Aberrant morphometric networks in Alzheimer's disease have hemispheric asymmetry and age dependence.

Alzheimer's disease (AD) is associated with abnormal accumulations of hyperphosphorylated tau and amyloid-ß proteins, resulting in unique patterns of atrophy in the brain. We aimed to elucidate some characteristics of the AD's morphometric networks constructed by associating different morphometric features among brain areas and evaluating their relationship to Mini-Mental State Examination total score and age. Three-dimensional T1-weighted (3DT1) image data scanned by the same 1.5T magnetic resonance imaging (MRI) were obtained from 62 AD patients and 41 healthy controls (HCs) and were analysed by using FreeSurfer. The associations of the extracted six morphometric features between regions were estimated by correlation coefficients. The global and local graph theoretical measures for this network were evaluated. Associations between graph theoretical measures and age, sex and cognition were evaluated by multiple regression analysis in each group. Global measures of integration: global efficiency and mean information centrality were significantly higher in AD patients. Local measures of integration: node global efficiency and information centrality were significantly higher in the entorhinal cortex, fusiform gyrus and posterior cingulate cortex of AD patients but only in the left hemisphere. All global measures were correlated with age in AD patients but not in HCs. The information centrality was associated with age in AD's broad brain regions. Our results showed that altered morphometric networks due to AD are left-hemisphere dominant, suggesting that AD pathogenesis has a left-right asymmetry. Ageing has a unique impact on the morphometric networks in AD patients. The information centrality is a sensitive graph theoretical measure to detect this association.

Turning and multitask gait unmask gait disturbance in mild-to-moderate multiple sclerosis: Underlying specific cortical thinning and connecting fibers damage.

Multiple sclerosis (MS) causes gait and cognitive impairments that are partially normalized by compensatory mechanisms. We aimed to identify the gait tasks that unmask gait disturbance and the underlying neural correlates in MS. We included 25 patients with MS (Expanded Disability Status Scale score: median 2.0, interquartile range 1.0-2.5) and 19 healthy controls. Fast-paced gait examinations with inertial measurement units were conducted, including straight or circular walking with or without cognitive/motor tasks, and the timed up and go test (TUG). Receiver operating characteristic curve analysis was performed to distinguish both groups by the gait parameters. The correlation between gait parameters and cortical thickness or fractional anisotropy values was examined by using three-dimensional T1-weighted imaging and diffusion tensor imaging, respectively (corrected p < .05). Total TUG duration (>6.0 s, sensitivity 88.0%, specificity 84.2%) and stride velocity during cognitive dual-task circular walking (<1.12 m/s, 84.0%, 84.2%) had the highest discriminative power of the two groups. Deterioration of these gait parameters was correlated with thinner cortical thickness in regional areas, including the left precuneus and left temporoparietal junction, overlapped with parts of the default mode network, ventral attention network, and frontoparietal network. Total TUG duration was negatively correlated with fractional anisotropy values in the deep cerebral white matter areas. Turning and multitask gait may be optimal to unveil partially compensated gait disturbance in patients with mild-to-moderate MS through dynamic balance control and multitask processing, based on the structural damage in functional networks.

Programmed Cell Death-1 Pathway Deficiency Enhances Autoimmunity Leading to Dacryoadenitis of Mice.

Programmed cell death protein (PD)-1 is a coinhibitory molecule that suppresses immune response and maintains immune homeostasis. Moreover, the PD-1 pathway blocks cancers from being attacked by immune cells. Anti-PD-1 antibody therapy such as nivolumab improves survival in cancer patients. However, the occurrence of autoimmune inflammatory disorders in various organs has been increasingly reported as an adverse effect of nivolumab. Of the disorders associated with nivolumab, Sicca syndrome occurs in 3% to 11% of cases and has unknown pathologic mechanisms. Whether the absence of the PD-1 pathway causes functional and morphologic disorders in lacrimal glands was determined by analyzing PD-1 gene-knockout (Pdcd1-/-) mice. Histopathologic analysis showed that Pdcd1-/- mice developed dacryoadenitis beginning at 3 to 4 months of age, and deteriorated with age. Flow-cytometric analysis confirmed that cells infiltrating the affected lacrimal glands consisted mainly of CD3+ T cells and only a small proportion of CD19+ B cells. Among infiltrating T cells, the CD4+ Th-cell subset consisted of Th1 cells producing interferon-γ in an early stage of dacryoadenitis in Pdcd1-/- mice. Experiments of lymphocyte transfer from Pdcd1-/- into irradiated wild-type mice confirmed that CD4+ T cells from Pdcd1-/- mice induced dacryoadenitis. These results indicate that PD-1 plays an important role in the prevention of autoimmune inflammatory disorders in lacrimal glands caused by activated CD4+ Th1 cells.

Blockade of costimulatory CD27/CD70 pathway promotes corneal allograft survival.

PURPOSE: To determine whether the CD27/CD70 pathway plays a significant role in corneal allograft rejection by investigating the effect of blocking the CD27/CD70 pathway by anti-CD70 antibody on corneal allograft survival. METHODS: Orthotopic penetrating keratoplasty was performed using C57BL/6 donor grafts and BALB/c recipients. Expression of CD27 and CD70 on rejected cornea was examined by immunohistochemistry. Corneal transplant recipients received intraperitoneal injection of anti-CD70 antibody (FR70) or control rat IgG. Alloreactivity was measured by mixed lymphoid reaction (MLR) in recipients administered control rat IgG and those administered anti-CD70 antibody. Corneal expression of IFN-γ and IL-12 was also examined in both groups. Graft opacity was assessed over an 8-week period and graft survival was evaluated using Kaplan-Meier survival curves. Proportion of CD4+CD44+ memory T cells in lymph nodes was measured by flow cytometry. RESULTS: CD4+CD27+ cells and CD11c+CD70+ cells were present in rejected cornea. Anti-CD70 antibody administration suppressed alloreactivity in corneal allograft recipients, and inhibited IFN-γ expression in recipient cornea (p < 0.05). Anti-CD70 antibody suppressed opacity score of recipient cornea and prolonged corneal allograft survival (p < 0.05). Proportion of CD4+CD44+ memory T cells in recipient lymph nodes was reduced by anti-CD70 antibody treatment. CONCLUSION: The CD27/CD70 pathway plays a significant role in corneal allograft rejection by initiating alloreactive Th1 cells and preserving memory T cells. Anti-CD70 antibody administration prolongs corneal allograft survival indicating the potential therapeutic effect of CD27/CD70 pathway blockade on corneal allograft rejection.

Striatal Dopamine Denervation Impairs Gait Automaticity in Drug-Naïve Parkinson's Disease Patients.

BACKGROUND: Gait automaticity, which is impaired in patients with Parkinson's disease (PD), can be quantified by gait variability analysis. Among the 3 regions of the striatum (sensorimotor, executive, and limbic), the sensorimotor region may play a crucial role in motor automaticity in healthy individuals. However, neural correlates of impaired gait automaticity are poorly investigated in PD. OBJECTIVE: We aimed to examine the relationship between gait automaticity and striatal dopaminergic depletion in drug-naïve PD patients. METHODS: A total of 21 drug-naïve PD patients and 12 healthy controls were enrolled. Gait parameters were measured via wearable inertial sensors under fast-paced gait or cognitive dual-task conditions, and their respective coefficient of variation (CV) and dual-task cost were calculated. The extent of striatal dopaminergic depletion was evaluated by dopamine transporter (DAT) imaging with single-photon emission computed tomography using N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-[123 I]iodophenyl)nortropane. Correlation between DAT uptake and gait variables was analyzed using the region-of-interest analysis for the 3 right or left striatal regions and voxel-based analysis. RESULTS: PD had higher mean bilateral CV and dual-task cost of stride length than healthy controls. The mean bilateral CV of stride length was negatively correlated with DAT uptake in the bilateral executive regions of the striatum. Voxel-based analysis revealed a negative correlation between the mean bilateral CV of stride length and DAT uptake in the anteromedial striatum. CONCLUSIONS: Dopaminergic denervation in the anteromedial striatum, a part of the executive region, is associated with impaired gait automaticity in drug-naïve PD patients. This region may compensate for the posterior sensorimotor striatum, maintaining gait automaticity. © 2020 International Parkinson and Movement Disorder Society.

Isolates and antibiotic susceptibilities of endogenous bacterial endophthalmitis: A retrospective multicenter study in Japan.

Endogenous bacterial endophthalmitis, also called metastatic endophthalmitis, is a rare bacterial endophthalmitis derived from distant infectious foci via the bloodstream. This infection can potentially cause not only severe visual disturbance, but also loss of the eyeball or death, as most patients are immunocompromised. This retrospective Japanese multicenter study analyzed 32 eyes in 25 definitive cases. Twelve patients (48.0%) had diabetes mellitus. Typical ocular findings were vitreous haze (87.5%), cells in the anterior chambers (62.5%) and retinal infiltrates (50.0%). Elevated body temperature (64.0%), high serum C-reactive protein (96.0%) and leukocytosis (52.0%) were also frequently observed. Culture positivity rates for intraocular fluid were higher in the vitreous (62.5%) versus aqueous humor (28.6%). High positivity rates were also observed for blood (57.1%) and central venous catheters (100%). The most common pathogen was Staphylococcus aureus (10 cases), including methicillin-resistant S. aureus (4 cases). The next most common pathogen was Klebsiella pneumoniae (7 cases), which was highly associated with liver abscess. Compared to a previous 1991 national multicenter study, there has been a fourfold increase in the ratio of S. aureus. Antibiotic susceptibility tests revealed that all Gram-positives were susceptible to vancomycin and all Gram-negatives were susceptible to third-generation cephalosporins, imipenem/cilastatin, gentamycin and levofloxacin. Prognostic factors influencing poor visual outcome included poor initial visual acuity (p < 0.01), K. pneumoniae (p = 0.027) and gram-negative bacteria (p = 0.014) as the causative bacteria. Intravitreal antibiotic injection in combination with vancomycin and ceftazidime may be applicable for use as part of the standard treatment regimen for EBE.

Rebamipide suppresses TNF-α production and macrophage infiltration in the conjunctiva.

PURPOSE: To evaluate the anti-inflammatory effect of rebamipide during corneal epithelial wound healing using a mouse wound repair model. METHODS: A 2-mm circular disc of the central cornea was demarcated in the right eye of C57BL/6 mice and the epithelium removed. Rebamipide 2% eyedrop was instilled onto the wounded eye 5 times a day (n = 26). Phosphate-buffered saline (PBS) was used in the control group (n = 26). Corneal and conjunctival IL-1ß and TNF-α levels were measured at 6 h and 24 h postinjury by ELISA. The wounded area was evaluated by fluorescein staining at 24 h postinjury. Macrophage infiltration was assessed immunohistochemically, and TNF-α secretion from macrophages was examined in vitro. RESULTS: Conjunctival IL-1ß and corneal IL-1ß levels were not significantly different between PBS-treated and rebamipide-treated groups. However, conjunctival TNF-α level was significantly lower in the rebamipide-treated group compared with the PBS-treated group. Macrophage migration into the conjunctiva, but not into the cornea, was suppressed by rebamipide treatment. In addition, TNF-α secretion from cultured macrophages was suppressed by rebamipide in a concentration-dependent manner. Rebamipide treatment significantly accelerated corneal epithelial wound healing at 24 h postinjury. CONCLUSIONS: In a mouse corneal epithelial wound model, rebamipide suppressed TNF-α secretion and macrophage infiltration in the conjunctiva, which might have contributed to accelerated corneal epithelial wound healing in the first 24 h following injury.

Wavelength dispersion of birefringence of oriented polyethylene films.

Oriented polyethylene films, in which stacked lamellae grow perpendicular to the flow direction, can show extraordinary wavelength dispersion of birefringence; i.e., birefringence increases with wavelength. Owing to the periodical change of the refractive indices between the crystalline and amorphous layers along the flow direction, with oriented long lamellae having a high refractive index, the form birefringence has negative values. Furthermore, the refractive indices of the crystalline region show a stronger wavelength dependence than those of the amorphous region, which is responsible for the marked wavelength dispersion in the form birefringence. The combination of negative form birefringence with strong wavelength dispersion and positive orientation birefringence can give extraordinary wavelength dispersion.

Differences in active range of motion measurements in the upper extremity of patients with writer's cramp compared with healthy controls.

STUDY DESIGN: Exploratory case-control study. INTRODUCTION: Writer's cramp (WC) is a type of focal hand dystonia. The central nervous system plays a role in its pathophysiology, but abnormalities in the affected musculoskeletal components may also be relevant. PURPOSE OF THE STUDY: We compared the active range of motion (ROM) in patients with WC and healthy volunteers (HVs) and correlated the findings with disease duration and severity. METHODS: Affected limb joints were measured with goniometers. Patients were assessed at least 3 months after their last botulinum toxin (botulinum neurotoxin) injection, and strength was clinically normal. t tests were used to compare the ROMs of WC with matched HVs. The Spearman correlation coefficient assessed the relationship of active ROMs to the disease duration and handwriting subscore of the Dystonia Disability Scale. RESULTS: ROMs of D1 metacarpophalangeal (MCP) joint extension as well as D2 and D5 MCP flexion were significantly smaller in WC, and distal interphalangeal joint extension in D3 and D5 was significantly greater compared with HVs. There were negative correlations between D2 MCP flexion and disease duration and with Dystonia Disability Scale. DISCUSSION: Abnormalities in ROMs in WC were found. Severity and disease duration correlated with reduced D2 MCP flexion. This may be related to intrinsic biomechanical abnormalities, co-contraction of muscles, or a combination of subclinical weakness and atrophy from repeated botulinum neurotoxin injections. CONCLUSIONS: Hand biomechanical properties should not be ignored in the pathophysiology of WC. LEVEL OF EVIDENCE: 2c.

Soluble vascular endothelial growth factor receptor-3 suppresses allosensitization and promotes corneal allograft survival.

PURPOSE: To investigate the effect of VEGF-C and VEGF-D blockade via soluble VEGFR-3 (sVEGFR-3) on T cell allosensitization, corneal neovascularization, and transplant survival. METHODS: Corneal intrastromal suture placement and allogeneic transplantation were performed on BALB/c mice to evaluate the effect of sVEGFR-3 on corneal neovascularization. Soluble VEGFR-3 trap was injected intraperitoneally to block VEGF-C/D (every other day starting the day of surgery). Immunohistochemical staining of corneal whole mounts was performed using anti-CD31 (PECAM-1) and anti-LYVE-1 antibodies to quantify the levels of hem- and lymphangiogenesis, respectively. Mixed lymphocyte reaction (MLR) was performed to assess indirect and direct host T cell allosensitization and the frequencies of IFN-γ-producing T cells in the draining lymph nodes were assessed using flow cytometry. Graft opacity and survival was evaluated by slit-lamp biomicroscopy. RESULTS: Treatment with sVEGFR-3 resulted in a significant blockade of lymphangiogenesis 2 weeks post-transplantation and significantly prolonged corneal allograft survival compared to the control group at 8 weeks post-transplantation (87.5 % vs. 50 %), and this was associated with significant reduction in the frequencies of allosensitized T cells and decreased frequencies of IFN-γ-producing CD4 T cells. CONCLUSIONS: Soluble VEGFR-3 suppresses corneal lymphangiogenesis and allograft rejection and may offer a viable therapeutic modality for corneal neovascularization and corneal transplantation.

In vivo challenging of polymyxins and levofloxacin eye drop against multidrug-resistant Pseudomonas aeruginosa keratitis.

The purposes of this study were to establish a rabbit multidrug-resistant Pseudomonas aeruginosa (MDRP) keratitis model, and test the efficacy of levofloxacin, colistin methanesulfate (CL-M), colistin sulfate (CL-S) and polymyxin B (PL-B) against MDRP infection. In a rabbit eye, making a 2-mm circular corneal excision, and MDRP strain #601 or representative P. aeruginosa strain IID1210 were instilled into the corneal concavity. IID1210 was used to confirm this model developed P. aeruginosa keratitis. After MDRP keratitis developed, we treated the eyes with levofloxacin, CL-M, CL-S or PL-B eye drops. The infected eyes were evaluated by clinical score, histopathological examination and viable bacterial count (CFU). Rabbits developed MDRP keratitis reproducibly after instilled the bacteria into the corneal lesion. MDRP produced severe keratitis similarly with IID1210, as shown by slit lamp examination and clinical score. In MDRP keratitis models, clinical scores and viable bacterial counts were significantly lower in levofloxacin- and CL-M-treated groups compared with PBS-treated group, but the magnitudes of reduction were not remarkable. However, clinical scores were dramatically lowered in CL-S- and PL-B-treated groups compared with PBS-treated group. CL-S- and PL-B-treated group were kept corneal translucency and little influx of polymorphonuclear neutrophils in histopathological examination. In addition, both CL-S- and PL-B-treated groups were not detected viable bacteria in infected cornea. Using our MDRP keratitis model, we showed that topical levofloxacin and CL-M are not adequately effective, while CL-S and PL-B are efficacious in controlling MDRP keratitis. Especially, PL-B, which is commercially available eye drop, might be most effective against MDRP.

Clodronate liposome treatment contributes to the nerve regeneration in corneal nerve involvement of diabetic mice.

The dense nerve and thin vascular structure of the corneal tissue provide the refractive function in healthy eyes. Diabetes mellitus causes ocular complications including corneal opacification because of corneal nerve degeneration. Diabetic neurotrophic keratopathy is characterized by reduced corneal sensitivity, delayed corneal wound healing, and nerve degeneration. Neurotization and vascularization inhibit each other in the cornea. Macrophages contribute to the corneal neovascularization. To investigate the role of macrophage in neurotrophic keratopathy, clodronate liposome was subconjunctivally injected into diabetic db/db mice with neurotrophic keratopathy. The clodronate liposome treatment decreased F4/80+ macrophage infiltration into the corneal epithelium, and improved corneal nerve involvement in diabetic db/db mice. Furthermore, we found that interleukin (IL)-1ß and IL-34 mRNA expression was increased in the corneal epithelium of clodronate-treated diabetic db/db mice. These cytokines contribute to the maintenance of nerve tissues via microglia and nerve regeneration; however, their role in corneal nerve involvement remains unknown. Notably, the intraocular injection of recombinant IL-1ß and IL-34 promoted nerve regeneration in the cornea of diabetic db/db mice. These results suggest that clodronate liposome treatment contributes to nerve regeneration during corneal involvement via IL-1ß and IL-34 signaling.

Is there a spinal tap responder in progressive supranuclear palsy? The first prospective study.

OBJECTIVE: Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disease, and sometimes shows idiopathic normal pressure hydrocephalus (iNPH)-like presentations. We aimed to evaluate spinal tap responsiveness in patients with PSP, including the effect of sham spinal tap. METHODS: Eleven patients with PSP, ten with probable/definite iNPH, and eight control patients were prospectively enrolled. All participants underwent sham spinal tap and spinal tap procedures. Gait was evaluated using wearable inertial sensors. We defined "tap responders" as individuals with a 10% or more improvement from baseline in any of the gait parameters (timed up-and-go test total time, stride length, and velocity during straight walking under single-task and cognitive dual-task conditions). We compared the ratio of responders in patients with PSP to patients with iNPH and controls. RESULTS: The ratio of tap responders and the ratio of sham tap responders in patients with PSP were significantly higher than those in control patients, and not different from those in patients with iNPH. PSP patients with iNPH-like MRI features tended to respond to the spinal tap compared to those without such imaging features. Notably, one patient with PSP, who responded to the spinal tap beyond the effect of sham spinal tap, was treated by the shunt operation. CONCLUSION: This is the first prospective study to demonstrate tap and shunt responsiveness in patients with PSP while highlighting the placebo effects of the spinal tap in patients with PSP or iNPH. Our findings suggest that some PSP patients have impaired cerebrospinal fluid circulation, contributing to a distinct component of the clinical spectrum.

Circular walking is useful for assessing the risk of falls in early progressive supranuclear palsy.

BACKGROUND: Progressive supranuclear palsy (PSP) is characterized by early onset postural instability and frequent falls. Circular walking necessitates dynamic postural control, which is impaired in patients with PSP. We aimed to explore gait parameters associated with the risk of falls in patients with PSP, focusing on circular walking. METHODS: Sixteen drug-naïve patients with PSP, 22 drug-naïve patients with Parkinson's disease (PD), and 23 healthy controls were enrolled. Stride lengths/velocities and their coefficients of variation (CV) during straight and circular walking (walking around a circle of 1-m diameter) were measured under single-task and cognitive dual-task conditions. Correlation analysis was performed between gait parameters and postural instability and gait difficulty (PIGD) motor subscores, representing the risk of falls. RESULTS: Patients with PSP had significantly higher CVs of stride lengths/velocities during circular walking than those during straight walking, and the extent of exacerbation of CVs in patients with PSP was larger than that in patients with PD under single-task conditions. Stride lengths/velocities and their CVs were significantly correlated with PIGD motor subscores in patients with PSP only during single-task circular walking. In addition, patients with PSP showed progressive decrements of stride lengths/velocities over steps only during single-task circular walking. CONCLUSIONS: Worse gait parameters during circular walking are associated with an increased risk of falls in patients with PSP. Circular walking is a challenging task to demand the compromised motor functions of patients with PSP, unmasking impaired postural control and manifesting sequence effect. Assessing circular walking is useful for evaluating the risk of falls in patients with early PSP.

Peroxisome proliferator-activated receptor-γ agonist pioglitazone suppresses experimental autoimmune uveitis.

Peroxisome proliferator-activated receptor (PPAR)-γ agonists are clinically used as anti-diabetes agents. Recent research has discovered that an anti-inflammatory effect of PPAR agonist may have the potential to treat autoimmune disease. In the present study, we investigated the anti-inflammatory effects of PPAR-γ agonist, pioglitazone, on murine model of endogenous uveitis. Experimental autoimmune uveoretinitis (EAU) was induced by immunizing C57BL/6 mice with human interphotoreceptor retinoid binding protein-derived peptide (1-20). Pioglitazone or vehicle was injected intravenously from day -1 (whole phase treatment) or day 8 (effector phase study) until day 20. Severity of EAU was assessed clinically and pathologically on day 21. Immunological status was assessed by measuring intraocular inflammatory factors, and activation and regulatory markers of CD4(+) T cells in draining lymph nodes (LNs). Treatment with pioglitazone suppressed both whole-phase and effector-phase of EAU. In effector-phase treatment, intraocular concentrations of TNF-α and IL-6 were significantly suppressed, and CD4(+)Foxp3(+) regulatory T cells and CD4(+)CD62L(high) naïve T cells increased in draining LNs, although there were no differences in CD4(+)CD44(high) effector T cells and IL-17 producing CD4(+) T cells between pioglitazone- and vehicle-treated mice. Administration of pioglitazone before and after the onset of EAU significantly reduced disease severity. The present results suggest that pioglitazone may be a novel therapeutic agent for endogenous uveitis.

Corneal Perforation Associated with Lacrimal Canaliculitis: A Case Series.

Purpose: To report seven eyes of six patients diagnosed with corneal perforation and lacrimal canaliculitis in a single facility. Methods: Clinical records of patients with corneal perforation accompanied by lacrimal canaliculitis seen by the authors were reviewed. Results: Six patients (7 eyes) with corneal perforation accompanied by lacrimal canaliculitis were identified. All patients were female, and all were treated with topical antibiotics while five were receiving topical corticosteroids. Two patients had a history of dacryocystitis and three had systemic immune diseases. The corneal lesions did not respond to topical antibiotics but were effectively treated by removal of concretions in the lacrimal canaliculi and lacrimal duct drainage together with conjunctival autograft or corneal transplantation. Conclusion: Lacrimal canaliculitis is a risk factor for corneal perforation. When corneal perforation does not respond to antibiotics, lacrimal canaliculitis should be considered.

Simultaneous Four Supratentorial Lesions Predict Tube Dependency Due to an Impaired Anticipatory Phase of Ingestion.

This study aimed to identify the neuroanatomical predictors of oropharyngeal dysphagia and tube dependency in patients with supratentorial or infratentorial ischemic strokes. Patients with acute ischemic stroke were enrolled and were classified into 3 groups: right supratentorial (n = 61), left supratentorial (n = 89), and infratentorial stroke (n = 50). Dysphagia was evaluated by a modified water swallowing test and the Food Intake LEVEL Scale to evaluate oropharyngeal dysphagia and tube dependency, respectively. As two dysphagia parameters, we evaluated the durations from onset of stroke to (1) success in the modified water swallowing test and to (2) rating 7 points or above on the Food Intake LEVEL Scale: patients regained sufficient oral intake and were not tube-dependent. Voxel-based lesion-symptom mapping analysis was performed for a spatially normalized lesion map of magnetic resonance imaging to explore the anatomies that are associated with the two dysphagia parameters for each stroke group. The right precentral gyrus and parts of the internal capsule are associated with oropharyngeal dysphagia. The four supratentorial areas are associated with tube dependency. The dorsal upper medulla is associated with both oropharyngeal dysphagia and tube dependency. These results suggest that supratentorial stroke patients can be tube-dependent due to an impaired anticipatory phase of ingestion. The simultaneous damage in the four supratentorial areas: the inferior part of the precentral gyrus, lenticular nucleus, caudate head, and anterior insular cortex, predicts tube dependency. In contrast, infratentorial stroke patients can be tube-dependent due to oropharyngeal dysphagia caused by lesions in the dorsal upper medulla, damaging the swallowing-related nucleus.

Verification of propagation hypothesis in patients with sporadic hand onset amyotrophic lateral sclerosis.

OBJECTIVE: If lesions in sporadic amyotrophic lateral sclerosis (ALS) originate from a single focal onset site and spread contiguously by prion-like cell-to-cell propagation at a constant speed, the lesion spread time should be proportional to the anatomical distance. We verify this model in the patients. METHODS: In 29 sporadic ALS patients with hand onset followed by spread to shoulder and leg, we retrospectively evaluated the inter/intra-regional spread time ratio: time interval of symptoms from hand-to-leg divided by that from hand-to-shoulder. We also obtained the corresponding inter-/intra-regional distance ratios of spinal cord from magnetic resonance imaging of 12 patients, and those of primary motor cortex from coordinates using neuroimaging software. RESULTS: Inter-/intra-regional spread time ratios ranged from 0.29 to 6.00 (median 1.20). Distance ratios ranged from 1.85 to 2.86 in primary motor cortex and from 5.79 to 8.67 in spinal cord. Taken together with clinical manifestations, of 27 patients with the requisite information available, lesion spreading was consistent with the model in primary motor cortex in 4 (14.8%) patients, and in spinal cord in only 1 (3.7%) patient. However, in more patients (12 of 29 patients: 41.4%), the inter-regional spread times in a long anatomical distance of hand-to-leg were shorter than or equal to the intra-regional spread times in a short anatomical distance of hand-to-shoulder. CONCLUSION: Contiguous cell-to-cell propagation at a constant speed might not play a major role at least in distant lesion spreading of ALS. Several mechanisms can be responsible for progression in ALS.

Correlation of callosal angle at the splenium with gait and cognition in normal pressure hydrocephalus.

OBJECTIVE: Idiopathic normal pressure hydrocephalus (iNPH) is characterized by ventricular enlargement that deforms the corpus callosum, making the callosal angle (CA) small. The authors aimed to evaluate the clinical usefulness of the CA in different planes in iNPH. METHODS: Forty patients with iNPH were included in the study. As a control group, 241 patients with other neurological diseases and 50 healthy controls were included. The subjects had been seen at the authors' institutions from 2010 to 2020. The Timed Up and Go (TUG) test total time and Mini-Mental State Examination (MMSE) total score were evaluated. CAs were measured in the axial plane at the splenium and genu and in the coronal plane at the anterior commissure and posterior commissure by using 3-dimensional T1-weighted MR images. As other hydrocephalus parameters, the Evans index, frontal-occipital horn ratio, and third ventricular width were also measured in patients with iNPH. Associations between each CA or hydrocephalus parameter and clinical parameters were evaluated. The classification efficacy of each CA in differentiating between iNPH and other neurological diseases and healthy controls was evaluated. RESULTS: The CA at the splenium, but no other hydrocephalus parameters, was correlated with TUG total time or MMSE total score in patients with iNPH. Receiver operating characteristic analysis showed that a CA of 71.1° at the splenium has 90.0% sensitivity and 89.0% specificity in discriminating iNPH from other neurological diseases and healthy controls. Probabilistic tractography analysis showed that neuronal fibers via the splenium connect the superior parietal lobules, temporal lobes, and occipital lobes. CONCLUSIONS: The study results suggest that interhemispheric disconnections at the splenium are, at least in part, responsible for gait and cognitive disturbance in iNPH. The CA at the splenium is a unique morphological feature that correlates with gait and cognition in iNPH, and it is useful for discriminating iNPH from other neurological diseases and healthy controls.

Long-term levodopa ameliorates sequence effect in simple, but not complex walking in early Parkinson's disease patients.

BACKGROUND: The sequence effect (SE) is characterized by the progressive decrement of movements and is often observed in Parkinson's disease (PD) patients. While acute effect of levodopa does not ameliorate the SE, the effect of long-term levodopa treatment for the SE remains unknown. OBJECTIVE: We aimed to elucidate the SEs during various gait conditions and their response to long-term levodopa treatment in drug-naïve PD patients. METHODS: Nineteen drug-naïve PD patients and 21 healthy controls were enrolled. Gait parameters were measured via wearable inertial sensors in the following conditions:1) straight walking, 2) circular walking: walking a circle of 1 m diameter in a clock-wise direction for 3 laps, 3) straight or circular walking under cognitive-motor dual-task (serial 7s subtractions). PD patients were evaluated at baseline, within 1 h after intravenous administration of levodopa, and after one, three, and six months treatment with levodopa. The SE was measured by a linear regression slope by plotting consecutive stride lengths over steps. Patients were also separately analyzed depending on laterality of symptoms. RESULTS: Long-term levodopa treatment ameliorated the SE only during single-task straight walking. The SE during circular walking was exacerbated after long-term levodopa treatment for right-side dominant patients. During dual-task straight walking, the SE at baseline was greater in right-side dominant PD patients. CONCLUSIONS: The SE only during single-task straight walking can be ameliorated by long-term levodopa treatment. However, the SE may be exaggerated by cognitive motor interference or by asymmetrical stride length with/without long-term levodopa treatment, depending on the laterality of symptoms.