The timed up and go test in idiopathic normal pressure hydrocephalus: a Nationwide Study of 1300 patients

Background The aim of this study was to describe the outcome measure timed up and go (TUG) in a large, nationwide cohort of patients with idiopathic normal pressure hydrocephalus (iNPH) pre- and post-operatively. Furthermore, to compare the TUG test to the 10-m walk test (10MWT), the iNPH scale, the modified Rankin scale (mRS) and the Mini Mental State Examination (MMSE), which are commonly applied in clinical assessment of iNPH. Methods Patients with iNPH (n = 1300), registered in the Swedish Hydrocephalus Quality Registry (SHQR), were included. All data were retrieved from the SHQR except the 10MWT, which was collected from patient medical records. Clinical scales were examined pre- and 3 months post-operatively. Data were dichotomised by sex, age, and preoperative TUG time. Results Preoperative TUG values were 19.0 [14.0–26.0] s (median [IQR]) and 23 [18–30] steps. Post-operatively, significant improvements to 14.0 [11.0–20.0] s and 19 [15–25] steps were seen. TUG time and steps were higher in women compared to men (p < 0.001) but there was no sex difference in improvement rate. Worse preoperative TUG and younger age favoured improvement. TUG was highly correlated to the 10MWT, but correlations of post-operative changes were only low to moderate between all scales (r = 0.22–0.61). Conclusions This study establishes the distribution of TUG in iNPH patients and shows that the test captures important clinical features that improve after surgery independent of sex and in all age groups, confirming the clinical value of the TUG test. TUG performance is associated with performance on the 10MWT pre- and post-operatively. However, the weak correlations in post-operative change to the 10MWT and other established outcome measures indicate an additional value of TUG when assessing the effects of shunt surgery.

Waiting time for surgery influences the outcome in idiopathic normal pressure hydrocephalus — a population-based study

Introduction Idiopathic normal pressure hydrocephalus (iNPH) is a disease that comes with a great impact on the patient’s life. The only treatment for iNPH, which is a progressive disease, is shunt surgery. It is previously indicated that early intervention might be of importance for the outcome. Aim To investigate if a longer waiting time for surgery, negatively influences the clinical outcome. Methods Eligible for this study were all iNPH patients (n = 3007) registered in the Swedish Hydrocephalus Quality Registry (SHQR) during 1st of January 2004–12th of June 2019. Waiting time, defined as time between the decision to accept a patient for surgery and shunt surgery, was divided into the intervals ≤ 3, 3.1–5.9 and ≥ 6 months. Clinical outcome was assessed 3 and 12 months after surgery using the modified iNPH scale, the Timed Up and Go (TUG) test and the mini mental state examination (MMSE). Results Three months after surgery, 57% of the patients with ≤ 3 months waiting time showed an improvement in modified iNPH scale (≥ 5 points) whereas 52% and 46% of patients with 3.1–5.9 and ≥ 6 months waiting time respectively improved (p = 0.0115). At 12 months of follow-up, the corresponding numbers were 61%, 52% and 51% respectively (p = 0.0536). Conclusions This population-based study showed that in patients with iNPH, shunt surgery should be performed within 3 months of decision to surgery, to attain the best outcome.

Preliminary Exploration of the Sequence of Nerve Fiber Bundles Involvement for Idiopathic Normal Pressure Hydrocephalus: A Correlation Analysis Using Diffusion Tensor Imaging

The study preliminarily explored the sequence and difference of involvement in different neuroanatomical structures in idiopathic normal pressure hydrocephalus (INPH). We retrospectively analyzed the differences in diffusion tensor imaging (DTI) parameters in 15 ROIs [including the bilateral centrum semiovale (CS), corpus callosum (CC) (body, genu, and splenium), head of the caudate nucleus (CN), internal capsule (IC) (anterior and posterior limb), thalamus (TH), and the bilateral frontal horn white matter hyperintensity (FHWMH)] between 27 INPH patients and 11 healthy controls and the correlation between DTI indices and clinical symptoms, as evaluated by the INPH grading scale (INPHGS), the Mini-Mental State Examination (MMSE), and the timed up and go test (TUG-t), before and 1 month after shunt surgery. Significant differences were observed in DTI parameters from the CS (pFA1 = 0.004, pADC1 = 0.005) and the genu (pFA2 = 0.022; pADC2 = 0.001) and body (pFA3 = 0.003; pADC3 = 0.002) of the CC between the groups. The DTI parameters from the CS were strongly correlated with the MMSE score both pre-operatively and post-operatively. There was association between apparent diffusion coefficient (ADC) values of anterior and posterior limbs of the IC and MMSE. The DTI parameters of the head of the CN were correlated with motion, and the ADC value was significantly associated with the MMSE score. The FA value from TH correlated with an improvement in urination after shunt surgery. We considered that different neuroanatomical structures are affected differently by disease due to their positions in neural pathways and characteristics, which is further reflected in clinical symptoms and the prognosis of shunt surgery.

White Matter Characteristics of Cognitive Impairment in Tap-Test Positive Idiopathic Normal Pressure Hydrocephalus: A Diffusion Tensor Tract-Based Spatial Study

The present study was designed to systemically evaluate changes in the diffusion tensor imaging (DTI)-derived parameters of iNPH (idiopathic normal pressure hydrocephalus) patients with different responses to the tap test (TT), and to correlate cognitive impairment with white matter (WM) degeneration. This study included 22 iNPH patients and 14 healthy controls with structural magnetic resonance imaging (MRI) and DTI scanning. DTI was used to explore the differences in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) for all participants. DTI parameters were evaluated using an ROI (region of interest)-based and tract-based spatial statistics (TBSS) approach. Neuropsychological assessments and the idiopathic normal pressure hydrocephalus grading scoring scale (iNPHGS) were performed. Compared to the TT non-responders, the TT responders group had significantly lower FA values in the corpus callosum, cingulum cingulate gyrus, superior longitudinal fasciculus, and lower AD values in the right cingulum cingulate gyrus and the left posterior thalamic radiation. Besides, the MD values were significantly increased in the corpus callosum, left anterior corona radiata, and the RD values in the corpus callosum and cingulum cingulate gyrus. In addition, the cognitive improvement was negatively correlated with FA of the corpus callosum, cingulum cingulate gyrus, and MD values of the genu of corpus callosum. While, the cognitive improvement was positively related to the AD of the cingulum cingulate gyrus, superior longitudinal, and RD values of the corpus callosum, cingulum cingulate gyrus and uncinate fasciculus. The ROI specific WM lesions in iNPH patients are the underlying basis for cognitive impairment.

White Matter Lesions May Aid in Differentiating Idiopathic Normal Pressure Hydrocephalus and Alzheimer’s Disease

Background: Idiopathic normal pressure hydrocephalus (iNPH) is often misdiagnosed as Alzheimer’s disease (AD) due to overlapping pathophysiology and similar imaging characteristics, including ventricular enlargement and increased white matter lesions (WMLs). Objective: To compare the extent and distribution of WMLs directly between iNPH and AD and examine the association with underlying pathophysiology. Methods: Twelve patients with iNPH (mean age: 78.08 years; 5 females), 20 with AD (mean age: 75.40 years; 13 females), and 10 normal cognition (NC) participants (mean age: 76.60 years; 7 females) were recruited. The extent and distribution of WMLs and the lateral ventricular volume (LV-V) were evaluated on MRI using voxel-based morphometry analysis. Concentrations of cerebrospinal fluid biomarkers, such as amyloid-β protein (Aβ)42, Aβ 40, Aβ 38, and tau species, were also measured. Risk factors for small vessel disease (SVD) were assessed by blood examination and medical records. Results: The periventricular WML volume (PWML-V) and deep WML volume (DWML-V) were significantly larger in iNPH than in AD and NC. The DWML-V was dominant in iNPH, while the PWML-V was dominant in AD and NC. GM-V was significantly smaller in AD than in iNPH and NC. The LV-V positively correlated with WML-V in all participants. There was a significant negative correlation between LV-V and Aβ 38 in iNPH. Furthermore, there was no significant difference in SVD risk factors between the groups. Conclusion: The differences in the extent and distribution of WMLs between iNPH and AD, especially predominance of DWML-V over PWML-V in iNPH, may reflect decreased fluid and Aβ clearance.

Elevated CSF inflammatory markers in patients with idiopathic normal pressure hydrocephalus do not promote NKCC1 hyperactivity in rat choroid plexus

Background Idiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible neurological condition of unresolved etiology characterized by a clinical triad of symptoms; gait disturbances, urinary incontinence, and cognitive deterioration. In the present study, we aimed to elucidate the molecular coupling between inflammatory markers and development of iNPH and determine whether inflammation-induced hyperactivity of the choroidal Na+/K+/2Cl− cotransporter (NKCC1) that is involved in cerebrospinal fluid (CSF) secretion could contribute to the iNPH pathogenesis. Methods Lumbar CSF samples from 20 iNPH patients (10 with clinical improvement upon CSF shunting, 10 without clinical improvement) and 20 elderly control subjects were analyzed with the novel proximity extension assay technique for presence of 92 different inflammatory markers. RNA-sequencing was employed to delineate choroidal abundance of the receptors for the inflammatory markers found elevated in the CSF from iNPH patients. The ability of the elevated inflammatory markers to modulate choroidal NKCC1 activity was determined by addition of combinations of rat version of these in ex vivo experiments on rat choroid plexus. Results 11 inflammatory markers were significantly elevated in the CSF from iNPH patients compared to elderly control subjects: CCL28, CCL23, CCL3, OPG, CXCL1, IL-18, IL-8, OSM, 4E-BP1, CXCL6, and Flt3L. One inflammatory marker, CDCP1, was significantly decreased in iNPH patients compared to control subjects. None of the inflammatory markers differed significantly when comparing iNPH patients with and without clinical improvement upon CSF shunting. All receptors for the elevated inflammatory markers were expressed in the rat and human choroid plexus, except CCR4 and CXCR1, which were absent from the rat choroid plexus. None of the elevated inflammatory markers found in the CSF from iNPH patients modulated the choroidal NKCC1 activity in ex vivo experiments on rat choroid plexus. Conclusion The CSF from iNPH patients contains elevated levels of a subset of inflammatory markers. Although the corresponding inflammatory receptors are, in general, expressed in the choroid plexus of rats and humans, their activation did not modulate the NKCC1-mediated fraction of choroidal CSF secretion ex vivo. The molecular mechanisms underlying ventriculomegaly in iNPH, and the possible connection to inflammation, therefore remains to be elucidated.