Common Early Feature Research Articles

New evidence of vascular defects in neurodegenerative diseases revealed by single cell RNA sequencing.

Neurodegenerative diseases (NDs) involve the progressive loss of neuronal structure or function in the brain and spinal cord. Despite their diverse etiologies, NDs manifest similar pathologies. Emerging research identifies vascular defects as a previously neglected hallmark of NDs. The development and popularization of single-cell RNA sequencing (scRNA-seq) technologies have significantly advanced our understanding of brain vascular cell types and their molecular characteristics, including gene expression changes at the single-cell level in NDs. These unprecedented insights deepen our understanding of the pathogenic mechanisms underlying NDs. However, the occurrence and role of vascular defects in disease progression remain largely unexplored. In this paper, we systematically summarize recent advances in the structure and organization of the central nervous system vasculature in mice, healthy individuals, and patients with NDs, focussing primarily on disease-specific alterations in vascular cell types or subtypes. Combining scRNA-seq with pathology evidence, we propose that vascular defects, characterized by disruptions in cell types and structural integrity, may serve as common early features of NDs. Finally, we discuss several pathways through which vascular defects in NDs lead to neuronal degeneration. A deeper understanding of the causes and contributions of vascular defects to NDs aids in elucidating the pathogenic mechanisms and developing meaningful therapeutic interventions.

Aquaporin-4 mis-localization slows glymphatic clearance of α-synuclein and promotes α-synuclein pathology and aggregate propagation.

The appearance of misfolded and aggregated proteins is a pathological hallmark of numerous neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. Sleep disruption is proposed to contribute to these pathological processes and is a common early feature among neurodegenerative disorders. Synucleinopathies are a subclass of neurodegenerative conditions defined by the presence of α-synuclein aggregates, which may not only enhance cell death, but also contribute to disease progression by seeding the formation of additional aggregates in neighboring cells. The mechanisms driving intercellular transmission of aggregates remains unclear. We propose that disruption of sleep-active glymphatic function, caused by loss of precise perivascular AQP4 localization, inhibits α-synuclein clearance and facilitates α-synuclein propagation and seeding. We examined human post-mortem frontal cortex and found that neocortical α-synuclein pathology was associated with AQP4 mis-localization throughout the gray matter. Using a transgenic mouse model lacking the adapter protein α-syntrophin, we observed that loss of perivascular AQP4 localization impairs the glymphatic clearance of α-synuclein from intersititial to cerebrospinal fluid. Using a mouse model of α-synuclein propogation, using pre-formed fibril injection, we observed that loss of perivascular AQP4 localization increased α-synuclein aggregates. Our results indicate α-synuclein clearance and propagation are mediated by glymphatic function and that AQP4 mis-localization observed in the presence of human synucleinopathy may contribute to the development and propagation of Lewy body pathology in conditions such as Lewy Body Dementia and Parkinson's disease.

Lyme Arthritis: A 50-Year Journey.

Lyme arthritis (LA) was recognized as a separate entity in 1975 because of geographic clustering of children often diagnosed with juvenile rheumatoid arthritis in Lyme, Connecticut. After identification of erythema migrans as a common early feature of the illness, a prospective study of such patients implicated Ixodes scapularis ticks in disease transmission. In 1982, the causative agent, now called Borrelia burgdorferi, was cultured from these ticks and from Lyme disease patients. Subsequently, it was shown that LA could usually be treated successfully with oral antibiotics but sometimes required intravenous antibiotics. Yet, a small percentage of patients developed a dysregulated, proinflammatory immune response leading to persistent postinfectious synovitis with vascular damage, cytotoxic and autoimmune responses, and fibroblast proliferation, a lesion similar to that of rheumatoid arthritis. The message from postinfectious LA for other autoimmune arthritides is that a complex immune response with autoimmune features can begin with a microbial infection.

Blood β-Synuclein and Neurofilament Light Chain During the Course of Prion Disease.

For early diagnosis and disease monitoring of neurodegenerative diseases (NDs), reliable blood biomarkers are needed. Elevated levels of neurofilament light chain protein (NfL), an axonal damage marker, have been described across different NDs, with highest values in prion diseases and amyotrophic lateral sclerosis (ALS). Synaptic degeneration is a common early feature in most NDs and seems to precede neuronal degeneration in prion disease. However, synaptic markers in blood are still missing. Here, we investigated whether the brain-specific protein β-synuclein might be a suitable blood biomarker for early diagnosis and evaluation of synaptic integrity in prion disease. We analyzed blood β-synuclein with a newly established digital ELISA and NfL with a single-molecule array in samples obtained from human participants and prion and ALS animal models. Furthermore, β-synuclein was investigated in brain tissue of individuals with Creutzfeldt-Jakob disease (CJD) and controls. We investigated 308 patients, including 129 cases with prion disease, 8 presymptomatic PRNP variation carriers, 60 with ALS, 68 with other ND, and 43 control patients. In CJD symptomatic cases, β-synuclein and NfL were markedly increased compared to all other diagnostic groups (p < 0.001). In the large majority of presymptomatic PRNP variation carriers, β-synuclein and NfL levels were within normal ranges. In prion disease animal models, β-synuclein and NfL displayed normal levels in the presymptomatic phase with a sudden elevation at disease onset and a plateau in the symptomatic phase. In contrast to NfL, β-synuclein was not elevated in either symptomatic patients with ALS or an ALS animal model. In the discrimination between prion disease and all other groups, β-synuclein (area under the curve 0.97, 95% CI 0.94-0.99, p < 0.001) was superior to NfL (area under the curve 0.91, 95% CI 0.88-0.94, p < 0.001). In addition, brain tissue β-synuclein showed significantly reduced levels in patients with CJD compared to control patients (p < 0.001). Blood β-synuclein was significantly elevated in patients with CJD, reflecting ongoing synaptic damage, and showed good discriminative characteristics. We therefore propose it as a candidate blood marker for early diagnosis and monitoring of synaptic integrity in prion disease. This study provides Class III evidence that serum β-synuclein concentration accurately distinguishes patients with symptomatic CJD from controls.

The potential utility of smell testing to screen for neurodegenerative disorders

ABSTRACT Introduction Loss of smell is a common early feature of neurodegenerative diseases including Alzheimer’s and Parkinson’s disease. Identifying these conditions in their early stages is important to understand more about early pathophysiological events and the development of disease modifying therapies. Smell testing may be an effective future tool for screening large populations for early neurodegeneration. Areas Covered In this review, we appraise the evidence for, and discuss the likelihood of, the use of smell testing in large screening programs to detect early neurodegeneration. We evaluate the predictive power of smell tests for neurodegenerative disease, compare performance to other established screening programs, and discuss ethical and practical considerations and limitations. Expert Opinion Even if disease modifying therapies were available for neurodegenerative disease, smell tests alone are unlikely to have high enough predictive power to be used in a future screening program. However, we believe they could be a valuable component of a short battery of tests or part of a stepwise process that together could more accurately identify early neurodegeneration in large populations.

Performance on the graded naming test in a population‐based sample of 72‐year‐olds: Associations with life‐course predictors and β‐amyloid pathology

AbstractBackgroundWord‐finding difficulties are a common early feature of Alzheimer’s disease (AD) and may be detectable during the preclinical stage. However, the relationship between changes in naming ability and accumulation of β‐amyloid pathology is not fully understood, and questions remain about the role of factors such as sex and education.MethodParticipants in Insight 46, a sub‐study of the British 1946 birth cohort, completed baseline cognitive assessments and neuroimaging (combined MRI/18F‐Florbetapir‐PET) at age 69‐71. Follow‐up assessments are currently underway (mean interval 28.9 months, SD 2.1) and include an audio‐recorded version of the 30‐item Graded Naming Test (GNT), which was not administered at baseline. Preliminary interim analyses have been conducted based on 211 cognitively‐normal individuals with complete neuroimaging data (see Table 1 for characteristics). A multivariable regression model was used to investigate predictors of picture naming accuracy, where the outcome was GNT score (max. 30) and predictors were sex, age at follow‐up assessment, β‐amyloid status at baseline (positive / negative), APOE genotype (ε4 carrier/non‐carrier), and prospectively‐collected measures of childhood cognitive ability, education and socioeconomic position (based on occupation). Due to the negatively‐skewed distribution of GNT scores, bootstrapping was used to produce bias‐corrected and accelerated 95% confidence intervals from 2,000 replications.Results will be updated to include the full sample before the conference. We also plan to include data on naming latency extracted from the audio‐recordings, which may be a more sensitive measure of early changes than naming accuracy.ResultHigher childhood cognitive ability predicted higher GNT scores over 60 years later (Table 2, Figure 1). Men scored 0.9 points higher than women on average. Amyloid‐positive participants scored 1.2 points lower than amyloid‐negative participants on average. These effects were all significant at the 5% level and were mutually independent.ConclusionSubtle changes in naming accuracy associated with β‐amyloid pathology are detectable in cognitively‐normal individuals as early as age 72. Performance is additionally influenced by sex and general cognitive ability, so these factors should be accounted for where possible in future studies and clinical trials that seek to detect and track the emergence of naming deficits.

Dysregulated liver lipid metabolism and innate immunity associated with hepatic steatosis in neonatal BBdp rats and NOD mice

In a previous study we reported that prediabetic rats have a unique gene signature that was apparent even in neonates. Several of the changes we observed, including enhanced expression of pro-inflammatory genes and dysregulated UPR and metabolism genes were first observed in the liver followed by the pancreas. In the present study we investigated further early changes in hepatic innate immunity and metabolism in two models of type 1 diabetes (T1D), the BBdp rat and NOD mouse. There was a striking increase in lipid deposits in liver, particularly in neonatal BBdp rats, with a less striking but significant increase in neonatal NOD mice in association with dysregulated expression of lipid metabolism genes. This was associated with a decreased number of extramedullary hematopoietic clusters as well as CD68+ macrophages in the liver of both models. In addition, PPARɣ and phosphorylated AMPKα protein were decreased in neonatal BBdp rats. BBdp rats displayed decreased expression of antimicrobial genes in neonates and decreased M2 genes at 30 days. This suggests hepatic steatosis could be a common early feature in development of T1D that impacts metabolic homeostasis and tolerogenic phenotype in the prediabetic liver.

Automated retinal layer segmentation in OCT images of age‐related macular degeneration

Age-related macular degeneration (AMD) is a common eye disease that causes progressive degeneration of the central vision. The presence of abundant drusen is a common early feature of AMD. Optical coherence tomography (OCT) can provide detailed structure information on drusen. The physiological structure of the retinal epithelium and drusen complex (RPEDC) and the Bruch's membrane (BM) layer boundaries will be influenced by the presence of drusen with AMD. Therefore, drusen quantification is important to diagnose and cure AMD. The authors proposed an automatic method to segment the inner limiting membrane, the retinal pigment epithelium and drusen complex (RPEDC) and BM layer boundaries from OCT images with AMD (termed as deep forest for layer segmentation (DF-LS)). In their method, image patches are extracted and used to train a deep-forest model to predict three boundary probability maps. In addition, they modify grapy theory and dynamic programming method to find the layer boundary. Finally, the layer boundary is smoothed by using a smoothing operation. The proposed DF-LS method is evaluated on three publicly available datasets (one healthy dataset and two AMD dataset). The proposed DF-LS method can yield superior mean unsigned error with an average error of 0.81 pixel on Tian et al.'s dataset, and 1.35, 1.23 pixel on Chiu et al.'s and Farisu et al.'s dataset, respectively.

Isolated seizures are a common early feature of paraneoplastic anti-GABAB receptor encephalitis.

To report the clinical features and long-term outcome of 22 newly diagnosed paraneoplastic patients with GABAB receptor antibodies (GABABR-Abs). Retrospective clinical study of CSF-confirmed cases of GABABR-Abs encephalitis. We identified 22 patients (4 female) with GABABR-Abs, with a median age of 64years (range 55-85). All were paraneoplastic: 20 small-cell lung cancer, one malignant thymoma, and one uncharacterized lung mass. The most frequent first symptom was the isolated recurrent seizures without cognitive inter-ictal impairment in 17 patients (77%). In the other, three presented the first behavioral disorders and two presented de novo status epilepticus (SE). After a median delay of 10days (range 1-30), the recurrent seizures' phase was followed by an encephalitic phase characterized by confusion in 100% of cases and SE in 81% (n = 17), with 53% (n = 9) non-convulsive SE. Dysautonomic episodes were frequent (36%, n = 8, bradycardia and central apnea) and killed three patients. CSF study was abnormal in 95% of the cases (n = 21). At the encephalitic phase, MRI showed a temporal FLAIR hypersignal in 73% (n = 16) of the cases. First-line immunotherapy was initiated after a median delay of 26days (range 6-65) from disease onset, and a partial response was observed in 10 out of 20 patients (50%). There was no complete response. Two years after onset, a massive anterograde amnesia affected all still alive patients. Nine patients died from cancer progression (median survival: 1.2years). Paraneoplastic GABABR-Abs encephalitis is characterized by a stereotype presentation with an epilepsy phase before an encephalitic phase with dysautonomia. The functional prognosis is poor.

Microglia control the glycinergic but not the GABAergic synapses via prostaglandin E2 in the spinal cord.

Microglia control excitatory synapses, but their role in inhibitory neurotransmission has been less well characterized. Herein, we show that microglia control the strength of glycinergic but not GABAergic synapses via modulation of the diffusion dynamics and synaptic trapping of glycine (GlyR) but not GABAA receptors. We further demonstrate that microglia regulate the activity-dependent plasticity of glycinergic synapses by tuning the GlyR diffusion trap. This microglia-synapse cross talk requires production of prostaglandin E2 by microglia, leading to the activation of neuronal EP2 receptors and cyclic adenosine monophosphate-dependent protein kinase. Thus, we now provide a link between microglial activation and synaptic dysfunctions, which are common early features of many brain diseases.

(Con)text-specific effects of visual dysfunction on reading in posterior cortical atrophy

Reading deficits are a common early feature of the degenerative syndrome posterior cortical atrophy (PCA) but are poorly understood even at the single word level. The current study evaluated the reading accuracy and speed of 26 PCA patients, 17 typical Alzheimer's disease (tAD) patients and 14 healthy controls on a corpus of 192 single words in which the following perceptual properties were manipulated systematically: inter-letter spacing, font size, length, font type, case and confusability. PCA reading was significantly less accurate and slower than tAD patients and controls, with performance significantly adversely affected by increased letter spacing, size, length and font (cursive < non-cursive), and characterised by visual errors (69% of all error responses). By contrast, tAD and control accuracy rates were at or near ceiling, letter spacing was the only perceptual factor to influence reading speed in the same direction as controls, and, in contrast to PCA patients, control reading was faster for larger font sizes. The inverse size effect in PCA (less accurate reading of large than small font size print) was associated with lower grey matter volume in the right superior parietal lobule. Reading accuracy was associated with impairments of early visual (especially crowding), visuoperceptual and visuospatial processes. However, these deficits were not causally related to a universal impairment of reading as some patients showed preserved reading for small, unspaced words despite grave visual deficits. Rather, the impact of specific types of visual dysfunction on reading was found to be (con)text specific, being particularly evident for large, spaced, lengthy words. These findings improve the characterisation of dyslexia in PCA, shed light on the causative and associative factors, and provide clear direction for the development of reading aids and strategies to maximise and sustain reading ability in the early stages of disease.

There is more than imitation

Reading deficits are a common early feature of the degenerative syndrome posterior cortical atrophy (PCA) but are poorly understood even at the single word level. The current study evaluated the reading accuracy and speed of 26 PCA patients, 17 typical Alzheimer's disease (tAD) patients and 14 healthy controls on a corpus of 192 single words in which the following perceptual properties were manipulated systematically: inter-letter spacing, font size, length, font type, case and confusability. PCA reading was significantly less accurate and slower than tAD patients and controls, with performance significantly adversely affected by increased letter spacing, size, length and font (cursive < non-cursive), and characterised by visual errors (69% of all error responses). By contrast, tAD and control accuracy rates were at or near ceiling, letter spacing was the only perceptual factor to influence reading speed in the same direction as controls, and, in contrast to PCA patients, control reading was faster for larger font sizes. The inverse size effect in PCA (less accurate reading of large than small font size print) was associated with lower grey matter volume in the right superior parietal lobule. Reading accuracy was associated with impairments of early visual (especially crowding), visuoperceptual and visuospatial processes. However, these deficits were not causally related to a universal impairment of reading as some patients showed preserved reading for small, unspaced words despite grave visual deficits. Rather, the impact of specific types of visual dysfunction on reading was found to be (con)text specific, being particularly evident for large, spaced, lengthy words. These findings improve the characterisation of dyslexia in PCA, shed light on the causative and associative factors, and provide clear direction for the development of reading aids and strategies to maximise and sustain reading ability in the early stages of disease.

Longitudinal analysis of the electroencephalogram and sleep phenotype in the R6/2 mouse model of Huntington’s disease

Deficits in sleep and circadian organization have been identified as common early features in patients with Huntington's disease that correlate with symptom severity and may be instrumental in disease progression. Studies in Huntington's disease gene carriers suggest that alterations in the electroencephalogram may reflect underlying neuronal dysfunction that is present in the premanifest stage. We conducted a longitudinal characterization of sleep/wake and electroencephalographic activity in the R6/2 mouse model of Huntington's disease to determine whether analogous electroencephalographic 'signatures' could be identified early in disease progression. R6/2 and wild-type mice were implanted for electroencephalographic recordings along with telemetry for the continuous recording of activity and body temperature. Diurnal patterns of activity and core body temperature were progressively disrupted in R6/2 mice, with a large reduction in the amplitude of these rhythms apparent by 13 weeks of age. The diurnal variation in sleep/wake states was gradually attenuated as sleep became more fragmented and total sleep time was reduced relative to wild-type mice. These genotypic differences were augmented at 17 weeks and evident across the entire 24-h period. Quantitative electroencephalogram analysis revealed anomalous increases in high beta and gamma activity (25-60 Hz) in all sleep/wake states in R6/2 mice, along with increases in theta activity during both non-rapid eye movement and rapid eye movement sleep and a reduction of delta power in non-rapid eye movement sleep. These dramatic alterations in quantitative electroencephalographic measures were apparent from our earliest recording (9 weeks), before any major differences in diurnal physiology or sleep/wake behaviour occurred. In addition, the homeostatic response to sleep deprivation was greatly attenuated with disease progression. These findings demonstrate the sensitivity of quantitative electroencephalographic analysis to identify early pathophysiological alterations in the R6/2 model of Huntington's disease and suggest longitudinal studies in other preclinical Huntington's disease models are needed to determine the generality of these observations as a potential adjunct in therapeutic development.

From the Radiologic Pathology Archives: Cardiac Lymphoma: Radiologic-Pathologic Correlation

Lymphoma of the heart and pericardium is usually present as one aspect of disseminated disease and rarely occurs as a primary malignancy. It accounts for 1.3% of primary cardiac tumors and 0.5% of extranodal lymphomas. Cardiac lymphomas are most commonly diffuse large cell lymphomas and frequently manifest as an ill-defined, infiltrative mass. Atrial location is typical; the right atrium is most often affected. Pericardial thickening or effusion is often a common early feature of disease. Infiltration of atrial or ventricular walls with extension along epicardial surfaces is also a notable feature. At computed tomography, the attenuation of cardiac lymphoma may be similar to or lower than that of normal myocardium. At magnetic resonance imaging, it has variable signal intensity and contrast enhancement. Clinical manifestations may include pericardial effusion, cardiac arrhythmias, and a variety of nonspecific electrocardiographic abnormalities, notably first- to third-degree atrioventricular block. Treatment most commonly includes anthracycline-based chemotherapy and anti-CD20 treatment. Chemotherapy has been used alone or combined with radiation therapy. Palliative surgery has been performed, mainly for tumor debulking. The prognosis for patients with either primary or secondary lymphomatous heart involvement is usually poor; late diagnosis is one of the major factors affecting outcome.

Asymptomatic Sleep Abnormalities Are a Common Early Feature in Patients with Huntington’s Disease

Huntington's disease (HD) is a fatal neurodegenerative disease characterized by motor, cognitive, and psychiatric disturbance. In this article, we used polysomnography, actigraphy and a variety of validated questionnaires to ascertain the extent to which sleep changes are identifiable and measurable in mild stage HD, and importantly, to see whether patients are negatively impacted by the changes in their sleep. We found significant differences in sleep architecture and sleep efficiency in patients compared with controls using polysomnography. However, patient scores on the Functional Outcomes of Sleep Questionnaire, Medical Outcomes of Sleep Scale, and Epworth Sleepiness Scale were not significantly different to controls. These results suggest that although marked changes in sleep architecture are present in early HD and can be detected using polysomnography, patients do not necessarily recognize or report these abnormalities.

Caspase-independent apoptosis in Friend’s erythroleukemia cells: role of mitochondrial ATP synthesis impairment in relocation of apoptosis-inducing factor and endonuclease G

Mitochondria have emerged as the central components of both caspase-dependent and independent apoptosis signalling pathways through release of different apoptogenic proteins. We previously documented that parental and differentiated Friend's erythroleukemia cells were induced to apoptosis by oligomycin and H(2)O(2) exposure, showing that the energy impairment occurring in both cases as a consequence of a severe mitochondrial F(0)F(1)ATPsynthase inactivation was a common early feature. Here we provide evidence for AIF and Endo G mitochondrio-nuclear relocation in both cases, as a component of caspase-independent apoptosis pathways. No detectable change in mitochondrial transmembrane potential and no variation in mitochondrial levels of Bcl-2 and Bax are observed. These results point to the osmotic rupture of the mitochondrial outer membrane as occurring in response to cell exposure to the two energy-impairing treatments under conditions preserving the mitochondrial inner membrane. A critical role of the mitochondrial F(0)F(1)ATP synthase inhibition in this process is also suggested.

FTY720 prevents renal T-cell infiltration after ischemia/reperfusion injury

Ischemia/reperfusion (I/R) injury, a common early feature in renal transplantation, results from both free radical species generation and local inflammatory responses that attract different types of cells. The interaction with infiltrating leukocytes could promote damage and death of resident renal cells contributing to worsening of renal function. It has been shown that depletion of host T cells protects against kidney damage after I/R injury, although the mechanism is not fully understood. FTY720, a synthetic analog of a natural product extracted from Isaria sincclairii has shown modulatory properties in experimental models of autoimmune disease, transplantation, and I/R injury. FTY720 alters lymphocyte responses to chemokine homing signals, thereby decreasing the number of lymphocytes in inflammatory sites. We evaluated renal function in mice at 3, 5, and 7 days after I/R injury in the presence or absence of FTY720 treatment. FTY720 treatment promoted earlier recovery of renal function associated with a lower number of renal-infiltrating lymphocytes. These findings confirm previous results showing a protective effect of FTY720 in I/R injury models.

Lymphatic Vessel Density and Vascular Endothelial Growth Factor-C Expression Correlate with Malignant Behavior in Human Pancreatic Endocrine Tumors

Metastatic dissemination of tumor cells to regional lymph nodes is a common early feature of many human cancers including pancreatic adenocarcinoma. In contrast, lymph node metastasis is more variably observed in pancreatic endocrine tumors. The objective of this study was to assess the lymphatic system of human pancreatic endocrine tumors and correlate this to clinical behavior. Immunohistochemistry was performed using antibodies to two recently identified markers of lymphatic endothelium, namely, LYVE-1 and podoplanin, and to the lymphangiogenic factor vascular endothelial growth factor (VEGF)-C. As has been reported previously, we observed that in the normal pancreas, islets of Langerhans are devoid of intra-islet lymphatics, but that lymphatics are present in connective tissue in association with ducts and blood vessels. We found that both benign and malignant pancreatic endocrine tumors contain intratumoral lymphatic vessels. Lymphatic vessel density was related to the size of the tumor in benign tumors and to the presence of liver metastasis but not to lymph node metastasis in malignant tumors. VEGF-C was expressed in tumor cells: 4 of 19 (21%) benign tumors were positive, whereas 6 of 9 (67%) borderline tumors and 9 of 11 (82%) carcinomas were positive. These findings strongly suggest that lymphangiogenesis occurs in pancreatic endocrine tumors and that lymphatic invasion and the development of metastases are associated with VEGF-C expression.

FTY720 impairs necrosis development after ischemia-reperfusion injury

Ischemia-reperfusion (IR) injury is a common early feature that contributes to graft damage by impairing resident cell function. Our previous results showed that IR injury impaired renal function, by causing extensive tubular necrosis and increasing MHC class II and ICAM-1 molecule expression by mesangial cells (MC). MCs are likely candidates to come into close contact with immune cells such as monocytes or lymphocytes. It has been suggested that under inflammatory circumstances, there is increased MC expression of MHC class II, of adhesion molecules (such as ICAM-1), of cytokines receptors, and of molecules associated with cellular death (apoptosis). The immunosuppressive properties of FTY720 have been shown in clinical and experimental situations. It has also been shown to be protective against IR injury in rats. We sought to evaluate the role of FTY720 in a murine IR model by measuring renal function, tubular necrosis, and surface molecule expression by cultured mesangial cells. Intravenous administration of FTY720 (1 mg/kg) immediately before IR induction did not improve the short-term (24 hours) outcome of renal function or reduced MHC class II and ICAM-1 surface molecule expression. However, there was a decreased percentage of tubular necrosis in mice treated with FTY720 (51.3% ± 1.6%) compared with vehicle-treated mice (66% ± 5.5%). These results suggest a protective role of FTY720 in an IR injury model. More studies are required to identify the mechanisms involved in the protective activity of FTY720 in the IR injury model.

Genetics of movement disorders and ataxia

Genetic disorders of the central nervous system have a propensity to cause movement disorders or ataxia, as a part of the phenotype, or sometimes as the main phenotypic manifestation. The...