Background. CoGNIT is a computerized test battery for cognitive assessment, used in diagnosing and treating patients with idiopathic normal pressure hydrocephalus (INPH). The disorder causes symptoms of dementia, among other things. Apart from other diseases with similar symptoms, like Alzheimer’s, INPH can be countered. CoGNIT is performed by a patient before and after drainage of cerebrospinal fluid. If a significant improvement in cognition is detected after the extraction, the patient receives shunt surgery which reduces all symptoms. The test battery is long and tedious, which makes it difficult for people with cognitive impairments to complete. Objectives. The objectives of this study are to rework original CoGNIT with carefully selected game design elements and analyze the effects of the alteration on performance and user experience. If users perform better in a gamified environment, the validity of gathered data will have improved as the data should better reflect their cognitive capabilities. Another objective is to introduce gamification to the medical field. Methods. Game design elements were picked and designed based on suitability for elderly people and with the impairments of INPH patients in mind. A gamified prototype was developed and put to test with healthy individuals against the original version in an experiment. The effects of gamification on performance was examined by comparing resulting score values from both versions of the test. Participants also filled in a questionnaire as proxy for the test’s target group, meaning that questions were answered with how the participants expected a cognitively impaired person to answer. Answers were used to investigate the effect of gamification ofuser experience. Results. The gamified version of CoGNIT shows an improvement in test segments regarding attention, psychomotor speed, executive function, and manual dexterity, but a negative inclination in segments regarding memory. Results from the user experience questionnaire indicates that the gamified version feels less dramatic, more playful, less "test-like" and less tedious compared to the non-gamified version. This suggests that the added game elementsare affecting the user experience in the desired way. Conclusions. An overall positive impact on both performance and user experience from gamification is concluded. The negative effect on memory tests could not be determined to be a cause of the gamification per se. / Bakgrund. CoGNIT är ett datoriserat testbatteri för kognitiv bedömning som används vid diagnos och behandling av patienter med idiopatisk normaltryckshydrocefalus (INPH). Sjukdomen orsakar bland annat symptom som demens. Till skillnad från andra sjukdomar med liknande symptom, som Alzheimers, kan INPH motverkas. CoGNIT utförs av en patient före och efter dränering av cerebrospinalvätska. Om en förbättring av patientens kognitiva förmågor upptäcks efter dräneringen, shuntoperaras patienten och alla symptom minskas. Testbatteriet är långt och tråkigt, vilket gör det svårt för personer med kognitiva nedsättningar att slutföra. Syfte. Syftet med denna studie är att omarbeta CoGNIT med noggrant utvalda speldesignelement och analysera hur prestation och användarupplevelse påverkas av förändringen. Om användare presterar bättre i en spelifierad miljö kommer validiteten av insamlad data att förbättras eftersom datan borde bättre återspegla deras kognitiva förmågor. Ett annat mål är att introducera spelifiering till det medicinska området. Metod. Speldesignelement valdes ut och utformades baserat på dess lämplighet för äldre och med de funktionsnedsättnigar som INPH-patienter har i åtanke. En spelifierad prototyp utvecklades och testades med friska individer mot originalversionen i ett experiment. Effekterna av spelifiering på prestation undersöktes genom att jämföra poängvärden från båda versionerna av testet. Deltagarna fyllde också i ett frågeformulär som "proxy" för testets målgrupp, vilket innebär att frågorna besvarades med hur deltagarna förväntade sig att en kognitivt nedsatt person hade svarat. Svaren användes för att undersöka effekten av spelifiering på användarupplevelsen. Resultat. Den spelifierade versionen av CoGNIT visar en förbättring i testsegmenten som utvärderar uppmärksamhet, psykomotorisk hastighet, exekutiva funktioner och fingerfärdighet, men en försämring i segmenten som utvärderar minne. Resultat från frågeformuläret indikerar att den spelifierade versionen upplevs mindre dramatisk, mer lekfull, mindre "testliknande" och mindre tråkig jämfört medden icke-spelifierade versionen. Detta visar att de tillagda spelelementen påverkar användarupplevelsen som önskat. Slutsatser. En övergripande positiv inverkan på både prestanda och användarupplevelse från spelfiering fastställs. Den negativa effekten på minnestesterna kunde inte bedömas vara en orsak av spelifiering i sig.

A validated model of water transport in the cerebral environment is both an ambitious and timely task; many brain diseases relate to imbalances in water regulation. From tumours to strokes, chronic or acute, transport of fluid in the brain plays a crucial role. The importance and complexity of the brain, together with the range of unmet clinical needs that are connected with this organ,make the current research a high-priority. One of the most paradoxical cerebral conditions, hydrocephalus, serves as an excellent metric for judging the success of anymodel developed. In particular, normal pressure hydrocephalus (NPH) is a paradoxical condition with no known cure and existing treatments display unacceptably high failure rates. NPH is considered to be a disease of old age, and like many such diseases, it is related to a change in the transport of fluid in the cerebral environment. This complex system ranges from organ-level transport to cellular membrane channels such as aquaporins; through integrating it in a novel mathematical framework, we suggest that the underlying logic of treatment methods may be misleading. By modelling the transport of cerebrospinal fluid (CSF) between the ventricular system, cerebral tissue and blood networks, we find that changes to the biophysical properties of the brain (rather than structural changes such as aqueduct obstruction) are capable of producing clinically relevant ventriculomegaly in the absence of any obstruction to CSF flowthrough the ventricular system. Specifically, the combination of increased leakiness and compliance of the capillary bed leads to the development of enlarged ventricles with a normal ventricular pressure, replicating clinical features of the presentation of NPH. These results, while needing experimental validation, imply that treatment methods like shunting, that are focussed on structural manipulation, may continue to fail at unacceptably high rates.

The volume defined by the rigid cranium is shared by the brain, blood and cerebrospinal fluid (CSF). With every heartbeat the arterial blood volume briefly increases and venous blood and CSF are forced out of the cranium, leading to pulsatility in CSF flow and intracranial pressure (ICP). Altered CSF pulsatility has been linked to idiopathic normal pressure hydrocephalus (INPH), which involves enlarged cerebral ventricles and symptoms of gait/balance disturbance, cognitive decline and urinary incontinence that may be improved by implantation of a shunt. The overall aim of this thesis was to investigate the fluid dynamics of the CSF system, with a focus on pulsatility, and how they relate to INPH pathophysiology and treatment. Mathematical modelling was applied to data from infusion tests, where the ICP response to CSF volume manipulation is measured, to analyse the relationship between mean ICP and ICP pulse amplitude (AMP) before and after shunt surgery in INPH (paper I-II). The observed relationship, designated the pulsatility curve, was found to be constant at low ICP and linear at high ICP, corresponding to a shift from constant to ICP dependent compliance (paper I). Shunt surgery did not affect the pulsatility curve, but shifted baseline ICP and AMP along the curve towards lower values. Patients who improved in gait after surgery had significantly larger AMP reduction than those who did not, while ICP reduction was similar, suggesting that improving patients had baseline ICP in the linear zone of the curve before surgery. Use of this phenomenon for outcome prediction was promising (paper II). The fluid dynamics of an empirically derived pulsatility-based predictive infusion test for INPH was also investigated, with results showing strong influence from compliance (paper III). Clinical ICP data at different body postures was used to evaluate three models describing postural effects on ICP. ICP decreased in upright positions, whereas AMP increased. The model describing the postural effects based on hydrostatic changes in the venous system, including effects of collapse of the jugular veins in the upright position, accurately predicted the measured ICP (paper IV). Cerebral blood flow and CSF flow in the aqueduct and at the cervical level was measured with phase contrast magnetic resonance imaging, and compared between healthy elderly and INPH (paper V). Cerebral blood flow and CSF flow at the cervical level were similar in INPH patients and healthy elderly, whereas aqueductal CSF flow differed significantly. The pulsatility in the aqueduct flow was increased, and there was more variation in the net flow in INPH, but the mean net flow was normal, i.e. directed from the ventricles to the subarachnoid space (paper V). In conclusion, this thesis introduced the concept of pulsatility curve analysis, and provided evidence that pulsatility and compliance are important aspects for successful shunt treatment and outcome prediction in INPH. It was further confirmed that enhanced pulsatility of aqueduct CSF flow was the most distinct effect of INPH pathophysiology on cerebral blood flow and CSF flow. A new model describing postural and hydrostatic effects on ICP was presented, and the feasibility and potential importance of measuring ICP in the upright position in INPH was demonstrated. / <p>Forskningsfinansiär: </p><p>European Union, ERDF: Objective 2, Northern Sweden (grant no. 158715-CMTF). </p>

Σποραδικές μελέτες περιγράφουν την προσωρινή εξωτερική οσφυϊκή παροχέτευση του ΕΝΥ, ως μία δοκιμασία υψηλής ακριβείας όσον αφορά στην πρόβλεψη του κλινικού αποτελέσματος μετά από κοιλιοπεριτοναϊκή παροχέτευση στους ασθενείς με ΥΦΠ. Παρόλα αυτά, σε μία πιο πρόσφατη μελέτη από τους Walchenbach και συνεργάτες, εκτιμήθηκε ότι η θετική προγνωστική αξία της ΕΟΠ ήταν υψηλή, ενώ η αρνητική χαμηλή. Δια ταύτα, πραγματοποιήσαμε μία προοπτική μελέτη με σκοπό να εκτιμήσουμε την προγνωστική αξία μιάς προσωρινής εξωτερικής οσφυικής παροχέτευσης (ΕΟΠ), η οποία ρυθμίζει την εκροή ΕΝΥ μέσω μιάς βαλβίδας μέσης πίεσης μονόδρομης ροής, σε ασθενείς με υδροκέφαλο φυσιολογικής πίεσης (ΥΦΠ). Είκοσι επτά 27 ασθενείς με ΥΦΠ εισήχθησαν στη Νευροχειρουργική Κλινική του ΠΓΝΠ και υπεβλήθησαν σε τοποθέτηση προσωρινής εξωτερικής οσφυικής παροχέτευσης (ΕΟΠ), η οποία ρυθμίζει την εκροή ΕΝΥ μέσω μιάς βαλβίδας μέσης πίεσης, για 5 ημέρες. 22 ασθενείς υπεβλήθησαν τελικά σε κοιλιοπεριτοναϊκή παροχέτευση με βαλβίδα μέσης πίεσης, βασιζόμενοι σε κλινικά και ακτινολογικά κριτήρια, ανεξαρτήτως του αποτελέσματος της ΕΟΠ. Κλινική εκτίμηση των διαταραχών της βάδισης, της ούρησης και της νόησης, όπως επίσης και ακτινολογική εκτίμηση, πραγματοποιήθηκε προ και μετά την δοκιμασία της ΕΟΠ καθώς και 3 μήνες μετά την ΚΠΠ. Είκοσι δύο 22 ασθενείς υπεβλήθησαν τελικά σε κοιλιοπεριτοναϊκή παροχέτευση και πληρούσαν τα κριτήρια για να συμπεριληφθούν τελικά στη μελέτη. Χρησιμοποιώντας ένα εγκεκριμένο σύστημα βαθμολόγησης, η συνολική βελτίωση μετά τη δοκιμασία ΕΟΠ συσχετιζόταν καλά με τη βελτίωση 3 μήνες μετά την μόνιμη ΚΠΠ. (Spearman’ s rho = 0,462, p=0,03). Όταν θεωρήσαμε κάθε βαθμό βελτίωσης ως θετική ανταπόκριση, η δοκιμασία ΕΟΠ-βαλβίδας μέσης πίεσης είχε υψηλή θετική προγνωστική αξία για κάθε μία ανεξάρτητη κλινική παράμετρο (διαταραχές της βάδισης 94%, 95% CI 71%-100%, ακράτεια στην ούρηση 100%, 95% CI 66%-100%, διαταραχές της νόησης 100%, 95% CI 66-100%), ενώ η αρνητική προγνωστική αξία ήταν χαμηλή (<50%) εκτός από τις διαταραχές της νόησης (85%, 95% CI 55%-98%). Η ανωτέρω μελέτη συμπεραίνει ότι η δοκιμασία της ΕΟΠ-βαλβίδας μέσης πίεσης, θα πρέπει να θεωρείται ένα αξιόπιστο κριτήριο για την προεγχειρητική επιλογή υδροκεφαλικών ασθενών φυσιολογικής πίεσης που βελτιώνονται κλινικά μετά την τοποθέτηση ΚΠΠ. Σε περίπτωση αρνητικής δοκιμασίας ΕΟΠ-βαλβίδας μέσης πίεσης, θα πρέπει να διενεργείται περαιτέρω διερεύνηση με επιπρόσθετες διαγνωστικές δοκιμασίες. / Although sporadic studies have described temporary external cerebrospinal fluid (CSF) lumbar drainage as a highly accurate test in predicting the outcome after ventricular shunting in normal pressure hydrocephalus (NPH) patients, a more recent study reports that the positive predictive value of external lumbar drainage (ELD) is high but the negative predictive value is deceptively low. Therefore, we conducted a prospective study in order to evaluate the predictive value of a continuous ELD, with CSF outflow controlled by medium pressure valve, in NPH patients. Twenty-seven patients with presumed NPH were admitted to our department and CSF drainage was carried out by a temporary (ELD), with CSF outflow controlled by medium pressure valve for five days. Twenty-two patients received a ventriculo¬peritoneal shunt with medium pressure valve based upon preoperative clinical and radiographic criteria of NPH, regardless of ELD outcome. Clinical evaluation of gait disturbances, urinary incontinence and mental status, and radiological evaluation with brain CT was performed prior to and after ELD test, as well as three months after shunting. Twenty-two patients were finally shunted and included in this study. In a three-month follow-up, using a previously validated score system, overall improvement after permanent shunting correlated well with improvement after ELD test (Spearman’s rho=0.462, p=0.03). When considering any degree of improvement as a positive response, ELD test yielded high positive predictive values for all individual parameters (gait disturbances 94%, 95% CI 71%-100%, urinary incontinence 100%, 95% CI 66%-100%, and mental status 100%, 95% CI 66%-100%) but negative predictive values were low (<50%) except for cognitive impairment (85%, 95% CI 55%-98%). This study suggests that a positive ELD-valve system test should be considered a reliable criterion for preoperative selection of shunt-responsive NPH patients. In case of a negative ELD-valve system test, further investigation of the presumed NPH patients with additional tests should be performed.

Despite decades of research of normal pressure hydrocephalus (NPH), a clear pathophysiological mechanism of the disease is sill unknown. This results in the absence of a unambiguous diagnostic biomarker. Moreover, NPH in contrast to similar neurodegenerative diseases is curable by insertion of a ventrikulo-peritoneal shunt. Now the diagnostics is based on invasive functional testing, on the contrary, imaging methods play only a supporting role. This work is processed with an effort to find a sufficiently sensitive and specific biomarker of MRI imaging using advanced analytical methods. For this reason, the structural volumetry and the phase contrast method were tested. The individual partial results of both of these modalities have already been described in the literature, but the conclusions were controversial. The main contribution of this work is the range of tested parameters and their to date untested advanced analysis - accurate automatic segmentation in volumetric study and machine learning algorithms in phase contrast study. In a volumetric study, we segmented a total of 26 structures in 74 patients (29 with diagnosed NPH, 45 without NPH). In the case of preoperative examination, we demonstrated statistically significant differences in the size of the left hippocampus, corpus callosum, left...

BACKGROUND: Idiopathic normal pressure hydrocephalus (INPH) is still a syndrome generating more questions than answers. Today, research focuses mainly on two areas: understanding the pathophysiology – especially how the malfunctioning CSF system affects the brain parenchyma – and finding better methods to select patients benefiting from a shunt operation. This thesis targets the aspect of finding better selection methods by investigating the measurability of intracranial pressure via lumbar space, and determining if intraparenchymal measurement of long-term ICP-oscillations (B-waves) could be replaced by short-term measurements of CSF pulse pressure waves via lumbar space. Furthermore, I look into the interaction between the CSF system and the parenchyma itself by investigating how the cortical activity of the brain changes after long-term CSF drainage, and if there is any regress in the suggested ischemia after this intervention. Finally, I examine if the neuronal integrity in the INPH brain is impaired, and if this feature is relevant for the likeliness of improvement after CSF diversion. METHODS: The comparison of intracranial and lumbar pressure was made over a vast pressure interval using our unique CSF infusion technique, and it included ten INPH patients. Pressure was measured via lumbar space and in brain tissue, and the pressures were compared using a general linear model. Short-term lumbar pressure waves were quantified by determining the slope between CSF pulse pressure and mean pressure, defined as the relative pulse pressure coefficient (RPPC). The correlation between RPPC, B-waves and CSF outflow resistance was investigated. In a prospective study, functional MRI was used to assess brain activity before and after long-term CSF drainage of 400 ml of CSF in eleven INPH patients. The functionalities tested included finger movement, memory, and attention. The results were benchmarked against the activity in ten healthy controls to identify the brain areas improving after drainage. The ischemia (Lactate) and neuronal integrity (NAA and Choline) were measured in a similar manner in 16 patients using proton MR spectroscopy, and the improvement of the patients after CSF drainage was based on assessment of their gait. RESULTS: There was excellent agreement between ICP measured in brain tissue and via lumbar space (regression coefficient = 0.98, absolute difference < 1 mm Hg). Adjusting for the separation distance between the measuring devices slightly worsened the agreement, indicating other factors influencing the measured difference as well. RPPC measured via lumbar space significantly correlated to the presence of B-waves, but not to outflow resistance. In the prospective study, controls outperformed patients on clinical tests as well as tasks related to the experiments. Improved behaviour after CSF drainage was found for motor function only, and it was accompanied by increased activation in the supplementary motor area (SMA). No lactate was detected, either before or after CSF drainage. NAA was decreased in INPH patients compared to controls, and the NAA levels were higher in the patients improving after drainage. CONCLUSIONS: ICP can be accurately measured via lumbar space in patients with communicating CSF systems. The close relation between RPPC and B-waves indicates that B-waves are primarily related to intracranial compliance, and that measurement of RPPC via lumbar space could possibly substitute B-wave assessment as selection method for finding suitable patients for shunt surgery. Improvement in motor function after CSF drainage was associated to enhanced activity in SMA, supporting the involvement of the cortico-basal ganglia-thalamo-cortical loop in the pathophysiology of INPH. There was no evidence indicating a widespread low-graded ischemia in INPH; however, there was a neuronal dysfunction in frontal white matter as indicated by the reduced levels of NAA. In addition, the level of neuronal dysfunction was related to the likeliness of improvement after CSF removal, normal levels of NAA predisposing for recovery.

Structural and diffusion imaging patterns that can be evaluated using MRI in patients with cognitive deficits are the central theme of the proposed work. First, the clinical and neuroimaging background of dementias has been reviewed in a broader context, with a special focus on Alzheimer's disease (AD) and differential diagnoses. The second part of this thesis contains four consecutive experimental studies. The primary objective of the first two studies was to obtain structural and microstructural information on the neurodegenerative processes characteristic for AD on global and regional levels. For this purpose, several complementary approaches were used and the focus was shifted from grey to white matter (GM/WM). The following two studies focused on the differential context of WM microstructural alterations in normal pressure hydrocephalus (NPH) and distinctive patterns of WM disintegrity in temporal lobe epilepsy (TLE). The most important conclusion of our studies is that structural and diffusion imaging proved to be useful in identifying regionally specific and disproportionate loss of brain volume and microstructure in several pathological processes underlying cognitive deterioration. The use of distinctive morphometric methods yielded complementary information on AD-related atrophy patterns,...

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Background: Normal pressure hydrocephalus (NPH) has been an ongoing and challenging field of research for the past decades because two main issues are still not fully understood: the pathophysiologic mechanisms underlying ventricular enlargement and prediction of outcome after surgery. Purpose: To evaluate changes in diffusion tensor imaging (DTI) derived parameters in patients with suspected normal pressure hydrocephalus before and after withdrawal of cerebrospinal fluid (CSF). Material and Methods: Twenty-four consecutive patients with clinical and radiological suspicion of NPH and 14 agematched control subjects were examined with DTI on a clinical 3T scanner. Patients were examined before and 6–36 h after CSF drainage (interval between scans, 5 days). Fifteen patients were finally included in data analysis. Fractional anisotropy (FA) and mean, parallel, and radial diffusivity (MD, PD, RD) were evaluated using a combination of a ROI-based approach and a whole-brain voxel-by-voxel analysis. Results: Alteration of DTI parameters in patients with suspected NPH is regionally different. Compared to the control group, we found an elevation of FA in the subcortical white matter (SCWM) and corpus callosum, whereas the other diffusion parameters showed an increase throughout the brain in variable extent.We also found a slight normalization of RD in the SCWM in patients after lumbar drainage. Conclusion: Our results show that DWI parameters are regionally dependent and reflect multifactorial (patho-) physiological mechanisms, which need to be interpreted carefully. It seems that improvement of gait is caused by a decrease of interstitial water deposition in the SCWM.