Noninvasive assessment of glymphatic dysfunction in idiopathic normal pressure hydrocephalus with diffusion tensor imaging.

OBJECTIVE: Diffusion tensor imaging (DTI) along the perivascular space (ALPS) (DTI-ALPS)-by calculating the ALPS index, a ratio accentuating water diffusion in the perivascular space-has been proposed as a noninvasive, indirect MRI method for assessing glymphatic function. The main aim of this study was to investigate whether DTI-ALPS would reveal glymphatic dysfunction in idiopathic normal pressure hydrocephalus (iNPH) and whether the ALPS index was associated with disease severity. METHODS: Thirty iNPH patients (13 men; median age 77 years) and 27 healthy controls (10 men; median age 73 years) underwent MRI and clinical assessment with the Timed Up and Go test (TUG) and Mini-Mental State Examination (MMSE); only the patients were evaluated with the Hellström iNPH scale. MRI data were analyzed with the DTI-ALPS method and Radscale screening tool. RESULTS: iNPH patients showed significantly lower mean ALPS index scores compared with healthy controls (median [interquartile range] 1.09 [1.00-1.15] vs 1.49 [1.36-1.59], p < 0.001). Female healthy controls showed significantly higher ALPS index scores than males in both hemispheres (e.g., right hemisphere 1.62 [1.47-1.67] vs 1.33 [1.14-1.41], p = 0.001). This sex difference was not seen in iNPH patients. The authors found a moderate exponential correlation between mean ALPS index score and motor function as measured with time required to complete TUG (r = -0.644, p < 0.001), number of steps to complete TUG (r = -0.571, p < 0.001), 10-m walk time (r = -0.637, p < 0.001), and 10-m walk steps (r = -0.588, p < 0.001). The authors also found a positive linear correlation between mean ALPS index score and MMSE score (r = 0.416, p = 0.001). Simple linear regression showed a significant effect of diagnosis (B = -0.39, p < 0.001, R2 = 0.459), female sex (B = 0.232, p = 0.002, R2 = 0.157), and Evans index (B = -4.151, p < 0.001, R2 = 0.559) on ALPS index. Multiple linear regression, including diagnosis, sex, and Evans index score, showed a higher predictive value (R2 = 0.626) than analysis of each of these factors alone. CONCLUSIONS: The ALPS index, which was significantly decreased in iNPH patients, could serve as a marker of disease severity, both clinically and in terms of neuroimaging. However, it is important to consider the significant influence of biological sex and ventriculomegaly on the ALPS index, which raises the question of whether the ALPS index solely reflects glymphatic function or if it also encompasses other types of injury. Future studies are needed to address potential confounding factors and further validate the ALPS method.

Idiopathic Normal Pressure Hydrocephalus: The Real Social and Economic Burden of a Possibly Enormous Underdiagnosis Problem.

Normal Pressure Hydrocephalus (iNPH) typically affects the elderly and can cause cognitive decline, resulting in its differential diagnosis with other neurodegenerative conditions. Moreover, it is probably underdiagnosed; such under- and misdiagnosis prevents the patient from receiving the right treatment and significantly affects the quality of life and life expectancy. This investigation is an in-depth analysis of the actual incidence of iNPH in the population of the province served by our hospital (circa 580,000 individuals). The first phase of this study was conducted by visualizing a total of 1232 brain CT scans performed in the Emergency Departments of the four hospitals of our network on patients who were admitted for different complaints yet screened as suspicious for iNPH. Subsequently, corresponding Emergency Department medical records were investigated to understand the medical history of each patient in search of elements attributable to an alteration of CSF dynamics. The cohort of positive CT scans, according to the radiological and clinical inclusion criteria, included 192 patients. Among the reasons to require acute medical care, "Fall" was the most common. The cumulative incidence of CT scans suggestive of iNPH among the patients undergoing CT scans was as high as 15.58%, and the period prevalence calculated for the total amount of patients accessing the Emergency Departments was 1.084%. The real incidence of iNPH in the population may be underestimated, and the social burden linked to the assistance of patients suffering from such untreated conditions could be significantly relieved.

A subject-specific assessment of measurement errors and their correction in cerebrospinal fluid velocity maps using 4D flow MRI.

PURPOSE: Phase-contrast MRI (PC-MRI) of cerebrospinal fluid (CSF) velocity is used to evaluate the characteristics of intracranial diseases, such as normal-pressure hydrocephalus (NPH). Nevertheless, PC-MRI has several potential error sources, with eddy-current-based phase offset error being non-negligible in CSF measurement. In this study, we assess the measurement error of CSF velocity maps obtained using 4D flow MRI and evaluate correction methods. METHODS: CSF velocity maps of 10 patients with NPH were acquired using 4D flow MRI (velocity-encoding = 5 cm/s). Distributed phase offset error was estimated for a whole 3D background field by polynomial fitting using robust regression analysis. This estimated phase offset error was then used to correct the CSF velocity maps. The estimated error profiles were compared with those obtained using an existing 2D correction approach involving local background information near the region of interest. RESULTS: The residual standard error of the polynomial fitting against the phase offset error extracted from the measured velocities was within 0.2 cm/s. The spatial dependencies of the phase offset errors showed similar tendencies in all cases, but sufficient differences in these values were found to indicate requirement of velocity correction. Differences of the estimated errors among other correction approaches were in the order of 10-2 cm/s, and the estimated errors were in good agreement with those obtained using existing approaches. CONCLUSION: Our method is capable of estimating the measurement error of CSF velocity maps obtained from 4D flow MRI and provides quantitatively reasonable characteristics for the main CSF profile in the cerebral aqueduct in patients with NPH.

Semi-automated assessment of the principal diffusion direction in the corpus callosum: differentiation of idiopathic normal pressure hydrocephalus from neurodegenerative diseases.

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) shares clinical and radiological features with progressive supranuclear palsy (PSP) and Alzheimer's disease (AD). Corpus callosum (CC) involvement in these disorders is well established on structural MRI and diffusion tensor imaging (DTI), but alterations overlap and lack specificity to underlying tissue changes. OBJECTIVE: We propose a semi-automated approach to assess CC integrity in iNPH based on the spatial distribution of DTI-derived principal diffusion direction orientation (V1). METHODS: We processed DTI data from 121 subjects (Site1: iNPH = 23, PSP = 27, controls = 14; ADNI: AD = 35, controls = 22) to obtain V1, fractional anisotropy (FA) and mean diffusivity (MD) maps. To increase the estimation accuracy of DTI metrics, analyses were restricted to the midsagittal CC portion (± 6 slices from midsagittal plane). Group-wise comparison of normalized altered voxel count in midsagittal CC was performed using Kruskal-Wallis tests, followed by post hoc comparisons (Bonferroni-corrected p < 0.05). ROC analysis was used to evaluate the diagnostic power of DTI alterations compared to callosal volume. RESULTS: We found specific changes of V1 distribution in CC splenium of iNPH compared to AD and PSP, while MD and FA showed patterns of alterations common to all disorders. ROC curves showed that, compared to splenial volume, V1 represented the most accurate marker of iNPH diagnosis versus AD and PSP. CONCLUSIONS: Our results provide evidence that V1 is a powerful biomarker for distinguishing patients with iNPH from patients with AD or PSP. Indeed, our findings also provide more specific insight into the pathophysiological mechanisms that underlie tissue damage across iNPH and its mimics.

Clinical application of intrathecal gadobutrol for assessment of cerebrospinal fluid tracer clearance to blood.

BACKGROUNDMethodology for estimation of cerebrospinal fluid (CSF) tracer clearance could have wide clinical application in predicting excretion of intrathecal drugs and metabolic solutes from brain metabolism and for diagnostic workup of CSF disturbances.METHODSThe MRI contrast agent gadobutrol (Gadovist) was used as a CSF tracer and injected into the lumbar CSF. Gadobutrol is contained outside blood vessels of the CNS and is eliminated along extravascular pathways, analogous to many CNS metabolites and intrathecal drugs. Tracer enrichment was verified and assessed in CSF by MRI at the level of the cisterna magna in parallel with obtaining blood samples through 48 hours.RESULTSIn a reference patient cohort (n = 29), both enrichment within CSF and blood coincided in time. Blood concentration profiles of gadobutrol through 48 hours varied between patients diagnosed with CSF leakage (n = 4), idiopathic normal pressure hydrocephalus dementia (n = 7), pineal cysts (n = 8), and idiopathic intracranial hypertension (n = 4).CONCLUSIONAssessment of CSF tracer clearance is clinically feasible and may provide a way to predict extravascular clearance of intrathecal drugs and endogenous metabolites from the CNS. The peak concentration in blood (at about 10 hours) was preceded by far peak tracer enhancement at MRI in extracranial lymphatic structures (at about 24 hours), as shown in previous studies, indicating a major role of the spinal canal in CSF clearance capacity.FUNDINGThe work was supported by the Department of Neurosurgery, Oslo University Hospital; the Norwegian Institute for Air Research; and the University of Oslo.

Detailed visual assessment of striatal dopaminergic depletion in patients with idiopathic normal pressure hydrocephalus: unremarkable or not?

BACKGROUND: Dopamine transporter (DAT) imaging may enable clinicians to discriminate idiopathic normal pressure hydrocephalus (iNPH) from other parkinsonian disorders. However, a specific pattern of dopaminergic loss in DAT imaging of iNPH patients remains to be further elucidated. METHODS: In this preliminary study, 11 patients with iNPH in our hospital between March 2017 and February 2019 were finally enrolled. A diagnosis of iNPH was made according to the two established criteria. For visual analysis of DAT imaging, a striatum was divided into five domains. A semi-quantitative visual assessment was performed with a consensus between a nuclear medicine specialist and an experienced neurologist who were blinded to the clinical diagnosis. RESULTS: Striatal dopaminergic deficits were abnormal in 90.9% (10/11) of patients with iNPH. The degree of dopaminergic reduction was mild and heterogeneous. However, a tendency of preferential striatal DAT loss in the caudate nucleus (90.9%, 10/11) than in the putamen (72.7%, 8/11) was observed, whereas ventral portion (9.1%, 1/11) was relatively preserved. CONCLUSION: Striatal dopaminergic depletion might be mild and heterogeneous in patients with iNPH. These dopaminergic deficits were more common in the caudate nucleus than in the putamen, suggesting a pattern different from other degenerative parkinsonian disorders.

Fluoroscopic-Guided Paramedian Approach for Lumbar Catheter Placement in Cerebrospinal Fluid Shunting: Assessment of Safety and Accuracy.

BACKGROUND: Spinal catheter insertion in lumboperitoneal (LP) shunt surgery for idiopathic normal pressure hydrocephalus (iNPH) is frequently associated with technical difficulties especially in patients with obesity and elderly patients with vertebral deformities. OBJECTIVE: To elucidate the accuracy and safety of image-guided spinal catheter placement using a paramedian approach (PMA). METHODS: We retrospectively analyzed 39 consecutive iNPH patients treated by LP shunting with spinal catheter insertion via the PMA. The success rate of catheter placement and the number of changes in puncture location were evaluated. Accuracy of catheter insertion was assessed by measuring both vertical and horizontal deviations in the point of catheter dural penetration from the center of the interlaminar space. RESULTS: The success rate of catheter placement was 100% (39/39). The difficulty rate for catheter insertion, measured by the number of changes in puncture location, was 2.6% (1/39). No bloody punctures or surgical infections were observed. Accuracy of catheter insertion, measured as the degree of deviation, was 0.5 ± 1.9 mm horizontally and 0.0 ± 2.4 mm vertically. The rates of minor complications, including caudal catheter insertion, transient low-pressure headache, and root pain, were 5.1% (2/39), 10.4% (4/39), and 0% (0/43), respectively. Subdural hematoma requiring surgical intervention occurred in 1 case (2.6%). During the mean follow-up period of 36 mo, spinal catheter rupture at the level of the spinous processes was not observed. CONCLUSION: Fluoroscopic-guided spinal catheter placement via the PMA was safe, accurate, and reliable, even for use in geriatric and obese patients.

Non-invasive assessment of pulsatile intracranial pressure with phase-contrast magnetic resonance imaging.

Invasive monitoring of pulsatile intracranial pressure can accurately predict shunt response in patients with idiopathic normal pressure hydrocephalus, but may potentially cause complications such as bleeding and infection. We tested how a proposed surrogate parameter for pulsatile intracranial pressure, the phase-contrast magnetic resonance imaging derived pulse pressure gradient, compared with its invasive counterpart. In 22 patients with suspected idiopathic normal pressure hydrocephalus, preceding invasive intracranial pressure monitoring, and any surgical shunt procedure, we calculated the pulse pressure gradient from phase-contrast magnetic resonance imaging derived cerebrospinal fluid flow velocities obtained at the upper cervical spinal canal using a simplified Navier-Stokes equation. Repeated measurements of the pulse pressure gradient were also undertaken in four healthy controls. Of 17 shunted patients, 16 responded, indicating high proportion of "true" normal pressure hydrocephalus in the patient cohort. However, there was no correlation between the magnetic resonance imaging derived pulse pressure gradient and pulsatile intracranial pressure (R = -.18, P = .43). Pulse pressure gradients were also similar in patients and healthy controls (P = .26), and did not differ between individuals with pulsatile intracranial pressure above or below established thresholds for shunt treatment (P = .97). Assessment of pulse pressure gradient at level C2 was therefore not found feasible to replace invasive monitoring of pulsatile intracranial pressure in selection of patients with idiopathic normal pressure hydrocephalus for surgical shunting. Unlike invasive, overnight monitoring, the pulse pressure gradient from magnetic resonance imaging comprises short-term pressure fluctuations only. Moreover, complexity of cervical cerebrospinal fluid flow and -pulsatility at the upper cervical spinal canal may render the pulse pressure gradient a poor surrogate marker for intracranial pressure pulsations.

The role of perfusion and diffusion MRI in the assessment of patients affected by probable idiopathic normal pressure hydrocephalus. A cohort-prospective preliminary study.

BACKGROUND: Invasive tests measuring resistance to cerebral spinal fluid (CSF) outflow and the effect of temporary drainage of CSF are used to select candidates affected by idiopathic normal pressure hydrocephalus (iNPH) for shunt surgery. Neither test, however, completely excludes patients from treatment. Perfusion and diffusion magnetic resonance imaging (MRI) are non-invasive techniques that might be of value in selecting patients for surgical treatment and understanding brain changes in iNPH patients. The aim of this study was to understand the role of perfusion and diffusion MRI in selecting candidates for shunt surgery and to investigate the relationship between cerebral perfusion and possible microstructural changes in brain tissue before and after invasive tests, and after ventricular-peritoneal (VP) shunt implantation, to better clarify pathophysiological mechanisms underlying iNPH. METHODS: Twenty-three consecutive patients with probable iNPH were included in this study. Patients underwent a clinical and neuroradiological evaluation before and after invasive tests, and after surgery. Only patients who showed a positive result in at least one of the invasive tests were submitted for VP shunt implantation. Perfusion and diffusion magnetic resonance imaging (MRI) was performed before and after invasive tests and after shunt surgery. RESULTS: Thirteen patients underwent surgery and all showed clinical improvement after VP shunt implantation and a significant increase in perfusion in both periventricular white matter (PVWM) and basal ganglia (BG) regions. The 10 patients that did not have surgery showed after invasive tests, a significant reduction in perfusion in both PVWM and BG regions. Comparing the changes in perfusion with those of diffusion in positive patients we found a significant positive correlation in BG and a significant inverse correlation in PVWM area. CONCLUSIONS: Perfusion MRI is a non-invasive technique that could be useful together with invasive tests in selecting patients for surgical treatment. Furthermore, the relationship between perfusion and diffusion data could better clarify pathophysiological mechanisms underlying iNPH. In PVWM area we suggest that interstitial edema could reduce microvascular blood flow and interfere with the blood supply to these regions. In BG regions we suggest that a chronic hypoxic insult caused by blood hypo-perfusion produces a chronic cytotoxic edema. Both in PVWM and in BG regions, pathophysiological mechanisms could be modified after VP-shunt implantation.

Diffusion imaging of reversible and irreversible microstructural changes within the corticospinal tract in idiopathic normal pressure hydrocephalus.

The symptoms of idiopathic normal pressure hydrocephalus (iNPH) can be improved by shunt surgery, but prediction of treatment outcome is not established. We investigated changes of the corticospinal tract (CST) in iNPH before and after shunt surgery by using diffusion microstructural imaging, which infers more specific tissue properties than conventional diffusion tensor imaging. Two biophysical models were used: neurite orientation dispersion and density imaging (NODDI) and white matter tract integrity (WMTI). In both methods, the orientational coherence within the CSTs was higher in patients than in controls, and some normalization occurred after the surgery in patients, indicating axon stretching and recovery. The estimated axon density was lower in patients than in controls but remained unchanged after the surgery, suggesting its potential as a marker for irreversible neuronal damage. In a Monte-Carlo simulation that represented model axons as undulating cylinders, both NODDI and WMTI separated the effects of axon density and undulation. Thus, diffusion MRI may distinguish between reversible and irreversible microstructural changes in iNPH. Our findings constitute a step towards a quantitative image biomarker that reflects pathological process and treatment outcomes of iNPH.

Regional cerebral metabolic rate of glucose evaluation and clinical assessment in patients with idiopathic normal-pressure hydrocephalus before and after ventricular shunt placement: a prospective analysis.

PURPOSE: We prospectively evaluated the regional cerebral metabolic rate of glucose (CMRglu) before and after ventricular shunt placement in idiopathic normal-pressure hydrocephalus (iNPH) patients, to investigate whether some brain regions are more involved than others; we also correlated the individual variations of CMRglu with the clinical scale score assessment after shunting. METHODS: Twenty iNPH patients (12 men; mean age 73 ± 9 years) underwent clinical scale score assessment and F-FDG PET-CT before and 1 week after shunting. RESULTS: Before shunting, CMRglu values were similar in right and left brain regions, as well as after shunting. After shunting, 17 of 20 iNPH patients were clinically improved; all scale scores decreased, and CMRglu significantly increased in all regions (P < 10). In 3 of 20 iNPH patients, the symptoms persisted, the scale scores did not change, and CMRglu increased only in 3 regions: left frontal, left putamen, and right thalamus. Before shunting, no difference in global CMRglu between clinically improved (n = 17) and not improved (n = 3) iNPH patients was found. After shunting, a significant (P = 0.01) correlation between individual variations of CMRglu and clinical assessment was found. CONCLUSIONS: These findings confirm that iNPH is a disease involving all cerebral regions almost in the same way, and shunt procedure has a similar effect on regional cerebral metabolism almost in the same way. Individual variations of CMRglu are more important than absolute values and correlate with clinical status after shunting. Clinical improvement depends not only on the capability to restore the cerebrospinal fluid dynamic, but also on the ability of cerebral parenchyma to recover the metabolic function.

Predictive assessment of shunt effectiveness in patients with idiopathic normal pressure hydrocephalus by determining regional cerebral blood flow on 3D stereotactic surface projections.

BACKGROUND: The regional cerebral blood flow (rCBF) and cerebral metabolism in patients with idiopathic normal pressure hydrocephalus (iNPH) remain to be studied in detail. PURPOSE: Using single-photon emission computed tomography (SPECT), we compared the characteristic rCBF patterns in iNPH patients who did, or did not, respond to shunt operations. MATERIALS AND METHODS: We studied 24 consecutive iNPH patients: 14 men and 10 women aged 68 to 88 years (mean 77.5 years). Using the Japanese normal pressure hydrocephalus grading scale, they were divided into responders and non-responders to shunt operations. Follow-up ranged from 10 to 36 months (mean 25 months). We obtained baseline single-photon emission computed tomography (SPECT) data on three-dimensional stereotactic surface projections (3D-SSP) before and after shunt operations, and compared rCBF in responders and non-responders. RESULTS: On statistical maps, responders manifested significantly lower rCBF in the basal frontal lobes and cingulate gyrus (anterior-dominant). CONCLUSIONS: The preoperative measurement of rCBF by 3D-SSP SPECT may help to identify iNHP patients expected to exhibit a good response to shunt operations.

Voxel-based assessment of spinal tap test-induced regional cerebral blood flow changes in normal pressure hydrocephalus.

OBJECTIVE: Normal pressure hydrocephalus (NPH) is a cause of dementia that may be amended by medical intervention. Its diagnosis is therefore of major importance and the establishment of response criteria to cerebrospinal fluid (CSF) shunting is essential. One of these criteria is the clinical response to spinal tap. The accuracy of the spinal tap test could potentially be improved by adding neuroimaging of regional cerebral blood flow (rCBF) changes to the response criteria. Statistical parametric mapping (SPM) is a voxel-based method of image analysis that may be used to statistically assess the significance of rCBF changes. The objective of this study was to evaluate, by SPM, spinal tap test-induced rCBF changes in patients with NPH syndrome. METHODS: Forty patients with NPH syndrome underwent hexamethylpropylene amine oxime (HMPAO) brain single photon emission computed tomography (SPECT) before and after a spinal tap test (1-day split-dose protocol). The differences in rCBF between these pairs of scans were analysed by SPM in the whole group and between subgroups divided according to gait improvement at the spinal tap test. RESULTS: In the whole group of patients, there was no statistical difference between pre- and post-spinal tap SPECT images. SPM analysis of patients grouped as a function of their clinical response to the spinal tap test revealed a significant post-spinal tap rCBF increase in the bilateral dorsolateral frontal and left mesiotemporal cortex in clinically responding compared with non-responding patients. CONCLUSION: According to SPM analysis, gait improvement at the spinal tap test in patients with NPH syndrome is associated with an rCBF increase localized in the bilateral dorsolateral frontal and left mesiotemporal cortex.

Cortical perfusion assessment with 123I-isopropyl amphetamine (123I-IAMP) in normal pressure hydrocepha lus (NPH).

NPH can be reversible after cerebrospinal fluid (CSF) diversion. In the past no reliable criteria could be defined to predict the successful outcome of CSF shunting. Several authors demonstrated an increased cerebral blood flow after lumbar puncture in patients with NPH, indicating an underlying impairment of cerebral circulation autoregulation. 123I-AMP brain tomoscintigraphy was applied to 23 individuals with NPH before and after CSF drainage. Of these 23 patients, 10 underwent surgical shunting. The frontal and parietal hypoactive cortical pattern was present in NPH but not pathognomonic. Under stimulation of CSF pressure lowering, seven patients with improved outcome after shunting demonstrated an increase of cerebral perfusion in these areas, whereas a decrease of activity was found in three patients whose clinical status was unchanged after CSF diversion. This tomoscintigraphic test may be an interesting additional criterion for surgical admission.