Long-term follow-up study of SWEDD patients with mild parkinsonian signs.

Background: Whether scan without evidence of dopaminergic deficit (SWEDD) can be a reliable indication of a clinical entity of Parkinson's disease (PD) is controversial. Objective: To evaluate the proportion of SWEDD patients with mild parkinsonian signs who are classifiable as idiopathic PD. Methods: 32 SWEDD patients with unilateral or asymmetric finger tremor with a rest component and unilateral rigidity (Unified Parkinson's Disease Rating Scale (UPDRS)-III scores of 3-5) were enrolled. They underwent longitudinal examination by UPDRS-III, Mini-Mental State Examination (MMSE), smell test and 123I-FP-CIT SPECT (DaTSCAN) at baseline (first DaTSCAN) and at follow-up (second DaTSCAN) after 27-83 months. Age-matched controls (n=112) also underwent MMSE and smell test. Results: At follow-up, 21 of 32 SWEDD patients (65.6%) showed significantly reduced specific binding ratios below the normal range, that is, positive DaTSCAN, sometimes with increased asymmetry index (n=11). Among these 21 patients, the mean (SD) UPDRS-III score at follow-up was significantly higher than that at baseline (5.5 (2.2) vs 4.0 (0.5)) (p=0.003). The mean (SD) MMSE scores in SWEDD patients (n=32) at baseline and follow-up were not significantly different compared with those in controls. Olfactory function both in SWEDD patients with positive and negative DaTSCAN was significantly impaired versus controls (p<0.001), although no significant difference was recognised between patients with positive (n=21) and negative (n=11) second DaTSCAN. Conclusion: The majority of SWEDD patients with mild rest tremor and rigidity could be classified as having idiopathic PD in this longitudinal and long-term follow-up study.

Anesthetic management of cesarean section in a patient with Takayasu's arteritis: a case report.

BACKGROUND: Takayasu's arteritis (TA) is a chronic, progressive, inflammatory arteritis. We presented the case of cesarean section in a patient with TA. CASE PRESENTATION: A 31-year-old pregnant woman with TA underwent a planned cesarean section at 34 weeks of pregnancy. She had stenosis of the cerebral and coronary arteries and heart failure due to aortic regurgitation. Spinal anesthesia was performed. In addition to standard monitoring, arterial blood pressure in the dorsalis pedis artery and regional cerebral tissue oxygen saturation were monitored. Intraoperative arterial blood pressure was maintained using continuous infusion of noradrenaline with a careful intermittent bolus infusion of phenylephrine. All the procedures were successfully performed without significant complications. CONCLUSIONS: In a pregnant woman with TA, severe stenosis of the cerebral and coronary arteries, and heart failure due to valvular heart disease, careful anesthetic management by selecting catecholamines and assessing the perfusion pressure for critical organs is important.

Atlantoaxial Rotatory Fixation after Microtia Reconstruction Surgery.

Nontraumatic atlantoaxial rotatory fixation after microtia reconstruction surgery is a rare complication. Intraoperative cervical hyperextension and/or excessive rotation and postoperative inflammation have been reported as causes of atlantoaxial rotatory fixation. We herein describe cases of atlantoaxial rotatory fixation after microtia reconstruction surgery. METHODS: This was a retrospective study of 80 patients (165 surgeries) who underwent microtia reconstruction surgery in Dokkyo Medical University Hospital between April 2006 and December 2012. The patient- and operation-related variables were obtained from medical charts. Neck radiographs and computed tomography scans of patients with atlantoaxial rotatory fixation were evaluated to check for cervical spine abnormalities. RESULTS: Five cases of atlantoaxial rotatory fixation after microtia reconstruction surgery were recorded. Three of these five cases were diagnosed with Klippel-Feil syndrome after the onset of atlantoaxial rotatory fixation. No significant difference was found in the operative duration and other variables between patients with atlantoaxial rotatory fixation and those without. All patients immediately underwent conservative treatment and showed complete recovery and no recurrences. CONCLUSIONS: Although atlantoaxial rotatory fixation is a rare complication, surgeons should consider it in patients with neck problems following microtia reconstruction surgery. A patient with microtia may have unrecognized Klippel-Feil syndrome. Patients with Klippel-Feil syndrome are more likely to develop atlantoaxial rotatory fixation, which may have severe consequences. Thus, it is crucial to preoperatively identify Klippel-Feil syndrome with neck radiography and to detect atlantoaxial rotatory fixation at the earliest.

Anesthetic Management Using Low Fraction of Inspiratory Oxygen for Living Donor Liver Transplantation in a Patient With Hepatopulmonary Syndrome Complicated by Interstitial Pneumonia: A Case Report.

BACKGROUND: Hepatopulmonary syndrome frequently complicates end-stage liver disease. It causes hypoxemia and requires oxygen administration. Additionally, interstitial pneumonia causes hypoxemia; however, it is known to be aggravated by high-concentration oxygen administration. CASE PRESENTATION: A 71-year-old woman with hepatopulmonary syndrome and interstitial pneumonia underwent living donor liver transplantation, requiring conflicting management in terms of the inspiratory oxygen concentration. We achieved a low intraoperative fraction of inspiratory oxygen by increasing the cardiac output with intravenous catecholamines. As a result, the transplanted liver functioned well postoperatively, and the patient was discharged without exacerbation of the interstitial pneumonia. CONCLUSION: We suggest that patients with hepatopulmonary syndrome complicated with interstitial pneumonia can undergo successful living donor liver transplantation without the use of high inspiratory oxygen concentration by using catecholamines to maintain a high mixed venous oxygen saturation.

High Prevalence of Early Parkinson's Disease in Patients With Subtle Parkinsonian Signs.

Background: Little is known about how frequently patients with a Unified Parkinson Disease Rating Scale part III (UPDRS-III) score of 3 or 4, including postural and action tremor, could be classified into early Parkinson's disease (PD). Objective: To examine the prevalence of early PD in patients with subtle parkinsonian signs (rest tremor, postural tremor, and rigidity) without bradykinesia, having a UPDRS-III score of 3 or 4. Methods: Parkinsonism was assessed using UPDRS-III based on both the United Kingdom PD Society Brain Bank criteria and the Movement Disorder Society PD criteria. Ninety patients with a UPDRS-III score of 3 or 4, including postural tremor, were evaluated by 123I-FP-CIT SPECT (DaTscan), brain MRI, the Mini-Mental State Examination, and smell test. Some patients were additionally examined by 123I-metaiodobenzylguanidine myocardial scintigraphy or 123I-N-isopropyl-p-iodoamphetamine SPECT. Results: Seventy-five [mean age (standard deviation): 76.9 (8.1)] out of 90 patients (83.3%) showed abnormal findings on DaTscan imaging: 57 out of 75 (76.0%) showed a reduced specific binding ratio (SBR) accompanied by an egg shape pattern (n = 37, 49.3%) or a mixed type pattern (n = 14, 18.7%), both reduced SBR and increased asymmetry index (AI) with a normal shape (n = 4, 5.3%), and reduced SBR only (n = 2, 2.7%); 18 (24.0%) showed an egg shape pattern or a mixed type pattern without reduced SBR. In other words, 69 out of 75 patients (92.0%) showed either an egg shape or a mixed type pattern with or without reduced SBR. All patients were free of dementia, and their olfactory function was significantly impaired compared with controls (n = 141) on the odor-stick identification test for Japanese (p < 0.0001). Conclusions: The prevalence of patients with subtle parkinsonian signs having a UPDRS-III score of 3 or 4, including postural tremor, is unexpectedly high in daily clinical practice, and most of these patients could be categorized into mild early-stage PD.

A Herniorrhaphy Lamination Technique for the Reconstruction of Midline Abdominal Wall Defects.

The primary goal of abdominal wall reconstruction is to prevent hernia recurrence through robust and durable repair. Synthetic mesh utilization can provide sound strength but is susceptible to extrusion, infection, and intestinal fistulization. The use of autologous fasciae latae to reinforce the primary fascial reapproximation has mostly been abandoned, presumably because synthetic patches are readily available. There is a specific demand for a sustainable, less-invasive, and ready-to-use repair method without mesh. The authors devised a herniorrhaphy lamination technique using local musculofascial flaps inspired by composite laminates. In this procedure, the primary fascial reapproximation is reinforced with 3 additional laminated musculofascial layers: (1) turnover hinge flaps of the anterior sheath of the rectus abdominis, (2) bilateral rectus abdominis, and (3) advancement flaps of newly generated edges of the fascia of the rectus sheath. Our technique's stability is essentially due to the mechanical superiority of the centralized pipe-like structure of musculofascia. Between February 2009 and November 2019, we used the lamination technique to repair midline incisional hernias in 10 patients. The operative procedure was successful in all patients, and there has been no evidence of recurrence. The follow-up period ranged from 12 to 69 months, with a mean follow-up of 35 months. The herniorrhaphy lamination technique to reinforce the primary repair can help prevent hernia recurrence. Although our technique is suitable for a small-sized defect, it is less invasive, and can be readily applied. Because it does not include any mesh, it is suitable for the contaminated abdominal wall reconstruction.

Association Between Olfactory Impairment and Disease Severity and Duration in Parkinson's Disease.

BACKGROUND: The association between olfactory dysfunction and disease duration and severity in Parkinson's disease (PD) remains controversial. OBJECTIVE: The objective of this study was to examine the relationship between olfactory dysfunction and disease severity and duration in patients with recently diagnosed parkinsonism and patients with PD with a previous diagnosis. METHODS: Olfactory function was evaluated in 79 patients with recently diagnosed parkinsonism, 71 patients with PD with a previous diagnosis-with patients in both groups free of cognitive impairment-and 128 age-matched controls. The Odor-Stick Identification Test for Japanese score was counted as the numbers of correct answers, responses of indistinguishable, and responses of odorless. Parkinsonism was evaluated using the Movement Disorder Society Criteria, the Unified Parkinson Disease Rating Scale (UPDRS) Part III, and 123iodine-labeled N-(3-fluoropropyl)-2ß-carbomethoxy-3ß-(4-iodophenyl) nortropane single photon emission computed tomography (DaTscan). RESULTS: In the patients with recently diagnosed parkinsonism having the UPDRS Part III score ≥5 (mean [standard deviation: SD] score: 6.3 [1.9]) and with a positive DaTscan, the mean (SD) numbers of correct answers, responses of indistinguishable and responses of odorless were 4.3 (2.2), 1.6 (2.0), and 1.2 (2.2), respectively. In patients with PD with a previous diagnosis (mean [SD] UPDRS Part III score: 10.9 [3.2]), these numbers were 2.5 (2.2), 2.2 (2.5), and 3.8 (4.6), respectively. The patients with PD with a previous diagnosis showed more significant deterioration than the patients with recently diagnosed parkinsonism in the numbers of correct answers and responses of odorless (P < 0.0001). Olfaction in the combined patient group was significantly impaired compared with age-matched controls in each category (P < 0.0001). CONCLUSIONS: These findings imply a close association between olfactory dysfunction and disease severity and duration in PD.

A Case of Logopenic Variant of Primary Progressive Aphasia with Parkinsonism and Anosmia.

A 69-year-old right-handed woman developed difficulty naming objects and word-finding. The clinical features of language disorder and predominant atrophy on MRI and predominant hypoperfusion on 123I-IMP SPECT in the left temporo-parietal junction area were consistent with the diagnostic criteria for the logopenic variant of primary progressive aphasia (lvPPA). Neurological examination showed slight right-side rigidity and resting tremor (UPDRS-III: 4). 123I-FP-CIT SPECT showed presynaptic dopamine transporter reduction in the posterior putamina with left-side predominance. The odor-stick identification test for Japanese exhibited complete loss of the sense of smell (anosmia). These findings suggest that lvPPA may be accompanied by parkinsonism and anosmia.

High prevalence of parkinsonism in patients with MCI or mild Alzheimer's disease.

INTRODUCTION: The objective of this study was to examine the prevalence of the coexistence of parkinsonism in patients with mild cognitive impairment (MCI) or mild Alzheimer's disease (AD). METHODS: Outpatients were evaluated with Mini-Mental State Examination, Clinical Dementia Rating Scale, NIA-AA criteria, MRI, and 123I-IMP SPECT (3D-SSP). Parkinsonism in patients diagnosed with MCI (Mini-Mental State Examination ≥24, n = 63) or mild AD (Mini-Mental State Examination 20-23, n = 43) was examined using the Unified Parkinson's Disease Rating Scale-III and 123I-FP-CIT dopamine transporter SPECT. RESULTS: One hundred six patients (60-97 years) were enrolled. Fifty-six patients (52.8%) were diagnosed as having concomitant parkinsonism with rigidity and resting tremor and dopamine transporter reduction in the basal ganglia. The mean (SD) age (n = 56) was 80.6 (6.1) years, significantly older than patients without parkinsonism [77.6 (7.0) years, n = 50] (P < .05). The mean (SD) UPDRS-III score was 5.8 (2.4). CONCLUSION: The prevalence rate of the coexistence of mild parkinsonism in MCI or mild AD may be higher than previously recognized.

High salt loading induces urinary storage dysfunction via upregulation of epithelial sodium channel alpha in the bladder epithelium in Dahl salt-sensitive rats.

We aimed to investigate whether high salt intake affects bladder function via epithelial sodium channel (ENaC) by using Dahl salt-resistant (DR) and salt-sensitive (DS) rats. Bladder weight of DR + high-salt diet (HS, 8% NaCl) and DS + HS groups were significantly higher than those of DR + normal-salt diet (NS, 0.3% NaCl) and DS + NS groups after one week treatment. We thereafter used only DR + HS and DS + HS group. Systolic and diastolic blood pressures were significantly higher in DS + HS group than in DR + HS group after the treatment period. Cystometrogram showed the intercontraction intervals (ICI) were significantly shorter in DS + HS group than in DR + HS group during infusion of saline. Subsequent infusion of amiloride significantly prolonged ICI in DS + HS group, while no intra-group difference in ICI was observed in DR + HS group. No intra- or inter-group differences in maximum intravesical pressure were observed. Protein expression levels of ENaCα in the bladder were significantly higher in DS + HS group than in DR + HS group. ENaCα protein was localized at bladder epithelium in both groups. In conclusion, high salt intake is considered to cause urinary storage dysfunction via upregulation of ENaC in the bladder epithelium with salt-sensitive hypertension, suggesting that ENaC might be a candidate for therapeutic target for urinary storage dysfunction.

Costal cartilage graft with perichondrium, a possible anti-adhesive material.

BACKGROUND: Adhesion occurs as a part of the wound healing process, but it sometimes compromises patients' daily activities. The authors were looking for materials and methods that could prevent adhesion, and noticed that the costal cartilage has possibility. The anti-adhesive property of the costal cartilage was examined histologically. METHODS: Thirty-five patients with microtia who provided consent for participating in this study were enrolled between April 2008 and March 2015. In the first stage of microtia reconstruction surgery, the excess cartilage was used to create these three types of specimens: (A) a piece of cartilage retaining the perichondrium on one side, (B) a piece of only cartilage parenchyma sliced with a plane parallel to the long axis of costal cartilage, and (C) the costal cartilage in a plane perpendicular to the long axis sliced pieces. These specimens were implanted into the subcutaneous fat of the chest. After at least 6 months in the second stage of surgery (i.e. auricular elevation), these specimens, wearing a little around the adipose tissue, we removed and examined histologically. RESULT: A fibrosis formation of the perichondrium side of Specimen A was thicker significantly than that of the cartilage side. A fibrosis formation of Specimen B was thicker significantly than that of the cartilage side of Specimen A. CONCLUSION: It was suggested that, if there is perichondrium, the costal cartilage parenchyma surface makes less adhesion with surrounding tissues. Costal cartilage with unilateral perichondrium is likely to be an effective surgical material for adhesion prevention.

Mineralocorticoid receptor stimulation induces urinary storage dysfunction via upregulation of epithelial sodium channel expression in the rat urinary bladder epithelium.

We aimed to evaluate mineralocorticoid receptor (MR) expression in rat bladder and the physiological role of the MR-epithelial sodium channel (ENaC) pathway in controlling bladder function in 10-12-week-old, male Sprague-Dawley rats. First, we examined the mRNA expression of MR and localization of MR and ENaC-α proteins in the urinary bladder. MR mRNA expression was observed in untreated-rat urinary bladders, and MR and ENaC-α proteins were localized in the epithelium. Next, rats were treated with vehicle (controls) or fludrocortisone (an MR agonist) for 3 days, and ENaC-α protein expression levels and bladder function were evaluated on day 4. ENaC-α protein expression was significantly higher in fludrocortisone-treated rats than in controls. In addition, cystometry was performed during intravesical infusion of saline and amiloride (an ENaC inhibitor). While intercontraction intervals (ICIs) during saline infusion were significantly shorter in the fludrocortisone group than in the controls, infusion of amiloride normalized the ICIs in the fludrocortisone group. However, no intra- or inter-group differences in maximum intravesical pressure were observed. Taken together, MR protein is localized in the rat urinary bladder epithelium, and may regulate ENaC expression and bladder afferent input. The MR-ENaC pathway may be a therapeutic target for ameliorating storage symptoms.

Laparoscopic Versus Open Radical Cystectomy for Patients Older than 75 Years: a Single-Center Comparative Analysis.

BACKGROUND: To explore the safety, efficacy, and oncological outcome of 3-port laparoscopic radical cystectomy (LRC) compared to open radical cystectomy (ORC) in patients older than 75 years. MATERIALS AND METHODS: From June 2010 to July 2014, we analyzed 16 radical cystectomies in patients older than 75 years (LRC group=8; ORC group=8). Demographic parameters, operative variables, and perioperative outcome in the 2 groups were retrospectively collected, analyzed, and compared. RESULTS: Patients in both groups had comparable preoperative characteristics. A significantly longer operating time (476 vs. 303 min, P=0.0002) and less estimated blood loss (627 vs. 2,106 mL, P=0.021) were observed in the LRC group compared to the ORC group. Infection and ileus were the most common early complications after surgery. Patients who underwent ORC suffered from more postoperative infection (22.2% vs. 0.0%, P=0.054) and ileus (25.0% vs. 12.5%, P=0.521) than the LRC group, but the difference was not significant. CONCLUSIONS: Judging from this initial trial, 3-port LRC can be safely carried out in elderly patients. We suggest 3-port LRC as the primary intervention to treat muscle-invasive or high-risk nonmuscle-invasive bladder cancer in elderly patients with an otherwise relatively long life expectancy.

Neuroendocrine Carcinoma of the Kidney and Bladder with Loss of Heterozygosity and Changes in Chromosome 3 Copy Number.

BACKGROUND: Neuroendocrine carcinomas (NECs) of the urological organs are observed occasionally, although simultaneous development in the kidney and blabber has not been reported. CASE REPORT: We report a case of a metastatic NEC of the kidney and bladder in a 77-year-old woman who underwent renal biopsy and transurethral resection of the bladder tumor. Pathological examination revealed NEC in the kidney and the bladder samples. Immunohistochemical examination revealed strongly positive staining for synaptophysin, chromogranin A, and CD56, and focally positive staining for cytokeratin AE 1/3 and Cam 5.2. Fluorescence in situ hybridization confirmed the increased chromosome 3 copy number, and loss of hybridization in 3q21, 5q22-23, 10q26, and 13q14 was detected when the tumor samples were compared with normal samples. CONCLUSIONS: This is a rare case of NEC-specific genetic abnormalities in a kidney-derived tumor, and is the first report to identify kidney-derived NEC that metastasized to the bladder via the urinary tract.

Alterations of the blood-spinal cord barrier in sporadic amyotrophic lateral sclerosis.

The blood-spinal cord barrier (BSCB) of the spinal cord capillary consists of non-fenestrated endothelial cells with tight junctions, basal laminae, pericytes and astrocyte feet processes, referred to as a "neurovascular unit." The primary function of the BSCB is the maintenance and control of homeostasis of the spinal cord parenchyma by the selective transport of molecules and cells from the systemic compartment. Dysfunction of the BSCB shows important function in the etiology or progression of several pathological conditions of the spinal cord, including amyotrophic lateral sclerosis (ALS). However, the role of BSCB in the pathogenesis of ALS is still unclear. Here the changes of BSCB in sporadic ALS patients were studied by electron microscopy to determine whether the BSCB is disrupted and involved in the pathogenesis of motor neuron degeneration. A total of 358 and 366 cross-sectioned capillaries were quantitatively examined in controls and ALS patients, respectively. The frequency of degenerated endothelia and pericytes, vacuolar changes of the cytoplasm in the endothelia and pericytes, and the replication of basement membranes was significantly higher in ALS patients than in the controls (P = 0.0175). The areas of the capillaries with diameters of ≤ 5 µm in the ALS patients were significantly smaller than those in the controls (P = 0.0124). The frequency of collagen fiber content of more than a moderate degree around the perivascular space was significantly higher in the ALS patients compared to the controls (P = 0.048), although there was no significant difference in the mild degree of accumulation of collagen fibers. Thus, the BSCB may be disrupted in sporadic ALS patients due to increased permeability and reduced microcirculation, leading to motor neuron degeneration and to the progression of the disease.

Flail arm syndrome with cytoplasmic vacuoles in remaining anterior horn motor neurons: A peculiar variant of amyotrophic lateral sclerosis.

Flail arm (FA) syndrome, a minor subtype of amyotrophic lateral sclerosis (ALS), is characterized by progressive weakness and upper girdle wasting, but the associated pathological changes remain unclear. A 59-year-old man was admitted to our hospital with a 3-year history of upper girdle weakness. Bulbar symptom and gait disturbance gradually developed, and he was clinically diagnosed with FA syndrome. After a 10-year disease course, he died of pulmonary adenocarcinoma. Neuropathological examination revealed severe motor neuronal loss in the brain stem and anterior horn of the cervical spinal cord with bilateral pyramidal tract degeneration. The histological findings were consistent with typical ALS, including Bunina bodies and Lewy body-like and skein-like inclusions. Cytoplasmic vacuoles were found in the remaining anterior horn motor neurons of the lumbar spinal cord. This is a unique autopsy case with a long-standing clinical course that suggests that FA syndrome is an atypical form of ALS.

Sporadic lower motor neuron disease with a snake eyes appearance on the cervical anterior horns by MRI.

OBJECTIVE: Lower motor neuron disease (LMND) is the term generally used to describe diseases in which only lower motor neuron signs are detected. A snake eyes appearance on magnetic resonance imaging (MRI) is associated with a wide spectrum of neurological conditions including LMND. The author reports on three unique LMND patients with upper limb muscle weakness and atrophy who show a snake eyes appearance by MRI. PATIENTS AND METHODS: The patients were aged 18, 40 and 52 years, respectively, at the onset of the disease and had a longstanding clinical course (more than 10 years for two patients and 8 years for one patient). They were followed up for more than 6 years. RESULTS: Clinical manifestations were characterized by (1) longstanding slow progression or delayed spontaneous arrest of asymmetric lower motor neuron signs localized exclusively in the upper extremities with unilateral predominance and distal or proximal preponderance; (2) the absence of upper motor neuron signs, bulbar signs, sensory disturbances and respiratory involvement; (3) a snake eyes appearance on the anterior horns of the cervical cord over more than 3 vertebrae by axial T2-weighted MRI and a longitudinal linear-shaped T2-signal hyperintensity by sagittal MRI; (4) neurogenic change with fasciculation and denervation potentials (fibrillation and a positive sharp wave) confined to the affected muscles by needle electromyogram; and (5) normal cerebrospinal fluid and a normal creatine kinase level. These cases did not fall into any existing category of LMND, such as progressive muscular atrophy, flail arm syndrome or Hirayama disease. CONCLUSIONS: These patients should be classified as sporadic LMND with snake eyes on MRI with a relatively benign prognosis.

Successful Combination Therapy with Rituximab and Glucocorticoids for Autoimmune Optic Neuropathy.

BACKGROUND: Autoimmune optic neuropathy is optic neuropathy caused by an autoimmune mechanism. As treatment, steroid is usually used. If steroid is ineffective to improve visual function, other immunosuppressive agents are used as needed. Rituximab is one of molecular target agents and is now used as treatment for several types of autoimmune disorders. CASE REPORT: A 77-year-old woman presented with vision loss in her left eye. Her past medical history included disturbances of multiple organs. Laboratory tests revealed positive myeloperoxidase-anti-neutrophil cytoplasmic antibody. We assumed that her vision loss was caused by autoimmune optic neuropathy and put her on high-dose glucocorticoid therapy. Her visual function quickly re-deteriorated after high-dose glucocorticoid therapy discontinuation. To achieve vision improvement, we added rituximab to her treatment regimen. Her visual acuity recovered to almost 20/20 within a week later. She received other 3 rituximab-infusions and her visual acuity remained 20/20 while tapering glucocorticoid. CONCLUSIONS: Autoimmune optic neuropathy may result in blindness if treatment fails. Rituximab may be a therapeutic option for autoimmune optic neuropathy and may produce immediate response.

Alterations in the blood-spinal cord barrier in TDP-43 conditional knockout mice.

We investigated whether the loss of motor neuron-specific TDP-43 protein causes any change in the blood-spinal cord barrier (BSCB) in the spinal cord of TDP-43 conditional knockout (TDP CKO) mice. The TDP CKO mice were divided into four groups: early presymptomatic, late presymptomatic, early symptomatic, and late symptomatic stages. The spinal cords were pathologically examined. TDP CKO mice showed the activation of MAC-2 (macrophages/microglia) and fibrinogen exclusively in the anterior horn from the early symptomatic through the late symptomatic stages. Immunohistochemical and western blot analyses detected no reduction in tight junction proteins in TDP CKO mice as compared to age-matched wild-type mice at any stage. Electron-microscopically, TDP CKO mice showed vacuoles in the cytoplasm of most endothelial cells at the early symptomatic stage. The endothelium occasionally exhibited swollen cytoplasm by edematous fluid with the intact tight junction. The cytoplasm of the pericytes was relatively well preserved in contrast to the endothelial disruption. Extravascular or perivascular spaces were frequently edematous and vacuolated. At other stages, the BSCB was well preserved as in the controls. Thus, the temporary and reversible breakdown of the BSCB with leakage or increased permeability at the early symptomatic stage observed in this study could be a direct pathogenic consequence of the loss of TDP-43 protein, and the temporal impairment of BSCB, in turn, might contribute to the motor neuron degeneration in TDP CKO mice.