Imaging cerebrospinal fluid dynamics in idiopathic normal pressure hydrocephalus

Imaging Cerebrospinal Fluid Dynamics in Idiopathic Normal Pressure Hydrocephalus

Geir André Ringstad

Dissertation Submitted for the Degree of Doctor of Philosophy

Division of Radiology and Nuclear Medicine, Oslo University Hospital - Rikshospitalet

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Faculty of Medicine, University of Oslo, Oslo, Norway

2018

©*HLU$QGUp5LQJVWDG, 2018

Series of dissertations submitted to the Faculty of Medicine, University of Oslo

ISBN 978-82-8377-

All rights reserved. No part of this publication may be

reproduced or transmitted, in any form or by any means, without permission.

Cover: Hanne Baadsgaard Utigard.

Print production: Reprosentralen, University of Oslo.

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The great tragedy of science, the slaying of a beautiful theory by an ugly fact.

T. H. Huxley (1825-1895

)

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Contents

Acknowledgements... 5

Abbreviations ... 7

Summary in English ... 9

Sammendrag på norsk ... 11

List of publications ... 13

1. Introduction ... 14

1.1. Historical overview of cerebrospinal fluid ... 14

1.2. From the bulk flow hypothesis to new concepts ... 15

1.3 Presentation of NPH ... 17

1.4 Pathogenesis ... 18

1.5 Classification ... 21

1.6 Epidemiology ... 22

1.7 Symptoms and co-morbidities ... 22

1.7.1 Gait disturbance ... 23

1.7.2 Urinary incontinence ... 23

1.7.3 Dementia ... 23

1.8 Treatment ... 24

1.9 Additional tests ... 25

1.9.1 CSF tap test, infusion test and external lumbar drainage ... 25

1.9.2 ICP monitoring ... 26

1.9.3 Imaging ... 26

1.10 Summary of key points from Introduction ... 35

2. Aims of the thesis ... 36

3. Methods ... 37

3.1 Assessments of aqueductal CSF flow parameters (Paper 1 and 3) ... 37

3.1.1. Study population and design ... 37

3.1.2. Clinical management and ICP monitoring ... 38

3.1.3 MRI ... 39

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3.1.4 Statistics ... 39

3.2 Assessment of the PC-MRI derived pulse pressure gradient (MRI-dP) (Paper 2) ... 40

3.2.1 Study population ... 40

3.2.2 Clinical management and ICP monitoring ... 40

3.2.3 PC-MRI ... 40

3.2.4 Statistics ... 41

3.3 Glymphatic MRI (Paper 4) ... 41

3.3.1 Study population and design ... 41

3.3.2 Clinical management ... 41

3.3.3 MR imaging ... 41

3.3.4 Statistics ... 42

4. Results ... 43

4.1 PC-MRI derived parameters of intracranial pulsatility ... 43

4.1.1 Aqueductal Stroke Volume (Paper 1) ... 43

4.1.2 Peak to peak pulse pressure gradient (MRI-dP) (Paper 2) ... 43

4.2 Characteristics of CSF flow in iNPH ... 45

4.2.1 Net Aqueductal Flow (Paper 3) ... 45

4.2.2 Glymphatic MRI (Paper 4) ... 46

5. Discussion ... 48

5.1 PC-MRI derived parameters of intracranial pulsatility ... 48

5.1.1 General methodological considerations (Paper 1 and 2) ... 48

5.1.2 Aqueductal stroke volume (Paper 1) ... 50

5.1.3 Peak to peak pulse pressure gradient (MRI-dP) (Paper 2) ... 54

5.2 Characteristics of CSF flow in iNPH ... 56

5.2.1 Net retrograde aqueductal flow and supra-aqueductal reflux of gadobutrol (Paper 3 and 4) ... 56

5.2.2 Glymphatic MRI (Paper 4) ... 62

5.3 Experiences with publications of negative results ... 66

6. Conclusions ... 68

7. Future developments ... 69

References ... 71

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Acknowledgements

This thesis derives from studies carried out at Oslo University Hospital – Rikshospitalet in cooperation with the Department of Neurosurgery, Department of Radiology and The Intervention Centre.

First, I wish to express my sincere gratitude to all patients who participated in the studies and endured extensive MR imaging for the best of science. Many thanks also go to the MRI technicians at the Intervention Centre and nursing staff at the Department of Neurosurgery, who provided the best possible care for all patients.

I am deeply grateful to my main supervisor, Per Kristian Eide, for his

invaluable support and for continuously sharing from his extensive experience and enthusiasm. Our countless, fruitful discussions and his open-mindedness to new perspectives and ideas have been of true inspiration to me. My

warmest thanks also go to co-supervisor Kyrre Eeg Emblem, who has masterly tutored and encouraged me from the beginning of this project and always impressed me with his many skills and efficiency. Noam Alperin has also been my co-supervisor, and I thank him for his contributions.

The present work had not been possible without the time granted me from the Department of Radiology, and I would like to especially thank head of

department, Paulina Due-Tønnessen, and head of neuroradiology, John K.

Hald, for their support and believe in me through these years. For this I also thank all my fellow neuroradiologists at Rikshospitalet, and particularly Bård Nedregaard, Øivind Gjertsen and Ruth Sletteberg, who also have assisted with intrathecal contrast agent injections with impressive skills and flexibility.

I am further thankful to my co-authors Oliver Marcel Geier, Erika Kristina

Lindstrøm, Svein-Are Sirirud Vatnehol and Kent-Andre Mardal for their

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important contributions. I also appreciate all statistical advice given by Are Hugo Pripp.

From my heart I thank my parents, Turid and Gunnar, for their always

thoughtful interest in my work, and for teaching values that I will always carry. I sincerely thank my wife Linn for her loving support, which is ever

indispensable to me. Finally, I thank my children and sunshine of my life;

Gyda, Håkon and Tarjei.

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Abbreviations

Aβ Amyloid-β

AD Alzheimer`s disease AQP4 Aquaporin 4

ASV Aqueductal stroke volume CCJ Craniocervical junction CNS Central nervous system CSF Cerebrospinal fluid

DWI Diffusion weighted imaging DTI Diffusion tensor imaging ECS Extracellular space

EI Evan`s index

FLAIR Fluid attenuated inversion recovery

Gd Gadolinium

Gd-DTPA Gadiolinium-diethylenetriaminpentaacetate gMRI Glymphatic magnetic resonance imaging ICP Intracranial pressure

iNPH Idiopathic normal pressure hydrocephalus ISF Interstitial space fluid

sNPH Secondary normal pressure hydrocephalus MRI Magnetic resonance imaging

MRI-dP MRI derived CSF peak to peak pulse pressure gradient MWA Mean ICP wave amplitudes

OUH Oslo University Hospital

PACS Picture archiving and communication system PC-MRI Phase-contrast MRI

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ROI Region of interest SAS Subarachnoid space SU Signal unit

TR Repetition time

TE Echo time

VENC Velocity encoding gradient

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Summary in English

This thesis explores short- and long-term characteristics of cerebrospinal fluid (CSF) flow in patients with idiopathic normal pressure hydrocephalus (iNPH), a condition with unknown cause, but typically characterized by gait disorder, urinary incontinence and dementia.

The first aim of the thesis was to investigate whether measurements of intracranial CSF flow based pulsatility by magnetic resonance imaging (MRI)

compared with measurements of intracranial pressure (ICP) pulsatility in iNPH. While iNPH patients with pathologically elevated ICP pulsatility have shown to benefit from surgery with high probability (~ 90 %), ICP monitoring in itself demands surgery and carries a risk of serious complications like intracranial hemorrhage and infection. The threshold for undertaking such ICP measurements therefore remains high, and a search for non-surgical alternatives seems mandated.

CSF flow-sensitive MRI studies were performed at two levels. One was at the level of the aqueduct, which connects CSF within the brain ventricles and the exterior surface of the brain and spinal cord. The other measurement was done at level of the upper cervical spinal canal. From these, we calculated the aqueductal stroke volume and the peak to peak pulse pressure gradient, respectively. Neither of the MRI

derived pulsatility measurements corresponded with over-night ICP monitoring. Their lack of association with ICP might be attributed to frequent pressure fluctuations observed at long-term ICP recordings as well as the influence on CSF flow by

respiration. Long- and short term impacts from such physiological factors may not be well represented in a cardiac gated PC-MRI acquisition lasting over a few minutes.

The second aim of the thesis was to characterize CSF flow in iNPH on a more conceptual basis. Here, net aqueductal flow was shown to be in the upward

(retrograde) direction, and thus into the ventricles above level of the aqueduct. The phenomenon was observed particularly frequently in patients with pathological ICP pulsatility. After shunting, from which 94 % of the patients responded, net flow increased in the downward direction. Net CSF flow measurements are sensitive to technical error, however, the evidence of retrograde net flow was further

strengthened by observations made at long-term MRI, where it was demonstrated

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ventricular reflux of a contrast agent that had been administered intrathecally. This direction of CSF flow may contradict previous evidence suggesting CSF production is limited to the ventricular compartment and might also carry implications for how we may better understand ventricular dilatation in iNPH.

Pulsations of intracranial arteries are typically restricted in iNPH. The pivotal role of arterial pulsations for CSF flow was further underlined by the particular distribution of contrast agent in CSF around large artery trunks on the brain surface.

In iNPH, contrast agent propagation in CSF was also delayed. Contrast

enhancement of CSF always preceded enhancement of adjacent brain parenchyma, particularly in the near vicinity of larger arteries, being most prominent at over-night scans. These observations support the existence of a brain-wide, perivascular pathway for clearance of macromolecular substances, which previously has been described in animals only and been denoted as the “glymphatic” system. Clearance of contrast agent was found delayed in iNPH compared to reference patients and may indicate that compromised glymphatic function is instrumental in iNPH pathogenesis.

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Sammendrag på norsk

Avhandlingen utforsker bevegelser av cerebrospinalvæsken (væsken som omgir hjernen og ryggmargen) hos pasienter med voksenvannhode av ukjent årsak (idiopatisk normaltrykkshydrocephalus, iNPH). Dette syndromet kjennetegnes typisk av ustø gange, urinlekkasje og demens.

Noen iNPH-pasienter kan behandles ved å operere inn et rør (shunting) som drenerer cerebrospinalvæske vekk fra hjernens indre hulrom (ventriklene). Det er tidligere vist at man kan vente seg effekt av slik behandling hos cirka 90 % av pasientene med forhøyet pulstrykk intrakranielt (inne i hodeskallen). Ved selve trykkmålingen, som krever kirurgi, er det imidlertid risiko for komplikasjoner i form av hjerneblødning og infeksjon. Derfor ville en alternativ undersøkelsesmetodikk med lavere risiko være ønskelig. Et delmål for avhandlingen var derfor å undersøke om parametere utledet fra hastighetsmålinger av cerebrospinalvæsken med magnetisk resonans (MR)-teknikk (fasekontrast-MR) var sammenlignbare med kirurgiske målinger av pulstrykket i hjernen hos iNPH-pasienter.

Målingene med fasekontrast-MR ble utført på to ulike steder. Den ene målingen ble gjort der cerebrospinalvæsken strømmer gjennom akvedukten, en rørformet åpning som forbinder hjernens indre hulrom (ventriklene) med

væskerommene utenfor hjernen og ryggmargen. Den andre målingen ble utført øverst i ryggmargskanalen. Ingen av MR-parameterne viste seg å være

sammenlignbare med direkte trykkmålinger som ble utført i løpet av natten. Siden bildeopptaket med fasekontrast-MR varer i kun noen få minutter, kan det hende disse målingene er av for kort varighet til å fange opp velkjente trykkendringer som skjer over lenger tid. Det kan også hende at væskestrømmer som endres når pasienten puster, ikke oppdages med MR, siden bildeopptaket er synkronisert med

hjerteslagene og ikke pusten.

Et annet delmål var å karakterisere strømninger av cerebrospinalvæsken i en mer fenomenologisk sammenheng. Med fasekontrast-MR fant vi ut at væsken strømmet gjennom akvedukten netto «baklengs» inn i ventriklene hos iNPH-

pasienter. Dette funnet karakteriserte særlig pasienter med økt pulstrykk intrakranielt.

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Etter kirurgisk behandling med shunting, som hadde effekt hos 94 % av pasientene, endret netto væskestrøm seg i retning ut av ventriklene. Slike målinger av netto væskestrøm er sårbare for tekniske feilkilder, men funnet ble vurdert som styrket da vi i en annen studie observerte at et MR-kontrastmiddel også fløt med

cerebrospinalvæsken fra utsiden av hjernen og inn til ventriklene hos iNPH-pasienter.

Dette flytmønsteret strider til dels mot tidligere oppfatninger om at

cerebrospinalvæske bare produseres på innsiden av ventriklene, og kan kanskje også si noe om hvorfor ventriklene er utvidet ved iNPH.

Et vanlig fenomen ved iNPH antas å være at pulsårene på overflaten av hjernen ikke kan utvide seg normalt. Den viktige rollen pulserende blodårer har for å drive bevegelsen av cerebrospinalvæsken, ble understreket av at kontrastmiddelet i cerebrospinalvæsken typisk fordelte seg langs etter pulsårer, men langsommere hos iNPH-pasientene. Deretter fant vi at kontrastmiddelet gikk fra væskerommet på overflaten og inn i hjernevevet, særlig i områder nært inntil de største pulsårene.

Dette var særlig tydelig på MR-bilder tatt dagen etter at kontrasten ble gitt. Basert på dyrestudier kan vi anta at kontrastmiddelet beveget seg inn i hjernevevet langs utsiden av blodårene. Funnet indikerer at det også hos mennesker kan finnes et

«glymfatisk» system for utskillelse av avfallsstoffer fra hjernen, slik det tidligere bare er beskrevet hos dyr. Normal funksjon av det glymfatiske systemet antas å være viktig for hjernens evne til å kvitte seg med sykdomsfremkallende avfallstoffer. Hos pasienter med iNPH fant vi ut at utskillelsen av kontrastmiddelet fra hjernen var forsinket, og dette kan indikere at redusert utskillelse av avfallsstoffer spiller en rolle ved utvikling av iNPH, og kanskje særlig iNPH demens.

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List of publications

I. Ringstad G, Emblem KE, Geier O, Alperin N, Eide PK. Aqueductal stroke volume: Comparisons with intracranial pressure scores in idiopathic normal pressure hydrocephalus. Am J Neuroradiol 2015;

36:1623-30

II. Ringstad G, Lindstrøm EK, Vatnehol SAS, Mardal K-A, Emblem KE, Eide PK. Non-invasive assessment of pulsatile intracranial pressure with phase-contrast magnetic resonance imaging. PLOS One 2017;

12(11):e0188896

III. Ringstad G, Emblem KE, Eide PK. Phase-contrast magnetic resonance imaging reveals net retrograde aqueductal flow in idiopathic normal pressure hydrocephalus. J Neurosurg 2016; 124:1850-1857

IV.

Ringstad G, Vatnehol SAS, Eide PK. Glymphatic magnetic resonance

imaging in idiopathic normal pressure hydrocephalus. Brain 2017; 140

(10): 2691-2705

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1. Introduction

1.1. Historical overview of cerebrospinal fluid

An awareness of a watery fluid within the skull can be traced to Hippocrates (460-375 BC), who commented on “water” surrounding the brain when he described congenital hydrocephalus [1]. Hippocrates considered, however, water merely to replace air as part of a pathological process [2], and adhered to the pneuma theory (air in

circulation). Later, Galen (129-?216 AD) considered psychic pneuma to be stored in and distributed by the brain ventricles [3]. This understanding would prevail for more than a millennium, as no scientific autopsies were performed between ancient times and the Renaissance [4] due to restrictions from religious believes. In the early 16^th century, Leonardo da Vinci revealed the anatomy of the ventricular system by

producing a wax cast of bovine brain ventricles in his search for “senso commune” – which is probably better translated to “the soul” rather than the somehow more trivial term “common sense”. Leonardo da Vinci finally concluded that the seat of “senso commune” is the “middle” (third) ventricle, as opposed to other thinkers who had argued for its location in the heart [5]. While being still influenced by the pneuma theory, da Vinci did not address CSF in particular. It may have been the Swedish mining engineer, scientist, inventor and visionary Emanuel Swedenborg who provided the very first description of CSF between 1741 and 1744.

Figure 1. Emanuel Swedenborg (1688-1772), painted by Per Kraftt the older (1724-1793). In the anatomy book “Regnum Animale” (The Soul`s Domain) (1744-1745) Swedenborg identified the localization of cerebrospinal fluid [6]. (Picture from Store Norske Leksikon 9. februar 2018, https://snl.no/Emanuel_Swedenborg)

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Swedenborg was a religious man, also searching for the seat of the soul and a connection between the spiritual and physical worlds. Due to his lack of medical credentials, he was unable to find a publisher, and his works were discovered in Stockholm one and a half centuries later and published in 1887 [1, 4]. In spite of this, many historians consider Domenico Cotugno to have first discovered CSF in 1764, and CSF was for some time referred to as “liquor cotugnii”. Francois Magendie was the first to use the term “cerebrospinal fluid” in 1842 [2], and also described CSF composition and flow between the ventricles and subarachnoid space through the foramen which still bears his name [4]. In 1891, Heinrich Quincke was the first to access the CSF compartment in living humans in order to treat increased CSF pressure [7]. With a fine cannula, he was also able to perform a chemical analysis of CSF [2]. Importantly, the method also allowed for measurement of CSF pressure and thereby an indirect assessment of intracranial pressure (ICP). Quincke further

demonstrated that cinnabar injected into CSF of animals enmeshed within the

Pacchionian granulations, already described in dissections by Pacchioni in 1705, and these observations were later confirmed in humans by Key and Retzius in 1875 [8].

1.2. From the bulk flow hypothesis to new concepts

The neurosurgeon Walter E. Dandy, inventor of x-ray air encephalography in 1918, representing the first neuroradiological procedure, also conducted the first experimental hydrocephalus studies in 1914 together with Blackfan. They

demonstrated that extirpation of the choroid plexuses in a dog modified the degree of internal hydrocephalus after occlusion of the Sylvian aqueduct. From this, they

inferred that CSF is formed inside the ventricles, at least more rapidly than it is removed [9]. The division of hydrocephalus between obstructive and communicating type derives from their contribution. The principal understanding of CSF absorption, still accepted by many scientist today, was formed by the experiments of Dandy`s contemporary, Weed [10]. In these, CSF, together with its solutes, was found to escape the subarachnoid space via the Pacchionian granulations, as well as through the cribriform plate to lymphatic vessels of the nasal mucosa, and also along

perineural spaces surrounding cranial nerves. Quite contrary to this, Dandy and Blackfan reported one month earlier that CSF is diffusely absorbed from the entire subarachnoid space and that resorption does not take place through Pacchionian granulations [9]. Still, Weed`s concept would prevail through the next decades, even

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though Dandy refuted the role of Pacchionian granulations, or arachnoid villi, in later experiments [11].

Figure 2. To the left: Walter Edward Dandy (1886-1946) (Picture from: Congress of Neurological Surgeons. https://www.cns.org/about-us/history/walter-e-dandy).To the right: Harvey Williams Cushing (1869-1939) (Picture from: Wikipedia. https://en.wikipedia.org/wiki/Harvey_Cushing)

In 1926, Cushing introduced the bulk flow theory, where he hypothesized CSF to circulate with a direction, streaming from the ventricles towards drainage pathways at the brain surface [12]. This “third circulation”, as it was coined by Cushing,

represented at the time a radical departure from the contemporary view that CSF moved by ebb and flow [13].

While the bulk flow paradigm may seem to still govern customary understanding of CSF flow in many aspects, several authors have called for a revision of concept due to an increasing body of opposing evidence [14-16]. First, the bulk flow hypothesis insufficiently incorporates the role of intracranial pulsations.

Important evidence of their importance was given in 1962, when Bering found

pulsatility from the choroid plexuses to be a force behind ventricular dilatation [17]. In 1978, Di Rocco produced hydrocephalus in lambs by increasing the intraventricular pulse pressure mechanically [18]. In vivo CSF pulsations were already observed using fluoroscopy in the 1960`s [19] and were later confirmed to be synchronous with the cardiac cycle using flow sensitive MRI [20]. The complexity of CSF flow dynamics has later been revealed and demonstrated to be dependent on various factors such as location [21], body posture [22] and respiration [23].

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Second, and neither contained by the bulk flow hypothesis, is the vast capacity for fluid exchange throughout different compartments of the brain parenchyma [24].

The brain ISF is in communication with the ventricular and subarachnoid fluid via the perivascular fluid spaces that penetrate the brain parenchyma, and these spaces are carrier pathways for brain metabolites [25]. Movement of fluid and substances along these pathways seem to be driven by pulsations from the cerebral arteries [26], and an impaired ability of substances to move within the extravascular domain may contribute to a number of brain diseases [27]. However, there are still unresolved issues, one of them being opposing views about the direction of paravascular water and solute flow within the brain. While some authors have found signs of periarterial flow out of the brain parenchyma after intraparenchymal tracer injections [28-30], injections of tracer directly to the subarachnoid space have led to the conclusion that periarterial pathways are the route for transport of CSF tracers into the brain [26, 31].

1.3 Presentation of NPH

In 1965, Hakim and Adams were the first to describe a symptom triade

consisting of disabling dementia with psychomotor retardation, unsteadiness of gait and unwitting urinary incontinence, from which the authors reported a “dramatic”

improvement of symptoms in three of their patients after surgical diversion of CSF (shunting) [32, 33]. As CSF pressure was within normal range upon lumbar puncture, the authors denoted the syndrome “Normal pressure hydrocephalus” (NPH). The hydrocephalus was referred to as “occult” as the patients` heads were of normal size, and as the ventricular system at the time could be imaged with x-ray air

encephalography only (x-ray imaging of the head after lumbar injection of air). It was reported a particularly promising effect of surgery on cognitive disability, and the authors concluded that further cases should be sought within the large group of patients with late-life dementia. The great benefits of surgery were subsequently confirmed by some authors [34], but were not reproduced to the same extent in later, prospective studies [35-37], and rate of shunt insertion declined [38].

Despite extensive study of this syndrome (a recent PubMed search of

“Hydrocephalus, Normal Pressure” [Mesh] yielded 1997 publications on the topic since 1965), NPH has to some degree remained controversial as a

clinicopathological entity, and the term NPH has been proposed replaced by “chronic hydrocephalus” [15, 39]. To date, there is no common gold standard to establish

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presence of NPH, nor are there uniform criteria for treatment indication. Even though shunt treatment undoubtedly may have a compelling effect on NPH symptoms, skepticism to the NPH diagnosis may probably be rooted in the presence of

symptomatic overlap with other disease, and poor understanding of NPH etiology and mechanisms behind CSF circulation.

1.4 Pathogenesis

Even though Hakim and Adams could not establish the etiology of NPH, they suggested the symptoms were result of decreased CSF resorption, and that

ventricular enlargement occurred compensatory to increased pressure acting on the nervous tissue surrounding the ventricles, especially around the frontal horns

adjacent to the frontal lobes. It was further postulated from “the hydraulic-press mechanism” that the intraventricular pressure exerted the greatest force against the widest part of the system. Further, expanded lateral ventricles were thought to promote tangential shearing forces on periventricular white matter fiber tracts associated with gait. With continued ventricular expansion, the cortex would be exposed to the same shearing forces, leading to dementia [40].

The most commonly identified causes of defective CSF resorption are meningitis and subarachnoid, or intraventricular, hemorrhage, which may cause inflammation and fibrosis of the arachnoid granulations, and thereby compromised CSF uptake. In the case of no identified cause, a previous head injury or subclinical viral infection may be considered, and biopsies in NPH patients without any known precipitating condition, have demonstrated leptomeningeal fibrosis [41]. There has also been established a significant association between NPH and vascular risk factors such as arterial hypertension and diabetes mellitus, and been suggested that these factors might be involved in pathophysiological mechanisms [42]. Stiff arteries and inability to dampen arterial pulsations in the subarachnoid compartment have been proposed to induce a “restricted arterial pulsation syndrome”, in which

pulsations are rather propagated centripetally into the brain parenchyma. This “water hammer effect”, occurring as the pulsating brain repeatedly pounds against

ventricular CSF, renders for compressive forces made upon periventricular white matter, and subsequent ventricular enlargement [15]. As restricted artery pulsations are a result of reduced intracranial compliance [43], the factors leading to reduced compliance have not been convincingly demonstrated. A pivotal role of ICP

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pulsations in iNPH pathogenesis has been substantiated by high shunt response rates in patients who are selected to surgery based on ICP pulse pressure above established thresholds [44]. Also, intracranial pressure pulsations have been

proposed instrumental to drive convective transport of fluid and solutes along brain perivascular and interstitial spaces, and restricted artery pulsations may reduce clearance of pathogenic macromolecules such as amyloid-β from the brain [31].

Whether such clearance pathways are compromised in NPH has never been addressed. Silverberg and colleagues hypothesized that NPH and AD share a common physiological basis with regards to clearance of toxic metabolites, which would lead to accumulation of Aβ and tau protein [45]. Contrary to previous, mechanistic approaches to understand NPH pathogenesis, a possible metabolic explanation for the dementia component in NPH was thereby introduced. Ventricular enlargement and stretching effects on associated white matter, particularly frontal fibers involved in micturition and executive motor function, was, however, maintained as the most probable cause of gait disturbance and urinary incontinence [46].

Furthermore, periventricular cerebral blood flow is found to be compromised in iNPH, which may promote watershed ischemia [47], and this is supported by

observations of restored blood flow after shunting [48]. Deep white matter ischemia may compensate an initial CSF pressure increase and thereby explain normal CSF pressure in NPH [49].

Pathogenic factors at the venous side have also been hypothesized, and it has been suggested that elevation of cortical vein pressure affecting CSF absorption pathways to veins may be instrumental. In part, this is based on observations of restored cortical vein pulsatility in patients responding to shunting [50], and it has been claimed that NPH should rather be denoted “venous compressive ischemic encephalopathy [51]. However, the cortical vein compression theory has not received broad scientific acceptance, and it may seem plausible that restored venous

pulsations after shunting is secondary to a general improvement in intracranial compliance provided by the shunt. It has even been proposed that lack of cortical vein compression is part of a viscous cycle in NPH [15].

With implications for a possible role of genetic, inborn factors behind NPH, some studies report larger head sizes in NPH patients than controls, and suggest the

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possibility that internal [52, 53] or external [54] hydrocephalus of childhood may present with symptoms later in life. As for the latter (also called benign external hydrocephalus, or benign enlargement of subarachnoid spaces hydrocephalus), deep white matter ischemia of late adulthood has been hypothesized to represent a

“second hit” by promoting increased resistance to CSF resorption into the ECS.

Indeed, patients with NPH have higher prevalence and severity of periventricular signal intensity changes at MRI [55, 56]. Reports of siblings with NPH add to the hypothesis that there might be present an inborn, genetic factor [57, 58].

In 2012, the Danish researcher Maiken Nedergaard and co-workers described what they denoted the “glymphatic”, or glia-lymphatic, system [31]. In many ways, this may be regarded as a re-discovery of pathways described by Rennels et al. in 1985 [26], who visualized that the intrathecal CSF tracer horse-radish peroxidase spread from CSF along arteriolar paravascular spaces of the brain, with further penetration into the extracellular space, and finally accumulated around veins on prolonged scans. Nedergaard`s group extended Rennels` concept by demonstrating such flow to be dependent on AQP4, a protein which forms a water-specific channel, coded for by the AQP4 gene, and covers up to 40 % of astrocytic (glial) end feet surrounding brain capillary vessels [59]. They further provided evidence that clearance of brain macromolecules, such as Aβ, was dependent on AQP4 status.

The Aβ peptide is a major constituent of extracellular aggregates known as neuritic plaques in AD [60].

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Figure 3. The glymphatic system as illustrated by Iliff et al.[31] (reprinted with permission obtained through Copyright Clearance Center`s Rightslink^®) (License No. 4285970774404).CSF and solutes enters and leave the brain along periarterial and perivenous spaces, respectively. CSF pulsations are a main force behind convective (net) flux through the brain interstitial space. This transport is

dependent on AQP4 water channels polarized to astrocytic end feet.

Glymphatic transport has also been proposed instrumental for clearance of metabolic waste products particularly during sleep [61], for removal of excess fluid in brain edema [62], to have a role in normal ageing [63], and to be impaired after head trauma [64]. In iNPH, brain biopsies have recently demonstrated reduced levels of AQP4 and its anchoring protein dystrophin 71 in astrocytic end feet, which surround brain vessels, indicating a possible link between glymphatic function and iNPH pathology, in particular iNPH dementia [65].

1.5 Classification

Currently, the causes of NPH and explanation for NPH symptoms are still debated [66] and should be considered incompletely described. NPH is typically

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categorized into idiopathic NPH (iNPH) and secondary NPH (sNPH) [67], the latter term is used when precipitating conditions such as subarachnoid hemorrhage, meningitis, or neoplastic disease are identified. As from here, the acronym “NPH”

without any prefix will only be used when NPH is uncategorized. Exactly how

precipitating conditions produce chronic hydrocephalus without increased pressure is not completely understood. The reported proportion of iNPH to sNPH varies. There have been proposed stratifications of iNPH after levels of probability for having iNPH.

The first Japanese guidelines introduced the categories possible, probable and definite. Possible iNPH included one or more of the classical symptom triad and ventricular dilation in a middle aged or elderly patient with effaced fluid spaces at the high convexity on MRI. Probable iNPH was defined as improvement of symptoms after CSF removal in a patient with possible iNPH. Definite iNPH demonstrated clinical improvement after shunt surgery [68]. The diagnosis was thus disproved when the patient had already been subjected to the risk of complications. Another group omitted shunt responsiveness as a diagnostic criterion and recommended that iNPH was classified into probable, possible and unlikely categories, depending on history, physical findings, and supporting studies [69].

1.6 Epidemiology

A prevalence study carried out in Vestfold County, Norway, reported a prevalence of probable iNPH to 21.9/100 000 in the general population, however, prevalence increases with age to a peak of 181.7/100 000 in the age group 70-79 years [70]. A Japanese study indicated a prevalence of 2.9 % in community residents aged 65 years or older [71]. It has further been estimated that 9-14 % of nursing home residents suffer from iNPH [72]. INPH seem to be underdiagnosed and

undertreated in Norway, as epidemiologic data suggest that less than one of five new cases each year receive surgical shunting [73], which is in line with surgery rates in Sweden [74].

1.7 Symptoms and co-morbidities

INPH occurs with varying combinations or degrees of gait impairment, urinary incontinence, and dementia. Symptoms, as well as prognosis and treatment

outcome, are prone to comorbidities, which include other causes of dementia, psychiatric and behavioral disorders, vascular disease, urinary problems and musculoskeletal conditions [75]. Contribution of comorbidity to overall morbidity,

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mortality and long-term outcome may be considerable. In a study of NPH patients with mean age 72 years, only 36 % of patients were alive and able to meet for a 5- year follow-up evaluation [76].

A careful clinical examination is therefore necessary for the iNPH diagnosis.

Grading scales incorporating at total score for different iNPH symptoms have been developed [44, 77] and are typically used to standardize the evaluation of treatment, but are insufficient as tools to decide which patients should be selected to surgical shunt treatment.

1.7.1 Gait disturbance

Gait disturbance is the most common symptom in iNPH and the symptom with most favorable response to shunting [67], where improvement in up to 93 % of

subjects is reported [78]. When untreated, it typically progresses from balance

difficulty, to shortened stride length and arrestments with turning difficulties [67]. Gait problems may be associated with other motor symptoms such as hypokinesia, tremor and hypo- or hyperkinetic movement patterns in up to 86 % of elderly iNPH patients [79]. The differentiation between iNPH and Parkinson`s disease may therefore be challenging. Further, gait disorders are generally common in the elderly population and may derive from a number of causes, ranging from hip, knee and spine

pathology to stroke and other neurological diseases.

1.7.2 Urinary incontinence

Urinary incontinence has been reported to occur in between 60 and 79 % of iNPH patients [80, 81]. Detrusor over activity with urgency is postulated to be the basis for most urinary urgency or frequency [75]. Urinary symptoms are reported to improve with shunting in 36 to 76 % of cases (reviewed by [67]). These symptoms are not specific features of iNPH, as symptoms of bladder dysfunction are common in the adult population and have been reported in 57 % of patients consulting office- based primary care physicians [82]

.

1.7.3 Dementia

While iNPH is found rather infrequently, it is estimated that an overall of 77 000 patients suffer from dementia in the Norwegian population, and may double within an ageing population by 2040 [83]. Imaging findings in iNPH may overlap significantly with other dementia types. INPH and AD can even occur in a mixed form

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[84], and Aβ in cortical biopsies has been detected in 42 % of patients with possible NPH [85] and in up to 75 % of those with severe iNPH dementia [86]. Elevated pulsatile ICP, a hallmark of iNPH, has been shown associated with brain amyloid accumulation [87]. Clinically, hippocampal dysfunction and rapid forgetting of newly acquired information is the most common presenting symptom of AD. This may be present in iNPH as well, however, more common symptoms are frontal executive disturbances that can be improved by cues or reminders [75]. Other

neurodegenerative diseases that may confound, or aggravate, iNPH dementia include Parkinson’s disease, dementia with Lewy bodies, and frontal lobe dementia.

Moreover, a primary depressive disorder with mental slowness may also mimic

symptoms of hydrocephalus. A wide range of neuropsychological deficits are found in iNPH patients, and these deficits may be aggravated by vascular comorbidity [88].

Indeed, vascular pathology is frequent among post-mortem NPH findings [89], and vascular risk factors are overrepresented in iNPH individuals [90]. In the overall population, subcortical vascular dementia is a more common cause to the classical symptom triad typical for NPH than NPH itself [91]. Dementia is only half as likely to improve following shunt surgery as compared to gait function [78].

1.8 Treatment

Diagnostic efforts should not be unnecessarily delayed, as treatment delay is associated with reduced treatment effect. Probably, there exists a therapeutic window in early phase of the disease process, and iNPH has shown more responsive to treatment of milder symptoms of less than 2 years` duration [92].

Surgical CSF diversion is the only treatment option for NPH. Different types of CSF diversion include placement of a shunt from the cerebral ventricles to the

peritoneum (VP-shunt), to the right atrium of the heart (VA-shunt), or between the lumbar subarachnoid space and peritoneum (LP-shunt). While endoscopic third ventriculostomy may also be considered, VP- or VA-shunting are considered the mainstay of surgical treatment [93]. However, a Cochrane Database Review reported that there had never been conducted a single, randomized controlled trial to assess the effect of surgical shunting compared to no shunt [94]. Ventricular shunting has indeed also been described as variable, short-lived and unpredictable [67]. Patient heterogeneity, and different assessment of treatment outcome, may well explain why shunt response rates for iNPH are reported to range from 15 to 96 % [95, 96]. Wide

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variability in use and interpretation of diagnostic tests to decide treatment exist between different neurosurgical centers [97]. This has also rendered for scientific controversy, as some authors call for shunting in “many more patients” [38], while others claim that shunt dependable dementia accounts for only 0,4 % of all dementia patients [95], and that shunt insertion carries a risk disproportionate to the potential benefit [98]. A meta-analysis of 44 articles found that the pooled, mean rate of shunt complication (including death, infection, seizures, shunt malfunction, subdural

hemorrhage or effusion) was 38% [67]. It has therefore been an urgent need for developing prognostic tests with low risk that identify iNPH patients who will respond to shunting, and also to spare non-responding patients from unnecessary surgical risks.

1.9 Additional tests

A diagnosis of iNPH requires a synthesis of converging evidence from clinical history, physical examination, and brain imaging. Because of iNPH symptom

heterogeneity and overlap with more common conditions, additional methods of assessment are mandated and with the primary aim to select iNPH patients who will benefit from surgical shunting. In practical terms, clinical work-up of iNPH is therefore more about evaluating the possibility of shunt response, rather than diagnosing its cause.

1.9.1 CSF tap test, infusion test and external lumbar drainage

In the 2005 Guidelines from the International NPH Consulting Group, it was recommended that all patients with possible and probable iNPH (based on clinical exam and imaging) should be considered for, in a stepwise order, a CSF tap test, an infusion test and external lumbar drainage [99]. The positive result of a CSF tap test with removal of 40-50 ml CSF by spinal puncture may increase probability for a favorable shunt response compared to clinical examination only, but cannot be used as an exclusionary test, and have low sensitivity (26 – 61 %). By lumbar infusion test, an isotonic solution is typically infused at constant rate, and the resistance to outflow Rout determined. There are several infusion methods with diverging results, however, infusion tests are generally considered to have higher sensitivity (57 – 100 %)

compared to the tap test, while prolonged external lumbar drainage of more than 300 ml has the highest positive predictive value [100]. From the European iNPH

multicenter study, it was concluded that infusion test (Rout) and CSF tap test did not

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correlate with results of surgery at 12 months, and should not be used to exclude patients from treatment [101]. This conclusion was later maintained by the

subcommittee of the American Academy of Neurology [96].

1.9.2 ICP monitoring

ICP monitoring is carried out in local anesthesia, where an ICP sensor is placed in the frontal lobe parenchyma through a burr hole in the scull. Increased pulsatile ICP in iNPH is common due to reduced intracranial compliance. When intracranial compliance is low, only a small intracranial volume increase, such as the one induced by a heartbeat, will lead to a significant pressure increase [43, 102].

Compliance may thus be defined as the ability of the intracranial compartment to accommodate a volume change. Unlike invasive monitoring of mean ICP, which relates to atmospheric pressure, over-night monitoring of pulsatile ICP (mean wave ICP amplitudes, MWA) represents the absolute per-cardiac-beat pressure change induced by the temporary intracranial volume increase. Pulsatile ICP has

demonstrated to predict shunt response in 9 of 10 iNPH patients when MWA in average >4 mmHg and/or percentage of MWA >5 mmHg in >10% of recording time are set as threshold levels for shunting [44, 103]. Software for automatic assessment of cardiac induced ICP single waves has not been readily available, and is still in use at only a few centers world-wide. Invasive pressure monitoring carries a risk of

complications, this risk may, however, be considered low, as infections and bleedings occur in 1-2 % [103, 104].

1.9.3 Imaging

1.9.3.1 Structural imaging

When NPH was first described in the mid 1960`s, methods for assessments of ventricular size and CSF compartments were restricted to use of x-ray air

encephalography. Since then, a tremendous development in imaging has occurred, and modern imaging can now reveal far more features of the entire intracranial compartment. In radiology, which historically has been a discipline utilizing mainly subjective image interpretation, there is presently a tendency towards a search for quantifiable imaging biomarkers to better standardize the diagnostic process and the assessment of treatment effect.

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The mainstay of radiological work-up in iNPH is computed tomography (CT) and MRI. Both CT and MRI provide volume acquisitions of the entire brain and its surroundings, where images are typically presented as consecutive image slices to cover the region of interest in any plane. CT depends on x-rays that pass through the object of interest, and where a detector at the opposite end of the radiation source register the proportion of radiation that has been absorbed, or attenuated, within the tissue. Degree of attenuation in every voxel element is presented on a greyscale image, in which the densest tissue is given the whitest shade of grey, and vice versa.

CT provides reliable information about ventricular size in patients with suspected iNPH and is also faster, cheaper and less sensitive to patient motion than MRI. MRI, on the other hand, is not dependent of ionizing radiation, but magnetism. The

physical principles behind MRI technology are complex and explained in detail elsewhere [105]. In short, an MRI scanner images protons, which are present throughout the body, mainly as constituents of fat and water. When the patient is placed in a strong external magnetic field, protons spin around their central axis (precession) at a certain frequency and add up to create a net magnetization in

tissues along the direction of the external magnetic field. When a radiofrequency (RF) pulse is emitted against protons precessing with similar frequency (hence the term

“resonance”), the direction of the net magnetization changes. The degree of angulation of the net magnetization from the direction of the external field is called the flip angle of the RF pulse. The component of the net magnetization that is

perpendicular to the external field causes a signal that can be detected by antennas (coils) placed close to the body surface. MR sequences can be configured to reflect different properties in tissues. In a T1 weighted sequence the image signal reflects how quickly the net magnetization vectors recover their longitudinal magnetism after the RF excitation (T1 relaxation). The T1 relaxation time varies between different biological and pathological tissues, providing for image contrast. T2 weighted image contrast is dependent upon tissue specific loss of the transversal component of the net magnetization after the emission of a RF pulse (T2 relaxation). An MR image of the brain may further be weighted in a number of other ways to focus on other properties of tissue, such as water diffusion (diffusion weighted imaging) and suppression of unbound water (fluid attenuated inversion recovery, FLAIR). Soft tissue image contrast is superior at MRI compared to CT.

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An essential part in evaluation of iNPH patients is to assess ventricular size with computed tomography CT or MRI, and to rule out a non-communicating hydrocephalus. Evans’ index (EI) is the ratio of the transverse diameter of the anterior horns of the lateral ventricles to the greatest internal diameter of the skull, and was developed for use in pneumoencephalograms [106]. A ratio > 0.3 is considered as definite ventricular enlargement. It has later been adapted for

application on CT images [107]. A CT study may thereby exclude iNPH, while MRI provides more diagnostic information and better identifies causes of CSF obstruction.

In the 2005 guidelines for diagnosis of idiopathic normal pressure hydrocephalus, an EI > 0.3 combined with gait dysfunction plus either urinary or cognitive dysfunction is required prior to consideration of treatment with ventriculo-periteoneal shunt [69]. EI can vary significantly between iNPH patients, and is not an ideal method for

estimating ventricular volume [108], but neither has ventricular volume shown predictive value in differentiating between NPH patients who will respond to shunt surgery, or not [109]. The European multicenter study on iNPH demonstrated, however, a shunt response in up to 84 % of subjects after one year when being diagnosed solely on clinical and MRI criteria using EI [110]. Furthermore, new EI threshold values, incorporating the range of EI values in the elderly population, have proven good sensitivity for the iNPH diagnosis [111].

EI does not discriminate between different causes of ventricular enlargement.

The callosal angle (CA, the angle between the lateral ventricles on a coronal image through the posterior commissure) has been found to be steeper (< 120 degrees) at air encephalography in NPH than in ventricular enlargement due to brain atrophy [112] and is also proven steeper at MRI in shunt responders compared to non- responders [113]. Recently, it was reported that CA and EI combined provided good accuracy as a screening tool to differentiate patients with NPH from AD and healthy controls, and that patients within given threshold levels should be further evaluated with automated MRI brain tissue segmentation, i.e. labeling brain and brain sub- regions by use of computerized methods [114]. Such segmentation has

demonstrated that shunt-responsive NPH is characterized by high preoperative ventricular and near normal grey matter volume compared to AD and healthy controls [115]. This is, however, in contradiction to a previous study, where no predictive value of shunt response in NPH could be demonstrated using volumetric

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assessments of different imaging variables, including ventricular and brain volume [109].

A commonly seen feature in those with probable iNPH is also ventricular enlargement associated with effaced CSF spaces outside the high convexities and medial subarachnoid spaces of the brain, while the Sylvian CSF volume is prominent [116]. As distribution of CSF here is disproportionate between the inferior and

superior subarachnoid spaces, the term DESH (disproportionate enlargement of subarachnoid spaces hydrocephalus) was coined, and was shown to have high positive predictive value in identifying shunt responders [80]. A broader assessment of several MRI features demonstrated that small CA, wide temporal horns and DESH, each independently, predicted a positive shunt response [117]. In the extensive, second edition of the Japanese guidelines for management of iNPH, iNPH is classified into DESH and non-DESH [118]. Negative predictive value of the DESH sign is, however, low, and absence of DESH should therefore not exclude patients from further diagnostic tests, or from receiving a shunt [119]. This is important, as non-DESH is the most frequent finding among patients with probable iNPH (70 %) [119]. With regards to differentiate the ventricular enlargement of iNPH from AD related brain atrophy, findings of a milder hippocampal atrophy and less widening of the parahippocampal sulci may be useful [118].

1.9.3.2 Imaging of CSF flow with phase-contrast MRI

While structural imaging maintains to be a cornerstone in imaging of NPH, a frozen image can never reveal, or embrace, the complexity of a CSF in continuous motion. PC-MRI extracts quantitative velocity information from images. In short, a bipolar magnetic gradient (velocity encoding gradient, VENC) is applied to change magnetic precession phase of moving protons, opposite to stationary protons, which remain unchanged. The MRI scanner calculates the phase difference for each picture element (voxel) between phase images with, and without, use of VENC. This phase difference is proportional to flow velocity and flow in both directions through the image plane is given. Zero flow is displayed by a medium image grey tone, and flows of opposite directions are lighter and darker, respectively. When flow velocity

exceeds velocities covered by the set VENC, aliasing will occur due to phase differences of more than 360 degrees in magnetic spin [105, 120].

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After its first applications for use in blood flow measurements, a phase

sensitive technique for the study of CSF flow was reported by Edelman et al. [20] and has later been further developed and sophisticated [121, 122]. By synchronizing image acquisition to the cardiac cycle, velocity information as function of the cardiac cycle is obtained, so-called cine phase contrast. This synchronization (cardiac gating) may be performed prospectively or retrospectively with respect to sampled R waves from the cardiac cycle. Retrospective gating has been shown to be more accurate as it enables continuous measurements throughout the cardiac cycle [122] and is

typically the method of choice in clinical investigations. The flow velocity curve

represents, however, an average measure over many cardiac cycles and is therefore not a real-time measurement, unlike, for example, ICP monitoring. Cardiac

contraction may be registered with an electrocardiogram (ECG), or with peripheral triggering using a finger plethysmograph. With the latter, a broadened velocity

distribution and a slightly lower maximum amplitude may be expected [122], but does not change the temporal relationship between cardiac systole (cardiac contraction) and diastole (cardiac relaxation) [121].

In healthy, PC-MRI technique and its use for investigating the relationship between cardiac dependent intracranial blood- and CSF flow has been extensively reviewed [123]. The net intracranial volume increase induced by arterial inflow is balanced by early displacement of CSF into the compliant spinal canal. This balances the ICP increase during the systolic phase, as venous blood, with its higher viscosity than CSF, is not drained instantaneously, but supplements the dampening of the ICP increase at a later phase of the cardiac cycle, and is also volumetrically larger than the CSF component. Compared to the craniocervical junction level, aqueductal CSF flow is almost ten times smaller, and occurs later in the cardiac cycle. As the

aqueduct is narrow, and relatively long, the impact of aqueductal flow on ICP change is low in healthy subjects [124]. In NPH, however, the ventricular (aqueductal) CSF flow contributes more to CSF flow exiting the intracranial compartment through the foramen magnum than in healthy [125].

PC-MRI derived CSF flow velocity measurements have mainly been

undertaken at level of the aqueduct in order to predict shunt response in iNPH. One important reason for this is the aqueductal hyper dynamic flow artifact (signal void) at T2 weighted images frequently observed in hydrocephalus [126]. Presence of this

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artifact was shown to possibly predict shunt response [127], particularly when flow compensation algorithms (gradient moment nulling) were turned off in the MR

scanner [40]. Secondly, the aqueduct is distinguished from many other regions of the CSF by its tubular-like shape and simple geometry, and by being the only

macrostructural connection between the supra-aqueductal ventricles at the interior brain CSF compartment and the external surface of the brain and spinal cord. PC- MRI have demonstrated feasibility [121] and good reproducibility for pulsatile CSF flow measurements in healthy subjects, both at level of the aqueductal and upper cervical spine [128].

Bradley et al. were the first in 1996 to demonstrate possible utility of PC-MRI derived aqueductal CSF flow as marker to select NPH patients for shunting, where pre-surgical ASV > 42 μl was observed in 12/12 shunt responders [40]. Later, several studies confirmed that aqueductal flow parameters, and in particular ASV, could be useful for selection of patients to surgical shunting [129-134] and in follow-up [135].

Other studies have not been able to reproduce these beneficial results [136-139]. A common weakness of many studies assessing aqueductal CSF flow is the lack of direct comparison with invasive measures from the intracranial compartment. One study compared ICP with aqueductal flow measured with PC-MRI in the sagittal plane, but unfortunately without the possibility to quantify flow velocities, as flow velocities should be measured in an image plane as perpendicular to flow direction as possible [140]. Another study found association between ASV and a temporal sub-peak of the ICP wave in a small number of patients [141], but its significance has later been disputed [142].

While aqueductal measures of flow based pulsatility, such as the ASV, has been regarded as a possible indicator of intracranial ICP pulsatility [15, 143], other PC-MRI methods have been proposed with the aim to directly measure pressure- volume relations and compliance, the latter being typically reduced in shunt-

responsive NPH [44], and characterized by increased ICP pulsatility [43]. Wåhlin et al. demonstrated that a combination of lumbar CSF infusion and PC-MRI proved feasible for assessment of the craniospinal cavity pressure-volume index in healthy elderly, and thereby enabled for a test of how well this compartment dampens the volume load represented by arterial pulsations [144]. While this test does not seem to have been taken widely into use clinically, a method for assessment of intracranial

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elastance (dP/dV), the inverse of compliance, has shown more promise by means of clinical utility [145]. Positive experiences with the method have been retrieved from studies with baboons [145], healthy subjects [146], as well as patients with

hydrocephalus [147, 148], Chiari 1 malformation [149] and NPH [150, 151]. However, this non-invasive method utilizes measurements of blood and CSF flow below level of the craniocervical junction, and has never been compared directly with invasive ICP monitoring in ill patients.

Moreover, PC-MRI derived velocity parameters, including flow phase, have been investigated for use in other anatomical locations than described above (prepontine cistern, 4^th ventricle, etc) [21], and combined with blood flow

measurements [125]. These procedures are time consuming, and may be considered to have more of an explorative character to assess features of hydrocephalus, and have not come to wide use outside the setting of scientific studies.

1.9.3.3 Diffusion weighted imaging and diffusion tensor imaging

With diffusion weighted imaging (DWI) and diffusion tensor imaging (DTI), free (isotropic) and directed (anisotropic) diffusion of water molecules, respectively, can be studied [152]. The apparent diffusion coefficient (ADC) is a measure of isotropic diffusion, and values above normal in the brain may indicate increased Virchow- Robin spaces, increased extracellular brain water fraction, and changes in myelin- associated bound water. Increased ADC has been demonstrated in several brain regions of NPH [153] as well as other hydrocephalic conditions [154], most typically in the periventricular region [54, 155, 156] and with a decline after shunt response [154, 156]. It therefore seems likely that brain water content, and/or extracellular brain water fraction, is increased in NPH.

DTI allows for further assessment of microstructural changes in cerebral white matter utilizing several parameters of anisotropic diffusion along brain fibers,

including fractional anisotropy (FA) and mean diffusivity (MD). In a recent review of 19 studies, where DTI was used for the identification and differentiation of iNPH from other neurodegenerative diseases, it was reported that FA had sensitivity of 94 % and specificity of 80 % for diagnosing iNPH. FA was typically increased in the corticospinal tract and negatively correlated with gait abnormality, whereas it was reduced after CSF drainage or shunting. Compared to healthy controls, MD was

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higher in the corticospinal tract and corpus callosum [157]. The relative importance of individual DTI measures with regard to predict response to CSF drainage remains, however, a matter for debate [49].

1.9.3.4 Imaging of the glymphatic system

To date, it has not been possible to undertake human CSF tracer experiments in which the brain paravascular and interstitial spaces can be assessed [158].

However, it has been shown in studies of rodents that an MRI contrast agent would be of suitable size to enter these pathways, constituting crucial elements of the glymphatic system, and that measures of macromolecular clearance from brain parenchyma may be obtained by MRI at multiple time points [159]. The technique has previously been used to demonstrate impaired glymphatic clearance after subarachnoid hemorrhage and ischemic stroke in mice [160] and later in nonhuman primates [161].It has furthermore been suggested that lumbar delivery of intrathecal contrast agent in conjunction with multiphase MRI may serve as a useful approach also in the study of human glymphatic function [162]. A human case report confirmed that an MRI contrast agent could be traced within brain parenchyma after

subarachnoid administration [163], but no studies have yet applied this method in a patient cohort. For iNPH in particular, the method would on one hand have the

potential to assess pathological distribution patterns of tracer substance in the interior and exterior of brain fluid compartments. Moreover, it could possibly reveal metabolic compromise by means of reduced parenchymal clearance of substances and thereby possibly shed new light on mechanisms behind neurodegeneration and dementia.

1.9.3.5 Nuclear medicine

NPH has been characterized by using radioactive isotope cisternography [164, 165], where a typical feature has been ventricular reflux of radiotracer, and lack of ability to reach the high convexities. However, a study reported no more than a 55 % shunt response rate in iNPH patients with typical signs at cisternography [166], and the test was shown inferior to lumbar external drainage and CSF tap test [167].

Cisternography is not regarded necessary for the iNPH diagnosis [118]. Today, it is therefore rarely performed as part of the routine imaging work-up for iNPH, but its use is still sporadically reported [168].

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Nuclear medicine studies such as PET and SPECT have been used to demonstrate changes in cerebral blood flow (CBF) and metabolism associated with iNPH. Several PET studies have utilized ¹⁵O-H2O to assess CBF in iNPH. Klinge et al. demonstrated that global CBF was lower in iNPH than controls, but even lower in shunt responders than non-responders, and early improvement in the

cerebrovascular reserve after shunting (assessed with acetazolamide) indicated a good prognosis [169]. Later, they revealed that cognitive impairment is associated with reduced CBF in mesial frontal and temporal areas, and that symptom

improvement after shunting was paralleled by a CBF increase in some of the same areas [170]. In a group of patients with both iNPH and sNPH, Owler et al. found reduced CBF in the cerebrum and cerebellum, as well as basal ganglia and thalamus [171]. The authors could, however, not conclude whether the changes were primary or secondary to NPH disease. While no reduction in CBF of white matter could be demonstrated in this study, another work utilizing the same method showed that white matter CBF was indeed reduced in NPH, with a gradient stretching from the lateral ventricles (poorest) to the subcortical white matter (least poor) [47]. There are fewer reports on NPH from SPECT studies, but worth noticing is a paper which reported CBF changes in the anterior cingulate gyrus and hippocampus associated with impaired wakefulness, a symptom typically relieved after shunting [172].

More recently, PET has shown able to detect amyloid-β in vivo (amyloid-PET) and possibly facilitate diagnosis of AD in patients with suspected NPH, both utilizing the imaging agents [¹⁸F]flutemetamol [173-175] and [¹¹C]Pittsburg Compound B [176]. In these quite small cohorts, amyloid-β pathology in biopsies was found in 23.5 to 50 % of patients with probable NPH.

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1.10 Summary of key points from Introduction

x Mechanisms behind CSF circulation and disease are incompletely understood.

x iNPH is characterized by enlarged brain ventricles and symptoms such as gait ataxia, urinary incontinence and dementia. Considerable influence from co- morbidities that often affect patients of same age may occur.

x More than 50 years after iNPH was first described as an entity, its etiology remains unknown, and iNPH may therefore be better defined by its response to treatment by surgical shunting than its cause.

x While a single standard for the prognostic evaluation of iNPH is lacking, the diagnosis typically requires a synthesis of converging evidence from clinical history, physical examination, and brain imaging.

x A positive CSF tap test, infusion test, or extended lumbar drainage test, will each increase probability for a positive shunt response, but should not be used to exclude patients from treatment.

x Invasive ICP monitoring has proven to have high sensitivity and specificity, but its use is limited by complication risks.

x A search for non-invasive methods to better characterize iNPH disease and identify shunt responders with high accuracy is warranted.

x Structural imaging to demonstrate communicating hydrocephalus is

considered mandatory for the iNPH diagnosis, and assessment of EI, CA and DESH may improve identification of shunt responders.

x Imaging of intracranial fluid flow dynamics utilizing PC-MRI has been proposed to identify iNPH patients suitable for shunting (ASV) and to non-invasively assess intracranial elastance (dP/dV).

x Multiphase MRI with contrast agent as CSF tracer is a new method that may characterize long-term CSF flow characteristics and detect reduced clearance of brain macromolecules in iNPH.

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2. Aims of the thesis

The overall aim of this thesis was to study short- and long-term CSF flow characteristics and pathologic alterations in the pre-surgical work-up of iNPH patients.

More specifically, the aims were

a) To study whether PC-MRI derived imaging biomarkers of intracranial pulsatility obtained at the aqueduct (ASV) and CCJ (MRI-dP) are associated with

invasive ICP monitoring

b) To assess net aqueductal flow in iNPH and compare findings with invasive ICP

c)

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3. Methods

The conclusions of this thesis derive from prospective studies of two iNPH cohorts: In the first, we explored CSF flow based imaging biomarkers with PC-MRI at the level of the aqueduct and CCJ. In the second, we studied CSF flow patterns in a wider

perspective by obtaining consecutive MRI acquisitions covering the intracranial compartment as a whole over an extended period of time using an MRI contrast agent as CSF tracer.

All patients were consecutively included in the studies and retrieved from referrals to the Department of Neurosurgery at Oslo University Hospital (OUH) for clinical and radiological work-up of suspected iNPH. Study related MR imaging sequences were performed at the final stage of a conventional imaging protocol for iNPH, and all pre- surgical imaging preceded ICP monitoring or other invasive tests, typically within a few weeks.

While patients were included and imaged prospectively, radiologic post-processing of images and comparisons with clinical data were performed in retrospect.

Written and oral informed consent to participate in the studies was retrieved from all patients, and the studies were approved by the Institutional Review Board and

Regional Ethics Committee. The study incorporating intrathecal administration of MRI contrast agent also received approval from the National Medicines Agency of

Norway.

3.1 Assessments of aqueductal CSF flow parameters (Paper 1 and 3)

3.1.1. Study population and design

For all patients, at the time of PC-MRI, ventricular enlargement had already been confirmed by a prior CT or MRI, and symptoms had been considered suggestive of iNPH at the referring hospital. An inclusion criterion for the study was the combination of a technically successful PC-MRI at the aqueduct level and overnight ICP

monitoring. In addition, patients were assessed clinically with determination of iNPH symptom severity. Patients, who were subsequently treated with surgical shunting, were invited to a second PC-MRI after one year with identical imaging protocol.