Lipocalin-type prostaglandin D synthase: a glymphopathy marker in idiopathic hydrocephalus.

Idiopathic normal pressure hydrocephalus in elderly people is considered a form of glymphopathy caused by malfunction of the waste clearance pathway, called the glymphatic system. Tau is a representative waste material similar to amyloid-ß. During neurodegeneration, lipocalin-type prostaglandin D synthase (L-PGDS), a major cerebrospinal fluid (CSF) protein, is reported to act as a chaperone that prevents the neurotoxic aggregation of amyloid-ß. L-PGDS is also a CSF biomarker in idiopathic normal pressure hydrocephalus and significantly correlates with tau concentration, age, and age-related brain white matter changes detected by magnetic resonance imaging. To investigate this glymphopathy, we aimed to analyze white matter changes and contributing factors in vivo and their interactions ex vivo. Cerebrospinal tap tests were performed in 60 patients referred for symptomatic ventriculomegaly. Patients were evaluated using an idiopathic normal pressure hydrocephalus grading scale, mini-mental state examination, frontal assessment battery, and timed up-and-go test. The typical morphological features of high convexity tightness and ventriculomegaly were measured using the callosal angle and Evans index, and parenchymal white matter properties were evaluated with diffusion tensor imaging followed by tract-based spatial statistics. Levels of CSF biomarkers, including tau, amyloid-ß, and L-PGDS, were determined by ELISA, and their interaction, and localization were determined using immunoprecipitation and immunohistochemical analyses. Tract-based spatial statistics for fractional anisotropy revealed clusters that positively correlated with mini-mental state examination, frontal assessment battery, and callosal angle, and clusters that negatively correlated with age, disease duration, idiopathic normal pressure hydrocephalus grading scale, Evans index, and L-PGDS. Other parameters also indicated clusters that correlated with symptoms, microstructural white matter changes, and L-PGDS. Tau co-precipitated with L-PGDS, and colocalization was confirmed in postmortem specimens of neurodegenerative disease obtained from the human Brain Bank. Our study supports the diagnostic value of L-PGDS as a surrogate marker for white matter integrity in idiopathic normal pressure hydrocephalus. These results increase our understanding of the molecular players in the glymphatic system. Moreover, this study indicates the potential utility of enhancing endogenous protective factors to maintain brain homeostasis.

Fluctuations in Upper and Lower Body Movement during Walking in Normal Pressure Hydrocephalus and Parkinson's Disease Assessed by Motion Capture with a Smartphone Application, TDPT-GT.

We aimed to capture the fluctuations in the dynamics of body positions and find the characteristics of them in patients with idiopathic normal pressure hydrocephalus (iNPH) and Parkinson's disease (PD). With the motion-capture application (TDPT-GT) generating 30 Hz coordinates at 27 points on the body, walking in a circle 1 m in diameter was recorded for 23 of iNPH, 23 of PD, and 92 controls. For 128 frames of calculated distances from the navel to the other points, after the Fourier transforms, the slopes (the representatives of fractality) were obtained from the graph plotting the power spectral density against the frequency in log-log coordinates. Differences in the average slopes were tested by one-way ANOVA and multiple comparisons between every two groups. A decrease in the absolute slope value indicates a departure from the 1/f noise characteristic observed in healthy variations. Significant differences in the patient groups and controls were found in all body positions, where patients always showed smaller absolute values. Our system could measure the whole body's movement and temporal variations during walking. The impaired fluctuations of body movement in the upper and lower body may contribute to gait and balance disorders in patients.

Association of gait and cognition after surgery in patients with idiopathic normal pressure hydrocephalus.

Idiopathic normal pressure hydrocephalus (iNPH) is a treatable disease in older adults. The association between gait and cognition has recently become a topic of interest. Sequential changes in this association were investigated in patients with iNPH using a newly developed statistical method. Data were extracted from the SINPHONI-2 multicenter study on iNPH. Fifty patients who underwent shunt surgery were included in this study. Gait and cognition were assessed using the Timed Up and Go (TUG) and Mini-Mental State Examination (MMSE) tests. In addition to the MMSE total score, changes in the sub-item scores were examined. The ordinal sub-items of the MMSE are usually treated as continuous or categorical; however, both are unsuitable. An ordinal smoothing penalty with a generalized additive model enables precise statistical inference of ordinal and binary predictors. The TUG time improved significantly at 3, 6, and 12 months after surgery. The MMSE total scores increased without statistical significance. Preoperatively, there was no association between TUG time and MMSE sub-items. At 3 months, the "Registration," "3-step command," "Read," and "Copy" sub-items were statistically significant. The number of significant sub-items increased after 12 months. Thus, the association between gait and cognition gradually increased after surgery in patients with iNPH.

Artificial Intelligence Distinguishes Pathological Gait: The Analysis of Markerless Motion Capture Gait Data Acquired by an iOS Application (TDPT-GT).

Distinguishing pathological gait is challenging in neurology because of the difficulty of capturing total body movement and its analysis. We aimed to obtain a convenient recording with an iPhone and establish an algorithm based on deep learning. From May 2021 to November 2022 at Yamagata University Hospital, Shiga University, and Takahata Town, patients with idiopathic normal pressure hydrocephalus (n = 48), Parkinson's disease (n = 21), and other neuromuscular diseases (n = 45) comprised the pathological gait group (n = 114), and the control group consisted of 160 healthy volunteers. iPhone application TDPT-GT captured the subjects walking in a circular path of about 1 meter in diameter, a markerless motion capture system, with an iPhone camera, which generated the three-axis 30 frames per second (fps) relative coordinates of 27 body points. A light gradient boosting machine (Light GBM) with stratified k-fold cross-validation (k = 5) was applied for gait collection for about 1 min per person. The median ability model tested 200 frames of each person's data for its distinction capability, which resulted in the area under a curve of 0.719. The pathological gait captured by the iPhone could be distinguished by artificial intelligence.

Quantitative Gait Feature Assessment on Two-Dimensional Body Axis Projection Planes Converted from Three-Dimensional Coordinates Estimated with a Deep Learning Smartphone App.

To assess pathological gaits quantitatively, three-dimensional coordinates estimated with a deep learning model were converted into body axis plane projections. First, 15 healthy volunteers performed four gait patterns; that is, normal, shuffling, short-stepped, and wide-based gaits, with the Three-Dimensional Pose Tracker for Gait Test (TDPT-GT) application. Second, gaits of 47 patients with idiopathic normal pressure hydrocephalus (iNPH) and 92 healthy elderly individuals in the Takahata cohort were assessed with the TDPT-GT. Two-dimensional relative coordinates were calculated from the three-dimensional coordinates by projecting the sagittal, coronal, and axial planes. Indices of the two-dimensional relative coordinates associated with a pathological gait were comprehensively explored. The candidate indices for the shuffling gait were the angle range of the hip joint < 30° and relative vertical amplitude of the heel < 0.1 on the sagittal projection plane. For the short-stepped gait, the angle range of the knee joint < 45° on the sagittal projection plane was a candidate index. The candidate index for the wide-based gait was the leg outward shift > 0.1 on the axial projection plane. In conclusion, the two-dimensional coordinates on the body axis projection planes calculated from the 3D relative coordinates estimated by the TDPT-GT application enabled the quantification of pathological gait features.

Risk factors for unfavourable outcomes after shunt surgery in patients with idiopathic normal-pressure hydrocephalus.

A number of vascular risk factors (VRFs) have been reported to be associated with idiopathic normal-pressure hydrocephalus (iNPH), but it remains unclear whether these VRFs are related to patient outcomes after shunt surgery. Therefore, we investigated the risk factors for unfavourable outcomes after shunt surgery in iNPH patients using two samples from Tohoku University Hospital and from a multicentre prospective trial of lumboperitoneal (LP) shunt surgery for patients with iNPH (SINPHONI-2). We enrolled 158 iNPH patients. We compared the prevalence of VRFs and clinical measures between patients with favourable and unfavourable outcomes and identified predictors of unfavourable outcomes using multivariate logistic regression analyses. The presence of hypertension, longer disease duration, more severe urinary dysfunction, and a lower Evans' index were predictors of unfavourable outcomes after shunt surgery. In addition, hypertension and longer disease duration were also predictors in patients with independent walking, and a lower Evans' index was the only predictor in patients who needed assistance to walk or could not walk. Our findings indicate that hypertension is the only VRF related to unfavourable outcomes after shunt surgery in iNPH patients. Larger-scale studies are needed to elucidate the reason why hypertension can affect the irreversibility of symptoms after shunt placement.

Development of Smartphone Application for Markerless Three-Dimensional Motion Capture Based on Deep Learning Model.

To quantitatively assess pathological gait, we developed a novel smartphone application for full-body human motion tracking in real time from markerless video-based images using a smartphone monocular camera and deep learning. As training data for deep learning, the original three-dimensional (3D) dataset comprising more than 1 million captured images from the 3D motion of 90 humanoid characters and the two-dimensional dataset of COCO 2017 were prepared. The 3D heatmap offset data consisting of 28 × 28 × 28 blocks with three red-green-blue colors at the 24 key points of the entire body motion were learned using the convolutional neural network, modified ResNet34. At each key point, the hottest spot deviating from the center of the cell was learned using the tanh function. Our new iOS application could detect the relative tri-axial coordinates of the 24 whole-body key points centered on the navel in real time without any markers for motion capture. By using the relative coordinates, the 3D angles of the neck, lumbar, bilateral hip, knee, and ankle joints were estimated. Any human motion could be quantitatively and easily assessed using a new smartphone application named Three-Dimensional Pose Tracker for Gait Test (TDPT-GT) without any body markers or multipoint cameras.

Tap Test Can Predict Cognitive Improvement in Patients With iNPH-Results From the Multicenter Prospective Studies SINPHONI-1 and -2.

Background: We analyzed the predictive value of the tap test (TT) on the outcome of cerebrospinal fluid (CSF) shunting in patients with idiopathic normal pressure hydrocephalus (iNPH) and cognitive impairment up to 12 months postoperatively. Methods: We analyzed the data of two prospective multicenter studies on ventriculoperitoneal shunt (VPS) and lumboperitoneal shunt (LPS) use in iNPH patients. We selected patients with Mini-Mental State Examination (MMSE) scores ≤ 26 points as study subjects. We used a multivariate logistic regression model to obtain the optimal threshold of MMSE scores after TT to predict the score improvement at 12 months following shunting and that helped to control for confounding factors such as age and MMSE scores before TT. We used logistic regression models to identify variables with age-adjusted odds ratio (A-OR) and multivariate-adjusted OR (M-OR). Results: For an improvement of ≥3 points in the MMSE score cutoff 7 days following TT in VPS and LPS cohort studies, the MMSE scores improved by 6 points after 12 months. The VPS cohort had sensitivity, specificity, and area under the curve (AUC) of 69.2, 73.7, and 0.771%, respectively; however, for the LPS cohort, they were 86.2, 90.9, and 0.906%, respectively. For MMSE scores that improved by ≥3 points in patients after the TT, the possibility of an improvement by 6 points at 12 months following CSF shunt had A-OR 7.77 and M-OR 6.3 times for the VPS, and A-OR 62.3 and M-OR 59.6 times for the LPS cohort. Conclusion: CSF shunting contributes to improved cognitive function in iNPH patients. Furthermore, MMSE score evaluation at the TT can sensitively predict improvement in postoperative MMSE scores following LPS intervention. Clinical Trial Registration: SINPHONI-1 (ClinicalTrials.gov, no. NCT00221091), first posted: September 22, 2005. SINPHONI-2 [University Hospital Medical Information Network (UMIN) Clinical Trials no. UMIN000002730], the posted: February 1, 2010.

Improvement in the long-term care burden after surgical treatment of patients with idiopathic normal pressure hydrocephalus: a supplementary study.

Idiopathic normal pressure hydrocephalus (iNPH) is a surgically treatable syndrome commonly observed in older adults. However, it is unclear whether clinical improvements after surgery can effectively reduce the long-term care burden (LTCB). In this study, we determined whether shunt surgery was effective in decreasing LTCB. We also investigated the degree of variability in patients and hospitals, using data from the iNPH multicenter study. This study involved 69 participants who underwent lumboperitoneal shunt surgery with follow-up for 12 months. A generalized linear mixed model was applied to analyze the fixed and random effects simultaneously. Regarding LTCB, the disability grades improved significantly. Although the dementia grades also improved, it was not statistically significant. The differences in the LTCB grades in most patients were within the range of the 95% confidence intervals, while in the case of hospitals, some were often out of the range. Further studies are needed to improve dementia in patients with iNPH. The incorporation of random variables, such as hospitals, is important for the analysis of data from multicenter studies.

Gait Assessment Using Three-Dimensional Acceleration of the Trunk in Idiopathic Normal Pressure Hydrocephalus.

Background: The subjective evaluation of pathological gait exhibits a low inter-rater reliability. Therefore, we developed a three-dimensional acceleration of the trunk during walking to assess the pathological gait quantitatively. Methods: We evaluated 97 patients who underwent the cerebrospinal tap test and were diagnosed with idiopathic normal pressure hydrocephalus (iNPH) and 68 healthy elderlies. The gait features of all patients were evaluated and classified as one of the following: freezing of gait, wide-based gait, short-stepped gait, shuffling gait, instability, gait festination, difficulty in changing direction, and balance disorder in standing up. All gait features of 68 healthy elderlies were treated as normal. Trunk acceleration was recorded automatically by a smartphone placed on the umbilicus during a 15-foot walking test. Two novel indices were created. The first index was a trunk acceleration index, which was defined as (forward acceleration fluctuation) + (vertical acceleration fluctuation) - (lateral acceleration fluctuation) based on the multivariate logistics regression model, and the second index was created by multiplying the forward acceleration with the vertical acceleration. Additionally, 95% confidence ellipsoid volume of the three-dimensional accelerations was assessed. Results: Forward and vertical acceleration fluctuations were significantly associated with the probability of an iNPH-specific pathological gait. The trunk acceleration index demonstrated the strongest association with the probability of an iNPH-specific pathological gait. The areas under the receiver-operating characteristic curves for detecting 100% probability of an iNPH-specific pathological gait were 86.9% for forward acceleration fluctuation, 88.0% for vertical acceleration fluctuation, 82.8% for lateral acceleration fluctuation, 89.0% for trunk acceleration index, 88.8% for forward × vertical acceleration fluctuation, and 87.8% for 95% confidence ellipsoid volume of the three-dimensional accelerations. Conclusions: The probability of a pathological gait specific to iNPH is high at the trunk acceleration fluctuation, reduced in the forward and vertical directions, and increased in the lateral direction.

Exploring mechanisms of ventricular enlargement in idiopathic normal pressure hydrocephalus: a role of cerebrospinal fluid dynamics and motile cilia.

Idiopathic normal pressure hydrocephalus (iNPH) is considered an age-dependent chronic communicating hydrocephalus associated with cerebrospinal fluid (CSF) malabsorption; however, the aetiology of ventricular enlargement in iNPH has not yet been elucidated. There is accumulating evidence that support the hypothesis that various alterations in CSF dynamics contribute to ventricle dilatation in iNPH. This review focuses on CSF dynamics associated with ventriculomegaly and summarises the current literature based on three potential aetiology factors: genetic, environmental and hydrodynamic. The majority of gene mutations that cause communicating hydrocephalus were associated with an abnormal structure or dysfunction of motile cilia on the ventricular ependymal cells. Aging, alcohol consumption, sleep apnoea, diabetes and hypertension are candidates for the risk of developing iNPH, although there is no prospective cohort study to investigate the risk factors for iNPH. Alcohol intake may be associated with the dysfunction of ependymal cilia and sustained high CSF sugar concentration due to uncontrolled diabetes increases the fluid viscosity which in turn increases the shear stress on the ventricular wall surface. Sleep apnoea, diabetes and hypertension are known to be associated with the impairment of CSF and interstitial fluid exchange. Oscillatory shear stress to the ventricle wall surfaces is considerably increased by reciprocating bidirectional CSF movements in iNPH. Increased oscillatory shear stress impedes normal cilia beating, leading to motile cilia shedding from the ependymal cells. At the lack of ciliary protection, the ventricular wall is directly exposed to increased oscillatory shear stress. Additionally, increased oscillatory shear stress may be involved in activating the flow-mediated dilation signalling of the ventricular wall. In conclusion, as the CSF stroke volume at the cerebral aqueduct increases, the oscillatory shear stress increases, promoting motor cilia shedding and loss of ependymal cell coverage. These are considered to be the leading causes of ventricular enlargement in iNPH.

Guidelines for Management of Idiopathic Normal Pressure Hydrocephalus (Third Edition): Endorsed by the Japanese Society of Normal Pressure Hydrocephalus.

Among the various disorders that manifest with gait disturbance, cognitive impairment, and urinary incontinence in the elderly population, idiopathic normal pressure hydrocephalus (iNPH) is becoming of great importance. The first edition of these guidelines for management of iNPH was published in 2004, and the second edition in 2012, to provide a series of timely, evidence-based recommendations related to iNPH. Since the last edition, clinical awareness of iNPH has risen dramatically, and clinical and basic research efforts on iNPH have increased significantly. This third edition of the guidelines was made to share these ideas with the international community and to promote international research on iNPH. The revision of the guidelines was undertaken by a multidisciplinary expert working group of the Japanese Society of Normal Pressure Hydrocephalus in conjunction with the Japanese Ministry of Health, Labour and Welfare research project. This revision proposes a new classification for NPH. The category of iNPH is clearly distinguished from NPH with congenital/developmental and acquired etiologies. Additionally, the essential role of disproportionately enlarged subarachnoid-space hydrocephalus (DESH) in the imaging diagnosis and decision for further management of iNPH is discussed in this edition. We created an algorithm for diagnosis and decision for shunt management. Diagnosis by biomarkers that distinguish prognosis has been also initiated. Therefore, diagnosis and treatment of iNPH have entered a new phase. We hope that this third edition of the guidelines will help patients, their families, and healthcare professionals involved in treating iNPH.

Reconsidering Ventriculoperitoneal Shunt Surgery and Postoperative Shunt Valve Pressure Adjustment: Our Approaches Learned From Past Challenges and Failures.

Treatment for idiopathic normal pressure hydrocephalus (iNPH) continues to develop. Although ventriculoperitoneal shunt surgery has a long history and is one of the most established neurosurgeries, in the 1970s, the improvement rate of iNPH triad symptoms was poor and the risks related to shunt implantation were high. This led experts to question the surgical indication for iNPH and, over the next 20 years, cerebrospinal fluid (CSF) shunt surgery for iNPH fell out of favor and was rarely performed. However, the development of programmable-pressure shunt valve devices has reduced the major complications associated with the CSF drainage volume and appears to have increased shunt effectiveness. In addition, the development of support devices for the placement of ventricular catheters including preoperative virtual simulation and navigation systems has increased the certainty of ventriculoperitoneal shunt surgery. Secure shunt implantation is the most important prognostic indicator, but ensuring optimal initial valve pressure is also important. Since over-drainage is most likely to occur in the month after shunting, it is generally believed that a high initial setting of shunt valve pressure is the safest option. However, this does not always result in sufficient improvement of the symptoms in the early period after shunting. In fact, evidence suggests that setting the optimal valve pressure early after shunting may cause symptoms to improve earlier. This leads to improved quality of life and better long-term independent living expectations. However, in iNPH patients, the remaining symptoms may worsen again after several years, even when there is initial improvement due to setting the optimal valve pressure early after shunting. Because of the possibility of insufficient CSF drainage, the valve pressure should be reduced by one step (2-4 cmH2O) after 6 months to a year after shunting to maximize symptom improvement. After the valve pressure is reduced, a head CT scan is advised a month later.

Cerebrospinal fluid dynamics in idiopathic normal pressure hydrocephalus on four-dimensional flow imaging.

OBJECTIVES: To evaluate complex CSF movements and shear stress in patients with idiopathic normal pressure hydrocephalus (iNPH) on four-dimensional (4D) flow MRI. METHODS: Three-dimensional velocities and volumes of the reciprocating CSF movements through 12 ROIs from the foramen of Monro to the upper cervical spine were measured in 41 patients with iNPH, 23 patients with co-occurrence of iNPH and Alzheimer's disease (AD), and 9 age-matched controls, using 4D flow imaging and application. Stroke volume, reversed-flow rate, and shear stress were automatically calculated. Relationships between flow-related parameters and morphological measurements were also assessed. RESULTS: Stroke volumes, reversed-flow rates, and shear stress at the cerebral aqueduct were significantly higher in patients with iNPH than in controls. Patients with pure iNPH had significantly higher shear stress at the ventral aspect of the cerebral aqueduct than those with co-occurrence of iNPH and AD. The stroke volume at the upper end of the cerebral aqueduct had the strongest association with the anteroposterior diameter of the lower end of the cerebral aqueduct (r = 0.52). The stroke volume at the foramen of Monro had significant associations with the indices specific to iNPH. The shear stress at the dorsal aspect of the cerebral aqueduct had the strongest association with the diameter of the foramen of Magendie (r = 0.52). CONCLUSIONS: Stroke volumes, reversed-flow rates, and shear stress through the cerebral aqueduct on 4D flow MRI are useful parameters for iNPH diagnosis. These findings can aid in elucidating the mechanism of ventricular enlargement in iNPH. KEY POINTS: • The CSF stroke volume and bimodal shear stress at the cerebral aqueduct were considerably higher in patients with iNPH. • The patients with pure iNPH had significantly higher shear stress at the ventral aspect of the cerebral aqueduct than those with co-occurrence of iNPH and AD. • The shear stress at the cerebral aqueduct was significantly associated with the diameter of the foramen of Magendie.

Longitudinal morphological changes during recovery from brain deformation due to idiopathic normal pressure hydrocephalus after ventriculoperitoneal shunt surgery.

The present study aimed to examine time-dependent change in cerebrospinal fluid distribution and various radiological indices for evaluating shunt effectiveness in patients with idiopathic normal pressure hydrocephalus (iNPH). This study included 54 patients with iNPH who underwent MRI before and after ventriculoperitoneal shunt surgery. The volume of the total ventricles and subarachnoid spaces decreased within 1 month after shunting. However, more than 1 year after shunting, the volume of the total ventricles decreased, whereas that of the total subarachnoid spaces increased. Although cerebrospinal fluid distribution changed considerably throughout the follow-up period, the brain parenchyma expanded only 2% from the baseline brain volume within 1 month after shunting and remained unchanged thereafter. The volume of the convexity subarachnoid space markedly increased. The changing rate of convexity subarachnoid space per ventricle ratio (CVR) was greater than that of any two-dimensional index. The brain per ventricle ratio (BVR), callosal angle and z-Evans index continued gradually changing, whereas Evans index did not change throughout the follow-up period. Both decreased ventricular volume and increased convexity subarachnoid space volume were important for evaluating shunt effectiveness. Therefore, we recommend CVR and BVR as useful indices for the diagnosis and evaluation of treatment response in patients with iNPH.

Agreement study on gait assessment using a video-assisted rating method in patients with idiopathic normal-pressure hydrocephalus.

Gait disturbance is a major symptom of idiopathic normal-pressure hydrocephalus (iNPH) and is assessed by raters of different professions or with different degrees of experience. Agreement studies are usually done by two raters or more, and comparisons among multiple groups of raters are rare. In this study, we aimed to examine the agreement among multiple groups of raters on gait patterns and a grading scale through a video-assisted gait analysis in patients with iNPH. Fifteen participants with iNPH were enrolled. Gait was assessed according to seven patterns, including freezing and wide-based gaits. The levels of severity (evident, mild, none) were rated by three groups of raters (two neurosurgeons [DR2], three experienced physiotherapists [PTe3], and two less experienced physiotherapists [PTl2]) through a simultaneous video viewing session. Severity of gait disturbance (GSg) was rated using the Japanese iNPH grading scaleiNPHGS, and Krippendorff alpha was computed to assess agreement, with alpha ≥0.667 indicating good agreement and alpha ≥0.8 indicating excellent agreement. For group comparisons, 84%, not 95%, confidence intervals were applied. Among the seven gait patterns in the first assessment, excellent agreement was observed in wide-based and short-stepped gaits in only DR2. Good agreement was observed in four patterns, but the agreement by two groups was in shuffling and wide-based gait. There were no gait patterns showing good agreement among three groups. In the second assessment, excellent agreement was observed in three patterns but no gait patterns showed good agreement between two groups or more. Learning effect was observed only for standing difficulty in DR2. In contrast, good or nearly good agreement on GSg was observed among the three groups with excellent agreement in two groups. Agreement on gait patterns among the three groups of raters was not high, but agreement on the iNPHGS was high, indicating the importance of a precise description facilitating differentiation between neighboring grades.

Two-Point Dynamic Observation of Alzheimer's Disease Cerebrospinal Fluid Biomarkers in Idiopathic Normal Pressure Hydrocephalus.

BACKGROUND: Extensive research into cerebrospinal fluid (CSF) biomarkers was performed in patients with idiopathic normal pressure hydrocephalus (iNPH). Most prior research into CSF biomarkers has been one-point observation. OBJECTIVE: To investigate dynamic changes in CSF biomarkers during routine tap test in iNPH patients. METHODS: We analyzed CSF concentrations of tau, amyloid-ß (Aß) 42 and 40, and leucine rich α-2-glycoprotein (LRG) in 88 consecutive potential iNPH patients who received a tap test. We collected two-point lumbar CSF separately at the first 1 ml (First Drip (FD)) and at the last 1 ml (Last Drip (LD)) during the tap test and 9 patients who went on to receive ventriculo-peritoneal shunt surgery each provided 1 ml of ventricular CSF (VCSF). RESULTS: Tau concentrations were significantly elevated in LD and VCSF compared to FD (LD/FD = 1.22, p = 0.003, VCSF/FD = 2.76, p = 0.02). Conversely, Aß42 (LD/FD = 0.80, p < 0.001, VCSF/FD = 0.38, p = 0.03) and LRG (LD/FD = 0.74, p < 0.001, VCSF/FD = 0.09, p = 0.002) concentrations were significantly reduced in LD and VCSF compared to FD. Gait responses to the tap test and changes in cognitive function in response to shunt were closely associated with LD concentrations of tau (p = 0.02) and LRG (p = 0.04), respectively. CONCLUSIONS: Dynamic changes were different among the measured CSF biomarkers, suggesting that LD of CSF as sampled during the tap test reflects an aspect of VCSF contributing to the pathophysiology of iNPH and could be used to predict shunt effectiveness.

Quantitative Evaluation of Gait Disturbance on an Instrumented Timed Up-and-go Test.

Although the 3-m timed up-and-go test (TUG) is reliable for evaluating mobility, TUG time is insufficient to evaluate mild gait disturbance; we, therefore aimed to investigate other measurements with instrumented TUG (iTUG) using a free smartphone application. Our inclusion criterion in this study is only that participants can walk without any assistance. This study included three heterogeneous groups; patients who underwent a tap test or shunt surgery, 29 inpatients hospitalized for other reasons, and 87 day-care users. After the tap test, 28 were diagnosed with tap-positive idiopathic normal-pressure hydrocephalus (iNPH) and 8 were diagnosed with tap-negative. Additionally, 18 patients were assessed iTUG before and after shunt surgery. During iTUG, time and 3-dimensional (3D) acceleration were automatically recorded every 0.01 s. A volume of the 95% confidence ellipsoid (95%CE) of all plots for 3D acceleration was calculated. Additionally, an iTUG score was defined as (95%CE volume) 0.8 / 1.9 - 1.9 × (time) + 60. The measurement reliability was evaluated using intraclass correlations and Bland-Altman plots. The participants with mild gait disturbance who accomplished within 13.5 s on the iTUG time had the 95%CE volumes for 3D acceleration of ≥70 m3/s6 and iTUG scores of ≥50. The mean iTUG time was shortened and the mean 95%CE volumes and iTUG scores were increased after the tap test among 28 patients with tap-positive iNPH and after shunt surgery among 18 patients with definite iNPH. Conversely, the mean iTUG score among 8 patients with tap-negative was decreased after the tap test. The intraclass correlations for the time, 95%CE volume and iTUG score were 0.97, 0.80 and 0.90, respectively. Not only the iTUG time but also the 95%CE volume was important for evaluating mobility. Therefore, the novel iTUG score consisting both is useful for the quantitative assessment of mobility.

Gait analysis in a component timed-up-and-go test using a smartphone application.

BACKGROUND: The timed-up-and-go test (TUG) is a popular test for mobility, but it only measures the total time to complete tasks. Recent advances in smartphone technology enables measuring respective times of 6 components in the test (Stand, Go, Turn1, Come, Turns and Sit). We examined availability of these data for assessing different gait patterns. METHODS: This study enrolled 32 patients with probable idiopathic normal-pressure hydrocephalus and 87 age-matched active participants as controls. All the patients responded positively to cerebrospinal fluid (CSF) removal, among whom 19 underwent surgery with positive outcomes. The TUG was performed using a free smartphone application. The components were automatically detected, and their respective times were computed. Statistical analyses included item cluster analysis. RESULTS: In the control group, high correlations (r ≥ 0.7) were observed in two pairs of Go and Come, and Turn1 and Turn2, which reflect straight walk and turn. This pattern was lost in the baseline and after CSF removal in the hydrocephalus group. After surgery, the two pairs in the control group regained high correlations. The item cluster analysis showed the pattern changes more clearly. CONCLUSIONS: A smartphone is useful for analyzing gait patterns in the TUG, which can be applicable for various gait disorders.

Location-specific characteristics of perivascular spaces as the brain's interstitial fluid drainage system.

PURPOSE: Brain interstitial fluid plays an important role in the excretion of metabolic waste products into the cerebrospinal fluid through perivascular spaces (PVS). To investigate the normal function of PVS in healthy elderly individuals, we assessed the relationship between PVS and white matter hyperintensity (WMH) on MRI in two locations. METHODS: This study included 296 healthy individuals aged ≥60 years without a history of brain disease who underwent brain MRI. The severities of PVS and WMH were assessed on the location-specific classification in the basal ganglia (BG-PVS) or centrum semiovale (CSO-PVS), and in the deep or periventricular WMH. RESULTS: The severity of BG-PVS was significantly associated with the severities of deep and periventricular WMHs. In contrast, the severity of CSO-PVS was inversely associated with the severity of deep WMH and was not significantly associated with that of periventricular WMH. The multivariate odds ratios of severe deep WMH for BG-PVS and CSO-PVS were 1.18 (95% CIs: 1.01-1.38) and 0.68 (0.54-0.86), respectively, compared with none deep WMH. CONCLUSIONS: CSO-PVS looks different from BG-PVS in their relationship with deep WMHs. Therefore, CSO-PVS might play an essential role in the normal interstitial fluid drainage system, not as a biomarker of arteriosclerosis.