Mats Tullberg

Background The underlying pathophysiology of idiopathic normal pressure hydrocephalus (iNPH) is incompletely understood and reliable predictors of shunt response are lacking. Cerebrospinal fluid (CSF) biomarkers may provide insights into disease mechanisms and help identify patients most likely to benefit from surgery. The aim of this study was to explore CSF biomarker dynamics following shunt surgery and their relationship with clinical outcome. Methods The POiNT (Prediction of Outcome in iNPH) was a prospective longitudinal study. One hundred and thirty-five patients with iNPH underwent standardized clinical assessment and lumbar CSF sampling 3.6 (SD 2.1) months before and 5.7 months (SD 2.4) after shunt surgery. CSF was analyzed for biomarkers of astrogliosis, axonal injury, amyloid, and tau pathology, and synaptic dysfunction. Clinical outcomes were assessed using the iNPH scale. Associations between baseline biomarker levels, postoperative biomarker changes, and clinical outcomes were evaluated using adjusted correlation and regression analyses. Results In total, 69% (n=93) improved after shunt surgery. Substantial postoperative increases were observed for most CSF biomarkers: The largest relative increases were seen for growth-associated protein 43 (GAP43) (2.92-fold change), followed by Phosphorylated tau (2.65-fold change), Neurogranin and total-tau (both 2.29-fold change) as well as Aβ40 (1.93-fold change), and Aβ42 (1.76-fold change) (all p<0.001). In adjusted analyses, postoperative change in several biomarker levels were associated with degree of clinical improvement. However, baseline biomarker levels generally showed limited predictive value. Lower baseline monocyte chemoattractant protein-1 (MCP1) levels were associated with greater odds of overall clinical improvement but had a modest predictive performance (AUC 0.67). No baseline biomarker demonstrated strong discrimination of treatment response. Conclusion Shunt surgery was associated with substantial changes in CSF biomarker concentrations, several of which correlated with the degree of clinical improvement. Although baseline levels did not predict clinical outcome, the observed biomarker changes may reflect biological responses to treatment, altered CSF dynamics, or both .iNPH. Future studies examining these processes relating to disease reversibility might help elucidate pathophysiological mechanisms in iNPH.

Background: Idiopathic Normal Pressure Hydrocephalus (iNPH) is a leading cause of reversible gait disturbance in older adults, yet diagnosis and treatment selection remain limited by low-sensitivity clinical assessments. Conventional tests such as the 10-metre walk and Timed Up-and-Go capture overall performance but overlook the multidimensional, joint-level alterations that characterise iNPH gait. This study aimed to deliver the first comprehensive, three-dimensional (3D) biomechanical characterisation of iNPH gait to inform more objective diagnostic frameworks. Methods: Twenty-three participants with clinically diagnosed iNPH and eighteen age-matched healthy controls underwent baseline gait analysis (iNPH: pre tap test) consisting of overground walking using a 3D optoelectronic motion capture system with integrated force plates. Spatiotemporal parameters were compared using independent-samples t -tests, while continuous kinematic (i.e., joint angle) waveforms for the pelvis, hip, knee, and ankle were analysed using one-dimensional statistical parametric mapping (SPM). A binary logistic regression model was developed to classify participants as iNPH or healthy control. Results: Compared with controls, individuals with iNPH demonstrated markedly slower gait speed (–60%), shorter stride length (–52%), and greater stride width (+ 64%), each with large effect sizes (1.5–3.3; p < .001). SPM revealed multi-joint, phase-specific impairments in sagittal and frontal plane kinematics, including reduced pelvic obliquity, diminished hip flexion/extension and abduction, attenuated knee flexion during swing, and blunted ankle plantarflexion at push-off ( p < .05). These findings indicate impaired supraspinal coordination consistent with frontal-subcortical motor network dysfunction. Further, the statistical modelling achieved excellent discrimination between patients with iNPH and healthy controls. Due to short-stepped iNPH gait causing multiple consecutive steps on a single force plate, kinetics (i.e., ground reaction forces; joint moments) could not be analysed. Conclusions: This study suggests the first detailed biomechanical signatures of gait in iNPH, identifying spatiotemporal and joint-specific alterations that together define a central coordination deficit. Beyond confirming known gait slowing, these results delineate kinematic markers with translational potential as digital biomarkers for diagnosis and postoperative monitoring. By advancing gait analysis from simple bedside tests to detailed quantification, 3D motion capture offers a rigorous, reproducible framework that may improve diagnostic sensitivity in patients with iNPH. However, larger future studies should include clinically more heterogeneous cohorts and incorporate relevant disease mimics (e.g., Parkinson’s disease, progressive supranuclear palsy) to determine differentiation capabilities of the predictive modelling.

Background: Cerebrospinal fluid tap test (CSF TT) is a key predictive method commonly used to identify candidates for shunt surgery in idiopathic Normal Pressure Hydrocephalus (iNPH), however, the sensitivity of this procedure is limited. The aim was to compare sensitivity of a broad set of physiotherapy-based clinical tests for assessing changes following CSF TT in a group of selected iNPH patients and to explore potential sex-based differences in the responses. Methods: Ninety-five selected iNPH patients (mean age 77, SD 6, 57% male), underwent CSF TT prior to shunt surgery. Clinical tests comprised different static balance tests in varying conditions including feet and heels apart and together; eyes open and closed; on floor and foam cushion, followed by gait and functional performance measures including 10-meter walk test (10MWT), 3-meter backward walking (3MBW), Timed-up and Go (TUG) and 6-minute walking test (6MWT). Duration in seconds (sec) and distance were noted. Assessments were conducted at set time points before and after the drainage procedure. Changes in performance were analyzed, and responses compared between sexes. Results: Significant increase was observed across most static balance tests except tandem eyes closed (EC) and one-legged stance tests. The largest enhancements were seen in the Romberg test (4.9 s), followed by foam cushion-eyes open (EO) tests (feet together: 3.9 s and heels together: 3.8 s), heels together-EC (3.8 s) and tandem-EO (3.1 s). Gait and functional tests significantly improved ( p < 0.001) and 3MBW showed the largest change, with a 32% reduction in sec and a 23% reduction in steps, followed by decrease in TUG sec (27%) and 10-MWT sec (21%), and 6MWT distance increase (25%). Males demonstrated significant increase in heels together-EO and feet together-EO duration which were not observed in females; after adjusting for baseline performances, no significant sex-related differences in responsiveness to CSF TT were found. Conclusions: Challenging comprehensive physiotherapy tests, including gait assessments in direction and capacity, such as 3MBW and 6MWT, together with postural control evaluations using foam cushion and tandem stance increases the sensitivity to change and are suggested to be used to detect functional changes after CSF TT in patients with iNPH. Trail registration: The project is registered in "FoU inSweden” (Research and Development in Sweden) ID: 285356.

Background: Gait impairment is a core symptom in idiopathic normal pressure hydrocephalus (iNPH), but commonly used tests like the 10-metre walk test (10MWT) may underestimate postoperative improvements. We evaluated the 6-minute walk test (6MWT) and 3-metre backward walk test (3MBWT) as outcome measures compared with 10MWT and Timed Up and Go (TUG) and explored sex-related and age-related differences in shunt-operated patients with iNPH. Methods: A retrospective study of 291 shunted patients with iNPH (62.5% male; mean age 73.3±6.2 years) was conducted. Gait function was assessed preoperatively and at a median of 5.4 months postoperatively. Outcomes were analysed using linear regression, with age and sex as covariates; improvement was described as per cent change from baseline. Correlations between tests were assessed with Spearman coefficients. Results: Postoperative changes were observed for all gait measures: 3MBWT time (40% reduction (95% CI 36% to 44%)), 6MWT distance (32% increase (95% CI 23% to 43%)), TUG time (28% reduction (95% CI 24% to 32%)) and 10MWT time (19–23% reduction (95% CI 16% to 25%)) at maximal speed and self-selected speed. Women performed worse than men both before and after shunt insertion, but improvement did not differ by sex when adjusting for baseline performance. Each 5-year increase in age reduced gait improvement by 3–8% (p<0.05). Preoperatively, 6MWT correlated strongly with 10MWT (ρ=−0.81) and 3MBWT with TUG (ρ=0.75), while the correlation between 6MWT and 3MBWT was moderate (ρ=−0.58) (all p<0.001). Conclusions: The 3MBWT and 6MWT capture postoperative gait changes and may provide complementary information to conventional gait assessments in iNPH.

Background: Ventricular cerebrospinal fluid (CSF) was analysed peri- and postoperatively to elucidate the pathophysiology of Idiopathic normal pressure hydrocephalus (iNPH). Objective: To capture the dynamics of biomarkers and their relation to clinical symptoms. Methods: In 113 consecutively diagnosed patients, the Hellström iNPH scale was used to quantify symptom burden pre- and postoperatively. CSF was collected at shunt insertion and postoperatively by shunt reservoir puncture, and analyzed for concentrations of GFAP, YKL40, MCP-1, NfL, Aβ ₄₀ , sAβPPα, sAβPPβ, GAP43, Alzheimer's disease biomarkers Aβ ₄₂ , Aβ _42/40 , total tau (T-tau), phosphorylated tau (P-tau), and neurogranin. Results: Concentrations increased postoperatively for Aβ ₄₀ (134%), Aβ ₄₂ (106%), sAβPPα (112%), sAβPPβ (83%), NfL (128%), YKL40 (86%), GAP43 (124%), and MCP-1 (5%) (p < 0.001, MCP-1 (p = 0.03)), while mean concentration reductions were seen in T-tau (32%), GFAP (31%), neurogranin (49%), and Aβ _42/40 (10%) (p < 0.001). A higher perioperative concentration of AβPPβ correlated with less pronounced gait disturbance (R _p 0.20 (0.01–0.38) (95% CI)), whereas higher levels of NfL (−0.23 (−0.41–(−)0.04) and MCP-1 (−0.21 (−0.37–(−)0.01)) correlated with impaired cognition. Higher MCP-1 correlated with a lower balance domain score (−0.20 (−0.37–(−)0.01)). Postoperative increases in levels of Aβ ₄₀ (R _s 0.27 (0.05–0.46)), Aβ ₄₂ (R _s 0.24 (0.02–0.44)) and YKL40 (R _s 0.22 (−0.00–0.43)) correlated with gait improvement, and a postoperative increase in Aβ ₄₀ (R _s 0.36 (0.05–0.60)) was associated with improvement in urinary continence (p 0.01–0.05). Conclusions: CSF biomarker concentrations change after shunt insertion. These changes, seen as increased concentrations for some biomarkers and decreased concentrations for others, are associated with improvement in core clinical symptoms and may illustrate reversibility of pathophysiological mechanisms in iNPH.

Background: The neurochemical alterations in cerebrospinal fluid (CSF) associated with the typical symptomatology in idiopathic normal pressure hydrocephalus (iNPH) and their association with outcome after shunt surgery are unsettled. Aim: To explore associations between concentrations of CSF biomarkers reflecting amyloid- and tau pathology, neuronal degeneration as well as astrocytic activation and the characteristic symptomatology in iNPH and to examine whether these biomarkers can predict the postoperative outcome in all patients and in patients without evidence of Alzheimer’s disease (AD) pathology. Methods: This explorative study included 81 patients diagnosed with iNPH at the Hydrocephalus research unit, Sahlgrenska. Symptoms were assessed using the iNPH-scale and standardized clinical tests measuring gait, balance, cognition and urinary incontinence before and median 8 months after shunt surgery. Pre-operative lumbar CSF concentrations of Aβ38, Aβ40, Aβ42, ratio Aβ42/Aβ40, sAPPα, sAPPβ, T-tau, P-tau, MCP-1, and NFL were analyzed. A low Aβ42/Aβ40 ratio defined patients with AD pathology. Correlation and regression analyses between biomarker concentrations and clinical symptoms at baseline as well as postoperative change in symptoms after surgery, were performed. Results: Higher NFL correlated with more pronounced impairment in all clinical tests, i.e. included measures of gait, balance, cognition and urinary incontinence (r_p=0.25–0.46, p < 0.05). Higher T-tau and P-tau correlated with poorer performance in cognitive tests (r_p=0.26–0.39, p < 0.05). No biomarker could differentiate between improved and unimproved patients in the whole sample or in AD-pathology negative patients. Low ratio Aβ42/Aβ40 lacked predictive value. A higher preoperative P-tau was weakly correlated with less pronounced overall clinical improvement (r_p = -0.238, p = 0.036). Conclusions: Axonal degeneration, as indicated by elevated NFL, is probably involved in the generation of the full iNPH tetrade of symptoms and tau pathology more specifically with iNPH cognitive impairment. No CSF biomarker could identify shunt responders. CSF evidence of Alzheimer pathology should not be used to exclude patients from shunt surgery.

Idiopathic normal pressure hydrocephalus (iNPH) increases with age but is still underdiagnosed and undertreated. In the last decade, iNPH research has expanded into understanding broader contributions to iNPH, the role of cerebrospinal fluid (CSF), and imaging biomarkers to aid early detection, help diagnosis and differentiation from iNPH mimics, and aid with outcome prediction. We performed a literature search on the PubMed database. English language articles published between 2015-2024 were included. The strategies focused on iNPH and specific terms related to the topics of this review. We first addressed the ambiguity of current classification terminology and reviewed the newly proposed classification system. This review has shown that prevalence is higher than previously reported. We have reviewed imaging and found numerous highly sensitive and specific imaging markers to aid diagnosis and differentiate from common mimics. CSF biomarkers have revealed that amyloid β and tau levels were lower in iNPH patients, which helped with differentiation from iNPH mimics, and that other emerging inflammatory markers need to be studied further. We also found numerous promising genetic markers in familial iNPH involved in cilial dysfunction, neuroinflammation, and neurodegeneration. Literature also reported the frequent presence of spinal stenosis, and studies reported better iNPH outcomes when these were addressed. This has shown that there is a need for the development of a structured and standardized classification system, iNPH assessment protocol with standardized testing, and standardized biomarkers to aid diagnosis and treatment, and that this needs an interdisciplinary team approach.

Objective: To determine the utility of symptoms, signs, comorbidities and background variables for the prediction of outcome of treatment in iNPH. Methods: A prospective observational study of consecutively included iNPH patients, who underwent neurological, physiotherapeutic and neuropsychological assessments before and after shunt surgery. The primary outcome measure was the total change on the iNPH scale, and patients were defined as improved postoperatively if they had improved by at least five points on that scale. Results: 143 iNPH patients were included, and 73% of those were improved after surgery. None of the examined symptoms or signs could predict which patients would improve after shunt surgery. A dominant subjective complaint of memory problems at baseline was predictive of non-improvement. The reported comorbidities, duration of symptoms and BMI were the same in improved and non-improved patients. Each of the symptom domains (gait, neuropsychology, balance, and continence) as well as the total iNPH scale score improved significantly (from median 53 to 69, p < 0.001). The proportions of patients with shuffling gait, broad-based gait, paratonic rigidity and retropulsion all decreased significantly. Discussion: This study confirms that the recorded clinical signs, symptoms, and impairments in the adopted clinical tests are characteristic findings in iNPH, based on that most of them improved after shunt surgery. However, our clinical data did not enable predictions of whether patients would respond to shunt surgery, indicating that the phenotype is unrelated to the reversibility of the iNPH state and should mainly support diagnosis. Absence of specific signs should not be used to exclude patients from treatment.