed NPH cases have AD pathology as determined by brain biopsy or autopsy. CSF biomarkers of AD can be altered in NPH and are not always conclusive, complicating the interpretation of results when formulating diagnoses and prognoses. Studies to refine the analyses of AD CSF biomarkers in NPH are needed. We aimed to examine the frequency of CSF biomarker results among patients presenting for NPH evaluations with LDTs.Participants and Methods:62 patients presented for LDTs upon physician recommendations. CSF specimens were sent to Mayo Clinic Laboratories for Alzheimer Disease Evaluation (ADEVL) that utilizes Elecsys (Lenexa, KS) CSF electrochemiluminescence immunoassays (Roche Diagnostics, Basel, Switzerland) to measure levels of amyloid-beta 42 (Aβ42), total tau (t-tau), and phosphorylatedtau (p-tau), and p-tau:Aβ42 ratio. Results were classified based on interpretation through the Amyloid/Tau/Neurodegeneration (ATN) framework1: 1) AD - biomarker profile consistent with AD pathologic change, 2) non-AD profile - biomarker levels normal or inconsistent with AD pathologic change, or 3) indeterminate - biomarkers were incongruous with only one or two abnormal levels of Aβ42, t-tau, p-tau, or ptau: Aβ42. Indeterminate cases may represent altered protein levels due to CSF dynamics or AD-related pathologic change. In reviewing recent research on CSF dynamics and AD biomarkers in NPH2 a p-tau threshold of 15 pg/mL was derived and implemented such that cases with Aß42 &lt;=1026 pg/mL and p-tau &lt;15 pg/mL were designated as suspected non-AD, and those with Aß42 &lt;=1026 pg/mL and p-tau &gt;15 pg/mL were designated suspected AD.Results:Of the 62 LDT cases, 12 (19.35%) were classified as AD, 31 (50%) were indeterminate and 22 (35.48%) were non-AD. Of the 31 indeterminate cases, 21 (33.87% of the overall sample) were suspected non-AD and 7 (11.29% of the full sample) were categorized as suspected AD.Conclusions:Our findings show that 20%-30% of patients presenting for LDT showed evidence for AD-type pathologic change, consistent with prior reports of AD pathology in cases of possible NPH. Half of all LDT cases had indeterminate AD CSF biomarker results, the interpretations of which were confounded by the potential alterations of CSF biomarkers levels due to NPH independent of AD. Our findings emphasize the need to establish better approaches to interpreting CSF AD biomarkers in evaluating NPH. Future research should examine the discriminative utility of CSF AD biomarkers and the selected p-tau threshold in indeterminate cases for predicting response to LDT and shunting.

Normal pressure hydrocephalus is a treatable cause of dementia associated with distinct mechanical property signatures in the brain as measured by MR elastography. In this study, we tested the hypothesis that specific anatomic features of normal pressure hydrocephalus are associated with unique mechanical property alterations. Then, we tested the hypothesis that summary measures of these mechanical signatures can be used to predict clinical outcomes. MR elastography and structural imaging were performed in 128 patients with suspected normal pressure hydrocephalus and 44 control participants. Patients were categorized into 4 subgroups based on their anatomic features. Surgery outcome was acquired for 68 patients. Voxelwise modeling was performed to detect regions with significantly different mechanical properties between each group. Mechanical signatures were summarized using pattern analysis and were used as features to train classification models and predict shunt outcomes for 2 sets of feature spaces: a limited 2D feature space that included the most common features found in normal pressure hydrocephalus and an expanded 20-dimensional (20D) feature space that included features from all 4 morphologic subgroups. Both the 2D and 20D classifiers performed significantly better than chance for predicting clinical outcomes with estimated areas under the receiver operating characteristic curve of 0.66 and 0.77, respectively (P < .05, permutation test). The 20D classifier significantly improved the diagnostic OR and positive predictive value compared with the 2D classifier (P < .05, permutation test). MR elastography provides further insight into mechanical alterations in the normal pressure hydrocephalus brain and is a promising, noninvasive method for predicting surgical outcomes in patients with normal pressure hydrocephalus.

Normal pressure hydrocephalus (NPH) is a reversible cause of dementia in older adults, characterized by the clinical triad of gait disturbance, cognitive decline, and urinary incontinence. Owing to overlapping symptoms and low cerebrospinal fluid (CSF) Aβ42 levels, NPH is frequently misdiagnosed as Alzheimer's or Parkinson's disease. Objective: To provide a comprehensive narrative review of the pathophysiology, diagnostic challenges, treatment options, and prognostic markers of NPH, with a particular focus on implications for low- and middle-income countries (LMICs). Methods: Relevant literature published between 2000 and 2025 was retrieved from PubMed, Scopus, and Google Scholar using the keywords "normal pressure hydrocephalus," "cerebrospinal fluid dynamics," "ventriculoperitoneal shunting," and "biomarkers." Both clinical and experimental studies addressing NPH's pathophysiology, diagnostic modalities, and treatment outcomes were reviewed, with emphasis on studies applicable to LMIC contexts such as Pakistan. Results: Evidence indicates that disrupted CSF circulation and ventriculomegaly underlie NPH, with diffusion tensor imaging and arterial spin-labelling MRI offering diagnostic refinement. However, limited access to advanced neuroimaging and cultural perceptions of symptoms as "normal aging" contribute to underdiagnosis in LMICs. Ventriculoperitoneal shunting, particularly with fixed-pressure devices, consistently improves gait performance, while cognitive and urinary outcomes are variable. Post-shunt changes in CSF biomarkers (Aβ42, tau) and serum markers (BDNF, TRPV4) demonstrate potential prognostic value. Functional imaging further correlates reduced cerebral blood flow with symptom severity. Conclusion: NPH remains an under-recognized yet treatable neurological disorder. Increasing awareness, developing simplified diagnostic approaches, and ensuring cost-effective treatment strategies are essential to optimizing patient outcomes, particularly in resource-constrained settings.

Hydrocephalus is a brain disease wherein the ventricles dilate and compress the parenchyma towards the skull. It is primarily characterized by the disruption of the cerebrospinal fluid (CSF) flow within the ventricular system. Normal pressure hydrocephalus (NPH) is a form of hydrocephalus for which the enlargement of ventricles occurs although the intracranial pressure (ICP) remains close to normal. The pressure gradient between the source of CSF production in the ventricles and the absorption sites is reported to be very low (∼1 mm Hg), i.e. within the experimental errors. The mechanism of NPH evolution is still obscure and its distinction from the other causes of dementia such as Alzheimer and neurodegenerative diseases is difficult. The present work contributes to a better understanding of the NPH mechanism in terms of CSF disturbances and/or parenchyma defects. To this end, imaging techniques such as Magnetic resonance imaging (MRI), Diffusion tensor imaging (DTI) and Magnetic resonance elastography (MRE) are used together with a finite element (FE) model. As a final step, NPH onset and evolution are clarified via a theoretical model for healthy and NPH brains assuming a spherical geometry. The proposed mechanism is further analyzed in a realistic 3D model of the brain parenchyma. Geometries of ventricular system and skull are obtained from MRI images of a human brain. DTI data are used to establish the fiber tracts direction as well as the local frame of anisotropic elasticity and permeability. The brain parenchyma is considered as a poro-elastic material where the tissue displacement and CSF flow are modeled using the Biot's theory. A link between the CSF diffusion and CSF permeability in brain parenchyma is established and the importance of space dependent CSF content and transverse isotropic (TI) permeability is highlighted in case of low pressure gradient hydrocephalus. Calculations are carried out to simulate the ventricular dilation using FE softwares such as MATLAB® and COMSOL®. The numerical results show that consideration of space dependent CSF content and TI permeability leads to a much more realistic model for NPH in terms of CSF velocity and CSF content. Anisotropic MRE experiment is conducted over selected slices of a healthy human brain. The experimental results are statistically refined and further used to assess the healthy brain stiffness as well as the degree of anisotropy in elasticity. Moreover, the constitutive behavior of the white matter is modeled as a composite material containing fiber tracts surrounded by a matrix; with the assumption of a low fiber-matrix bonding and fiber tract undulation. A non-linear elastic model is proposed in order to take into account the load transfer from white matter matrix to fiber tracts when these are fully stretched. The unknown value of the elastic coefficients in a sick brain is determined by using inverse modeling, i.e. by adjusting these coefficients so that the right ventricle dilation is obtained. It is demonstrated that NPH development can be associated with a degradation of the brain parenchyma elastic stiffness in NPH patients. It is shown that during NPH development, a load transfer from the white matter matrix (cell bodies and interstitial fluid) to fiber tracts takes place, initiating elastic anisotropy in white matter tissues at rather large strains. An analytical approach is developed to seek the underlying NPH mechanism in a simplified model of brain. Without further refinement in the constitutive equation or adding complexity to the material behavior, the Biot's formulation is regarded as the basis. However, an absorption term is added to the Biot's model to consider the possible transparenchymal CSF resorption. The ventricle stability concept is introduced and is further utilized to investigate the equilibrium positions. The influence of different biomechanical parameters on the stable ventricle geometry is assessed and the healthy and NPH equilibrium positions are found to be dependent in particular on the CSF seepage through the ventricle wall and the absorption and permeability coefficients of the brain parenchyma. Although very simple, the proposed analytical model is able to predict the onset and development of NPH conditions as a deviation from healthy conditions. Incorporating the stability concept in a more realistic geometry of brain (3D), the respective equilibrium positions are recaptured using the parameter values provided by the analytical spherical model. The disruption of ventricle surface during the NPH development increases CSF seepage and consequently the medium permeability. A dilation dependent permeability is moreover incorporated in a 3D model of the brain. The results emphasize the importance of strain dependent permeability which favors the ventricle equilibrations in more realistic geometries of brain. Future works might consider the time dependent deformation (creep effects and stress induced remodeling) of ventricles and the incorporation of anisotropic permeability and elasticity in the 3D model. The geometry should be extended to the full ventricular system including the subarachnoid spaces (SAS).

Normal pressure hydrocephalus (NPH) in elderly patients is reviewed. Since the clinical signs that characterize NPH--incontinence, difficulty walking, and dementia--occur frequently in the elderly in association with a wide variety of disorders, attention is paid to the differential diagnosis of NPH on the basis of both clinical findings and laboratory tests. Success rates for treatment of NPH using surgical shunting are discussed, as are mortality rates and complication rates for this type of surgery in the elderly. Factors that may be of value in predicting which NPH patients are most likely to benefit from surgical intervention are reviewed, and the need for the development of pharmacological alternatives to surgery for elderly NPH patients is emphasized. As one of the most treatable causes of dementia in the elderly, NPH should be considered in the diagnosis of demented elderly patients with continence and gait disturbances, and it merits further research.

Cerebrospinal fluid (CSF) dynamics and long-term shunt survival of the Strata CSF shunt were evaluated in patients with idiopathic normal pressure hydrocephalus (INPH). Seventy-two patients with INPH received a Strata valve. A CSF infusion test, neuroimaging and video recording of gait were performed at baseline and at 6 months (n = 68) after surgery. Long-term shunt survivals were obtained from patient records. The shunt survival at 1 year was 94% and at 3 years 92.5%. Forty-nine patients (72%) had an improved gait. Two patients were improved despite non-functioning shunts, indicating a possible placebo response. Nineteen patients were not improved at the 6-month follow-up. The shunt tests revealed a functioning shunt in 12; thus, unnecessary shunt revisions could be avoided. Seventeen patients showed a siphoning effect. Shunt revisions were made in six patients. Eight hygromas/subdural hematomas were found. The long-term survival of the Strata valves was good, and a concern of complications is not a reason to exclude elderly with INPH from shunt surgery. Studies are needed to evaluate pros and cons of the anti-siphon device. Using a CSF shunt test, unnecessary shunt revisions may be avoided.

Age-Related Changes in Cerebrospinal Fluid Dynamics in the Pathogenesis of Chronic Hydrocephalus in Adults

BackgroundIn the cerebrospinal fluid (CSF) dynamics, the pulsations of cerebral arteries and brain is considered the main driving force for the reciprocating bidirectional CSF movements. However, measuring these complex CSF movements on conventional flow-related MRI methods is difficult. We tried to visualize and quantify the CSF motion by using intravoxel incoherent motion (IVIM) MRI with low multi-b diffusion-weighted imaging.MethodsDiffusion-weighted sequence with six b values (0, 50, 100, 250, 500, and 1000 s/mm2) was performed on 132 healthy volunteers aged ≥ 20 years and 36 patients with idiopathic normal pressure hydrocephalus (iNPH). The healthy volunteers were divided into three age groups (< 40, 40 to < 60, and ≥ 60 years). In the IVIM analysis, the bi-exponential IVIM fitting method using the Levenberg–Marquardt algorithm was adapted. The average, maximum, and minimum values of ADC, D, D*, and fraction of incoherent perfusion (f) calculated by IVIM were quantitatively measured in 45 regions of interests in the whole ventricles and subarachnoid spaces.ResultsCompared with healthy controls aged ≥ 60 years, the iNPH group had significantly lower mean f values in all the parts of the lateral and 3rd ventricles, whereas significantly higher mean f value in the bilateral foramina of Luschka. In the bilateral Sylvian fossa, which contain the middle cerebral bifurcation, the mean f values increased gradually with increasing age, whereas those were significantly lower in the iNPH group. In the 45 regions of interests, the f values in the bilateral foramina of Luschka were the most positively correlated with the ventricular size and indices specific to iNPH, whereas that in the anterior part of the 3rd ventricle was the most negatively correlated with the ventricular size and indices specific to iNPH. Other parameters of ADC, D, and D* were not significantly different between the two groups in any locations.ConclusionsThe f value on IVIM MRI is useful for evaluating small pulsatile complex motion of CSF throughout the intracranial CSF spaces. Patients with iNPH had significantly lower mean f values in the whole lateral ventricles and 3rd ventricles and significantly higher mean f value in the bilateral foramina of Luschka, compared with healthy controls aged ≥ 60 years.

The premature fusion of the sagittal suture (scaphocephaly) may be associated with intracranial cerebrospinal fluid (CSF) dynamics alterations resulting in pericerebral effusion (PE) and/or ventriculomegaly. However, the etiology and development of such collections are not fully elucidated. The aims of this study are to clarify the characteristics of intracranial CSF collection in scaphocephaly, consider the role of surgery, and analyze the prognostic factor on CSF dynamics. The pre- and postoperative cerebral imaging of 63 children (48 boys, 15 girls) with scaphocephaly who underwent craniotomy with decompression of the superior sagittal sinus (SSS) before 6months of age between 2008 and 2015 were retrospectively studied. The PE was compared to the estimated value corrected for age (normal control). Evans' index (EI) was calculated. Correlations among these values and indices were analyzed. Preoperatively, 36 of 63 patients (57%) had larger PE than expected, and 36 of 63 patients (57%) had pathological EI (EI>0.3), and among them, 26 (46%) had both. Patients with large PE tended to have pathological EI (p=0.005). The PE and the EI were significantly decreased postoperatively (p<0.001). The PE decreased faster than the expected natural course in 59 of 63 patients (92%) postoperatively. The precise comparison with estimated PE prevalence corrected for age showed that PE can be found in more than half of the children with scaphocephaly, associated with ventriculomegaly. Surgery has a significant efficacious role in decreasing those CSF collections. The long-term significance of such CSF collections in scaphocephaly is still to be elucidated.

Cerebrospinal fluid (CSF) pressure-volume compensation may change over time as part of normal ageing, where the resistance to CSF outflow increases and the formation of CSF decreases with age. Is CSF compensation dependent on duration of symptoms in idiopathic normal pressure hydrocephalus (iNPH)? We investigated 92 patients presenting with iNPH. Mean age was 73 (range 47-86). There were 60 men and 32 women. They all presented with gait disturbance and ventricular dilatation. Memory deficit occurred in 72% and urinary incontinence in 52% of patients. All patients underwent computerized CSF infusion tests. Sixty-four shunted patients were available for follow-up, and their improvement was expressed using the NPH score. Mean intracranial pressure (ICP) was 10.1±5.1 mmHg, and mean resistance to CSF outflow was 17.3±5.2 mmHg/(ml/min). Mean duration of symptoms was 24±19 months (range from 2 weeks to 86 months). Baseline ICP, magnitude of ICP pulse waveform, brain compliance and improvement after shunting (72% of patients improved) did not exhibit any dependency on the duration of symptoms. The resistance to CSF outflow showed a strong tendency to decrease in time with the duration of symptoms beyond 2 years (R= -0.702; P<0.005). This is a preliminary observation, and it suggests that for patients with duration of symptoms longer than 2-3 years, the threshold for normal resistance to CSF outflow should be duration-adjusted.