A novel TBK1 loss-of-function variant associated with ALS and parkinsonism phenotypes.

Loss-of-function (LoF) variants in the TANK binding kinase 1 (TBK1) gene are implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In this study, we present the first familial cases of ALS and parkinsonism associated with a novel TBK1 variant. We describe two siblings: one diagnosed with classical ALS and the other with a unique syndrome overlapping ALS and parkinsonism. Comprehensive clinical and imaging evaluations supported these diagnoses. Genetic analysis through whole-genome sequencing revealed a previously unknown heterozygous splice site variant in TBK1. Functional assessments demonstrated that this splice site variant leads to abnormal splicing and subsequent degradation of the mutated TBK1 allele by nonsense-mediated decay, confirming its pathogenic impact. Our findings suggest a broader involvement of TBK1 in neurodegenerative diseases and underscore the need for further research into TBK1's role, advocating for screening for TBK1 variants in similar familial cases.

The time-course augmentation of perivascular space enlargement in the basal ganglia among a community-dwelling elder population.

PURPOSE: We examined whether time-course augmentation of perivascular space enlargement in the basal ganglia (BG-PVS) reflected cerebral small vessel disease (CSVD) severity by considering white matter hyperintensity lesion (WMHL) as an indicator for CSVD. MATERIALS AND METHODS: This study population included 416 older participants from a community-based cohort. They participated in magnetic resonance imaging (MRI) studies more than once during the study period. The grades for BG-PVS and WMHL were evaluated by visual rating scales; BG-PVS time-course augmentation in 4-9 years was also evaluated. At baseline, the participants were asked about their smoking and drinking history, and medical history. They also underwent a blood examination and their office blood pressure (BP) examination. In addition, 24-h ambulatory BP monitoring was also performed within the study period. RESULTS: Of the 416 participants, 48 participants (11.5%) had BG-PVS time-course augmentation. The participants with BG-PVS augmentation had significantly lower LDL levels, hyper-nighttime BP, and lower nighttime BP fall in univariate analysis (p = 0.03, p = 0.03, p = 0.003, respectively). In multivariate analysis, lower nighttime BP fall and male sex showed significance (p = 0.02, 0.03, respectively). Additionally, BG-PVS time-course augmentation was significantly associated with subsequent WMHL severity in univariate analysis (p < 0.001), which remained significant in multivariate analysis adjusted by imaging and demographic factors (p = 0.03). In multivariate analysis, additionally adjusted by the clinical factors, the significance disappeared (p = 0.07). CONCLUSION: This study revealed that the lower nighttime BP fall in ambulatory blood pressure monitoring was a factor significantly associated with BG-PVS augmentation. Moreover, the BG-PVS time-course augmentation would be a notable finding that was associated with the subsequent WMHL.

Augmentation of perivascular space visualization in basal ganglia and white matter hyperintensity lesion is a meaningful finding for subsequent cognitive decline.

BACKGROUND: Cerebral small vessel disease (CSVD) causes cognitive decline and perivascular space enlargement is one of the image markers for CSVD. PURPOSE: To search for clinical significance in the time-course augmentation of perivascular space in basal ganglia (BG-PVS) for cognitive decline. MATERIAL AND METHODS: This study population included 179 participants from a community-based cohort, aged 70 years at baseline. They had undergone magnetic resonance imaging (MRI) studies two or three times between 2000 and 2008. Based on the severity of BG-PVS or white matter hyperintensity lesions (WMHL) in 2000, the participants were divided into low-grade or high-grade groups, respectively. In addition, their time-course augmentation was evaluated, and we created a categorical BG-PVS WMHL change score based on their augmentation (1 = neither, 2 = BG-PVS augmentation only, 3 = WMHL augmentation only, 4 = both). Cognitive function was assessed based on the Mini-Mental State Examination (MMSE); the change was defined as the difference between scores in 2000 and 2008. We used simple or multiple regression analysis for MMSE score change according to MRI findings and clinical characteristics that were probably related to cognitive decline. RESULTS: In univariate analysis, MMSE score change was negatively associated with BG-PVS high grade at baseline and BG-PVS WMHL change score 4; this remained significant in multivariate analysis. In the final model based on the Akaike Information Criterion, BG-PVS WMHL change score 4 was associated with a 3.3-point decline in subsequent MMSE score. CONCLUSIONS: This study suggested that augmentation in both BG-PVS and WMHL was associated with subsequent cognitive decline.

Modeling cerebrospinal fluid dynamics across the entire intracranial space through integration of four-dimensional flow and intravoxel incoherent motion magnetic resonance imaging.

BACKGROUND: Bidirectional reciprocal motion of cerebrospinal fluid (CSF) was quantified using four-dimensional (4D) flow magnetic resonance imaging (MRI) and intravoxel incoherent motion (IVIM) MRI. To estimate various CSF motions in the entire intracranial region, we attempted to integrate the flow parameters calculated using the two MRI sequences. To elucidate how CSF dynamics deteriorate in Hakim's disease, an age-dependent chronic hydrocephalus, flow parameters were estimated from the two MRI sequences to assess CSF motion in the entire intracranial region. METHODS: This study included 127 healthy volunteers aged ≥ 20 years and 44 patients with Hakim's disease. On 4D flow MRI for measuring CSF motion, velocity encoding was set at 5 cm/s. For the IVIM MRI analysis, the diffusion-weighted sequence was set at six b-values (i.e., 0, 50, 100, 250, 500, and 1000 s/mm2), and the biexponential IVIM fitting method was adapted. The relationships between the fraction of incoherent perfusion (f) on IVIM MRI and 4D flow MRI parameters including velocity amplitude (VA), absolute maximum velocity, stroke volume, net flow volume, and reverse flow rate were comprehensively evaluated in seven locations in the ventricles and subarachnoid spaces. Furthermore, we developed a new parameter for fluid oscillation, the Fluid Oscillation Index (FOI), by integrating these two measurements. In addition, we investigated the relationship between the measurements and indices specific to Hakim's disease and the FOIs in the entire intracranial space. RESULTS: The VA on 4D flow MRI was significantly associated with the mean f-values on IVIM MRI. Therefore, we estimated VA that could not be directly measured on 4D flow MRI from the mean f-values on IVIM MRI in the intracranial CSF space, using the following formula; e0.2(f-85) + 0.25. To quantify fluid oscillation using one integrated parameter with weighting, FOI was calculated as VA × 10 + f × 0.02. In addition, the FOIs at the left foramen of Luschka had the strongest correlations with the Evans index (Pearson's correlation coefficient: 0.78). The other indices related with Hakim's disease were significantly associated with the FOIs at the cerebral aqueduct and bilateral foramina of Luschka. FOI at the cerebral aqueduct was also elevated in healthy controls aged ≥ 60 years. CONCLUSIONS: We estimated pulsatile CSF movements in the entire intracranial CSF space in healthy individuals and patients with Hakim's disease using FOI integrating VA from 4D flow MRI and f-values from IVIM MRI. FOI is useful for quantifying the CSF oscillation.

The grasp reflex in patients with idiopathic normal pressure hydrocephalus.

OBJECTIVE: To investigate the prevalence and intensity of grasp reflexes and to examine changes in these reflexes after shunt surgery in patients with idiopathic normal pressure hydrocephalus (iNPH). METHODS: We enrolled 147 patients with probable iNPH. A standard procedure was used to determine the presence of grasp reflexes, and the intensity of these reflexes was assessed using a four-category classification. Clinical rating scales and their correlation with grasp reflexes were also evaluated. Grasp reflexes were reassessed in 72 patients 1 year after surgery. RESULTS: We found that approximately 50.3% of patients with iNPH exhibited a positive grasp reflex. Among these patients, 69% exhibited bilateral positivity, while the remaining patients showed unilateral positivity. Furthermore, the intensity of the grasp reflex was significantly correlated with the severity of gait and with cognitive, urinary, motor, and behavioural symptoms. Surgical interventions led to a reduction (41.7%) or maintenance (30.6%) of the reflex intensity in 72.3% of iNPH patients. The changes in reflex intensity showed significant positive correlations with changes in the number of steps of the Timed Up and Go test and Trail Making Test-A scores but not with changes in total scores on the iNPH Grading Scale. CONCLUSION: This retrospective study identified grasp reflexes as a highly prevalent phenomenon in patients with iNPH. These reflexes can assist in evaluating the severity of various symptoms, including cognitive, gait, urinary, motor and emotional symptoms.

Automatic assessment of disproportionately enlarged subarachnoid-space hydrocephalus from 3D MRI using two deep learning models.

Background: Disproportionately enlarged subarachnoid-space hydrocephalus (DESH) is a key feature for Hakim disease (idiopathic normal pressure hydrocephalus: iNPH), but subjectively evaluated. To develop automatic quantitative assessment of DESH with automatic segmentation using combined deep learning models. Methods: This study included 180 participants (42 Hakim patients, 138 healthy volunteers; 78 males, 102 females). Overall, 159 three-dimensional (3D) T1-weighted and 180 T2-weighted MRIs were included. As a semantic segmentation, 3D MRIs were automatically segmented in the total ventricles, total subarachnoid space (SAS), high-convexity SAS, and Sylvian fissure and basal cistern on the 3D U-Net model. As an image classification, DESH, ventricular dilatation (VD), tightened sulci in the high convexities (THC), and Sylvian fissure dilatation (SFD) were automatically assessed on the multimodal convolutional neural network (CNN) model. For both deep learning models, 110 T1- and 130 T2-weighted MRIs were used for training, 30 T1- and 30 T2-weighted MRIs for internal validation, and the remaining 19 T1- and 20 T2-weighted MRIs for external validation. Dice score was calculated as (overlapping area) × 2/total area. Results: Automatic region extraction from 3D T1- and T2-weighted MRI was accurate for the total ventricles (mean Dice scores: 0.85 and 0.83), Sylvian fissure and basal cistern (0.70 and 0.69), and high-convexity SAS (0.68 and 0.60), respectively. Automatic determination of DESH, VD, THC, and SFD from the segmented regions on the multimodal CNN model was sufficiently reliable; all of the mean softmax probability scores were exceeded by 0.95. All of the areas under the receiver-operating characteristic curves of the DESH, Venthi, and Sylhi indexes calculated by the segmented regions for detecting DESH were exceeded by 0.97. Conclusion: Using 3D U-Net and a multimodal CNN, DESH was automatically detected with automatically segmented regions from 3D MRIs. Our developed diagnostic support tool can improve the precision of Hakim disease (iNPH) diagnosis.

[Epidemiology, Natural History, and Genetic Factors of Idiopathic Normal Pressure Hydrocephalus].

According to a cohort study in a Japanese rural area, the prevalence of idiopathic normal pressure hydrocephalus (iNPH) in the 80s was 7.7% among the older inhabitants, despite only a small percentage of the population seeking consultation. The 16-year observation of the cohort revealed that people were in the state of asymptomatic ventriculomegaly with features of iNPH on magnetic resonance imaging or asymptomatic ventricular enlargement several years before presenting symptoms and intracranial changes of iNPH. SFMBT1 was found to be a risk gene for iNPH, and investigating these risk genes will further the study of iNPH pathophysiology.

A Case of Anti-IgLON5 Disease Showing an Improvement in Dysautonomia, Including Vocal Cord Palsy, via Combined Immunotherapy.

Anti-IgLON5 disease shows various neurological manifestations, of which dysautonomia is one of the major symptoms and is rarely improved by immunotherapy. We herein report a patient with anti-IgLON5 disease who showed several autonomic failures, including vocal cord palsy for four months. The patient presented with cognitive impairments, bulbar symptoms accompanied by myorhythmia in the pharynx and tongue, cerebellar ataxia with tremor, motor neuron symptoms in the limbs, gastrointestinal dysfunction, orthostatic hypotension, non-rapid eye movement sleep disorder on polysomnography, and severe vocal cord palsy. Combined immunotherapy improved his symptoms, including vocal cord palsy, suggesting that combined immunotherapy might improve dysautonomia in anti-IgLON5 disease.

Paraneoplastic Cerebellar Degeneration Accompanied by Seropositivity for Anti-GAD65, Anti-SOX-1 and Anti-VGCC Antibodies Due to Small-cell Lung Cancer.

Paraneoplastic cerebellar degeneration (PCD) is a paraneoplastic neurological syndrome that is rarely accompanied by seropositivity with a combination of multiple antibodies. We herein report a 50-year-old man with PCD accompanied by small-cell lung cancer (SCLC). This patient was seropositive for anti-glutamic acid decarboxylase 65, anti-SRY-related HMG-box gene 1 and anti-voltage-gated calcium channel antibodies. After chemoradiation therapy without immunotherapy, cerebellar ataxia of the trunk and limbs markedly improved, along with a notable amelioration of SCLC. This case suggests that tumor therapy should be started immediately and that a panel of anti-neuronal antibodies should be evaluated when PCD with SCLC is suspected.

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.

Aging and Sex Differences in Brain Volume and Cerebral Blood Flow.

How do regional brain volume ratios and cerebral blood flow (CBF, mL/min) change with aging, and are there sex differences? This study aimed to comprehensively evaluate the relationships between regional brain volume ratios and CBF in healthy brains. The study participants were healthy volunteers who underwent three-dimensional T1-weighted MRI, time-of-flight MR angiography, and four-dimensional (4D) flow MRI between 2020 and 2022. The brain was automatically segmented into 21 brain subregions from 3D T1-weighted MRI, and CBF in 16 major intracranial arteries were measured by 4D flow MRI. The relationships between segmented brain volume ratios and CBFs around the circle of Willis were comprehensively investigated in each decade and sex. This study included 129 healthy volunteers (mean age ± SD, 48.2 ± 16.8; range, 22-92 years; 43 males and 86 females). The association was strongest between the cortical gray matter volume ratio and total outflow of the intracranial major arteries distal to the circle of Willis (Pearson's correlation coefficient, r: 0.425). In addition, the mean flow of the total inflow and outflow around the circle of Willis were significantly greater in women than men, and significant left-right differences were observed in CBFs even on the peripheral side of the circle of Willis. Moreover, the correlation was strongest between the left cortical gray matter volume ratio and the combined flows of the left anterior and posterior cerebral arteries distal to the circle of Willis (r: 0.486). There was a trend toward greater total intracranial CBF, especially among women in their 40s and younger, who had a larger cortical gray matter volume. This finding may be one of the reasons for the approximately twofold higher incidence of cerebral aneurysms and subarachnoid hemorrhage, and a threefold higher incidence of migraine headaches.

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.

Effect of cerebrospinal fluid area mask correction on 123I-FP-CIT SPECT images in idiopathic normal pressure hydrocephalus.

BACKGROUND: Cerebrospinal fluid (CSF) area mask correction reduces the influence of low [123I]-N-fluoropropyl-2b-carbomethoxy-3b-(4-iodophenyl) nortropane (123I-FP-CIT) accumulation in the volume of interest (VOI) by CSF area dilatation on the specific binding ratio (SBR) calculated using the Southampton method. We assessed the effect of CSF area mask correction on the SBR for idiopathic normal pressure hydrocephalus (iNPH) characterized by CSF area dilatation. METHODS: We enrolled 25 patients with iNPH who were assessed using 123I-FP-CIT single-photon emission computed tomography (SPECT) before shunt surgery or the tap test. The SBRs with and without CSF area mask correction were calculated, and changes in quantitative values were verified. Additionally, the number of voxels in the striatal and background (BG) VOI before and after CSF area mask correction were extracted. The number of voxels after correction was subtracted from that before correction, and the volume removed by the CSF area mask correction was calculated. The volumes removed from each VOI were compared to verify their effect on SBR. RESULTS: The images of 20 and 5 patients with SBRs that were decreased and increased, respectively, by CSF area mask correction showed that the volumes removed from the BG region VOI were higher and lower, respectively than those in the striatal region. CONCLUSIONS: The SBR before and after CSF area mask correction was associated with the ratio of the volume removed from the striatal and BG VOIs, and the SBR was high or low according to the ratio. The results suggest that CSF area mask correction is effective in patients with iNPH. TRIAL REGISTRATION: This study was registered in the UMIN Clinical Trials Registry (UMIN-CTR) as UMIN study ID: UMIN000044826. 11/07/2021.

A Case with Anti-ganglioside Antibodies Showing Multiple Cranial Nerve Palsies Detected on Gadolinium-enhanced Magnetic Resonance Imaging.

The anti-GQ1b IgG antibody is often accompanied by other anti-ganglioside antibodies, which induces various neurological symptoms. We herein report a patient with anti-ganglioside antibodies, including anti-GQ1b IgG and anti-GT1a IgG antibodies, showing bilateral ophthalmoplegia, facial nerve palsies, dysarthria, dysphagia, dysesthesia in both hands, and enhancement of the bilateral oculomotor, abducens, and facial nerves on gadolinium (Gd)-enhanced T1-weighted brain magnetic resonance imaging (MRI). He was first treated with intravenous immunoglobulin, which improved ophthalmoplegia, bulbar palsies, and dysesthesia of hands, but the facial nerve palsies worsened, and Gd enhancement of the brain nerves persisted. High-dose methylprednisolone therapy subsequently improved the facial nerve palsies and Gd enhancement of the cranial nerves. This is the first case with anti-ganglioside antibodies presenting with multiple cranial nerve palsies that was followed to track the changes in the Gd enhancement of cranial nerves on MRI.

Association between visualization of the perivascular space and morphological changes in the brain among the community-dwelling elderly.

PURPOSE: We aimed to investigate the association between perivascular space (PVS) visible on MRI and brain atrophy or morphological change using quantitative indexes. METHOD: This population-based cohort study included 216 older participants. The PVS in basal ganglia (BG-PVS) and cerebral white matter (WM-PVS) was evaluated using a four-point visual rating scale. We segmented brain parenchyma and CSF, and calculated the CSF/intracranial volume ratio, which represents atrophic change. WM lesions were classified using the Fazekas scale. We introduced a new category "idiopathic normal pressure hydrocephalus (iNPH)-like conformation", which was based on two quantitative indexes: Evans index and callosal angle. The association between PVS grade and demographic or morphological factors was evaluated. RESULTS: A stepwise increase in the CSF/intracranial volume ratio with BG-PVS grade progression and a stepwise decrease with WM-PVS grade progression were observed. A higher CSF/intracranial volume ratio was significantly related to a higher BG-PVS grade in a univariate analysis, but this significance disappeared in a multivariate analysis. The iNPH-like group was significantly related to a lower WM-PVS grade in a univariate analysis, and this significance remained in a multivariate analysis. CONCLUSIONS: The association between BG-PVS enlargement and atrophic changes was verified. On the contrary, WM-PVS showed a different trend, and a lower WM-PVS grade was associated with an iNPH-like conformation. This result implies that the less-visible WM-PVS on imaging as well as BG-PVS enlargement would reflect abnormal brain change.

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.

Valosin-containing protein Asp395Gly mutation in a patient with frontotemporal dementia: a case report.

BACKGROUND: Variants in the valosin-containing protein (VCP) gene were identified as one of the causes for inclusion body myopathy associated with Paget disease of the bone and frontotemporal dementia (FTD). Previously identified pathogenic variants in VCP are associated with frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) pathologically, but p.Asp395Gly VCP was recently reported to cause familial FTD with tauopathy characterized by neurofibrillary tau tangles (NFT) and not FTLD-TDP. We describe the clinical and genetic findings of a patient with p.Asp395Gly valosin-containing protein (VCP), who was diagnosed with FTD without a family history and in the absence of muscle or bone disease comorbidity. CASE PRESENTATION: The patient was a 62-year-old man, who developed atypical depression at the age of 37 years. Subsequently, he presented with self-centered behavior at the age of 45 years. The self-centered behavior intensified from around the age of 50 years, which was accompanied by the development of executive dysfunction; therefore, he visited our hospital at 52 years of age. Magnetic resonance imaging revealed bilateral frontal lobe atrophy. Brain perfusion single-photon emission computed tomography revealed bilateral frontal lobe hypoperfusion. The patient fulfilled the diagnostic criteria for behavioral variant of FTD. Ten years after the diagnosis, computed tomography of the trunk and limbs, muscle biopsy, and bone scintigraphy revealed the absence of concomitant muscle and bone disease. The concentrations of cerebrospinal fluid (CSF) total tau and phosphorylated tau proteins were 389 pg/mL and 53.2 pg/mL (cut-off: 50 pg/mL), respectively. Genetic analyses were performed using the whole-exome and Sanger sequencing methods. We identified p.Asp395Gly VCP in this patient with pure FTD. CONCLUSIONS: p.Asp395Gly VCP was identified in a patient with likely sporadic FTD without concomitant muscle and bone disease. The CSF analysis suggested that our patient may have FTD due to NFT accumulation similar to the familial FTD patients with p.Asp395Gly VCP recently reported. Our findings suggest that a genetic search for the pathogenic variants of VCP should be considered not only for familial FTD, but also for patients with sporadic FTD, even in the absence of comorbid muscle or bone disease.

Prevalence and development of idiopathic normal pressure hydrocephalus: A 16-year longitudinal study in Japan.

OBJECTIVE: We previously investigated the preclinical state of idiopathic normal pressure hydrocephalus (iNPH): asymptomatic ventriculomegaly with features of iNPH on magnetic resonance imaging (AVIM) found in community inhabitants. The aim of the study was to determine how iNPH develops longitudinally. MATERIALS AND METHODS: A previous longitudinal prospective community-based cohort study was initiated in 2000. The 271 70 year-old participants were followed up in 2016 at the age of 86 years. At this time, 104 participants could be reached for clinical examinations and brain magnetic resonance imaging (MRI). iNPH in this study was diagnosed if the participant had more than one symptom in the clinical triad and disproportionately enlarged subarachnoid space hydrocephalus (DESH) on MRI, fulfilling at least an Evans index >0.3 (ventricular enlargement, VE) and a narrowing of the subarachnoid space at the high convexity (tight high convexity, THC). Asymptomatic VE (AVE) plus THC were considered AVIM. RESULTS: Longitudinally throughout 16 years, 11 patients with iNPH were found. The hospital consultation rate was only 9%. Five of the eight patients with AVIM (62.5%) and six of 30 with AVE (20.0%) developed iNPH. Cross-sectionally, eight patients had iNPH (8/104, 7.7% prevalence at the age of 86) in 2016. Disease development was classified into THC-preceding and VE-preceding iNPH. One VE-preceding iNPH case was considered a comorbidity of Alzheimer's dementia. CONCLUSION: Idiopathic normal pressure hydrocephalus had a high prevalence among octogenarians in the evaluated community. iNPH developed not only via AVIM but also via AVE, the latter was also frequent in the elderly.

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.

Differing clinical features between Japanese siblings with cerebrotendinous xanthomatosis with a novel compound heterozygous CYP27A1 mutation: a case report.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is an autosomal-recessive lipid storage disorder caused by mutations in the CYP27A1 gene encoding the key enzyme in the bile acid synthesis, sterol 27-hydroxylase. Here, we report two Japanese CTX siblings with a novel compound heterozygous CYP27A1 mutation, showing different clinical phenotypes and responses to chenodeoxycholic acid (CDCA) therapy. CASE PRESENTATION: The proband, a 32-year-old man, who had chronic diarrhea, bilateral cataracts, and xanthomas, demonstrated progressive neurological manifestations including ataxia, and spastic paraplegia during a 5-year follow-up period despite normalization of serum cholestanol after initiation of CDCA treatment. He also exhibited cognitive decline although improvement had been observed at the beginning of treatment. Follow-up brain magnetic resonance imaging (MRI) revealed pronounced progressive atrophy in the cerebellum, in addition to expanding hyperintense lesions in the dentate nuclei, posterior limb of the internal capsule, cerebral peduncles, and inferior olives on T2-weighted images. In contrast, the two-year-younger sister of the proband presented with chronic diarrhea, cataracts, xanthomas, and intellectual disability but no other neurological symptoms at the time of diagnosis. CDCA treatment lead to improvement of cognitive function and there were no characteristic CTX-related MRI features during the follow-up period. The siblings shared a paternally inherited c.1420C > T mutation (p.Arg474Trp) and a maternally inherited novel c.1176_1177delGA mutation, predicting p.(Glu392Asp*20). CONCLUSIONS: Our cases suggest that early diagnosis and subsequent initiation of CDCA treatment are crucial before the appearance of characteristic MRI findings and severe neurological manifestations related to CTX. Further studies are required to elucidate mechanisms responsible for the clinical diversity of CTX and prognostic factors for long-term outcomes following initiation of CDCA treatment.