Presence of Endogenous PACAP-38 Ameliorated Intestinal Cold Preservation Tissue Injury

Cold preservation tissue injury remains an unsolved problem during small intestinal transplantation. Pituitary adenylate cyclase-activating polypeptide (PACAP) plays a central role in the intestinal physiology. The aim of our study was to compare the cold ischemic injury in wild-type and PACAP-38 deficient mice after small bowel cold storage. Cold ischemia was produced with small bowel preservation in a University of Wisconsin solution at 4°C in wild-type (n = 35) mice for 1 h (GI), for 3 h (GII), and for 6 h (GIII); and in PACAP-38 deficient (n = 35) mice for 1 h (GIV), for 3 h (GV), and for 6 h (GVI). Small bowel biopsies were collected after laparotomy (Control) and at the end of the ischemia periods. To determine oxidative stress parameters, malondialdehyde (MDA), reduced glutathione (GSH), and superoxide dismutase (SOD) were measured. Tissue damage was analyzed by qualitative and quantitative methods on hematoxylin/eosin-stained sections. In PACAP-38 deficient animals, tissue lipid peroxidation was elevated. These changes were significant after 6 h (153.04 ± 7.2) compared to sham-operated (110.44 ± 5.5) and compared to wild-type results (120.0 ± 1.1 μmol/g, p < 0.05). Meanwhile, the capacity and activity of the endogenous antioxidant system decreased significantly after 3 and 6 h preservation (GSH: 808.7 ± 5.2; 720.4 ± 8.7 vs. 910.4 ± μmol/g; SOD: 125.1 ± 1.4; 103.3 ± 1.9 vs. 212.11 ± 5.8 IU/g). Qualitative and quantitative histological results showed destruction of the mucous, submucous layers, and crypts in PACAP-38 deficient mice compared to wild-type tissues. These processes depended on the time of the cold preservation periods. Our present study showed that the presence of PACAP-38 in the small bowel tissue has a key role in the protection against intestinal cold preservation injury.     

Influence of PACAP on Oxidative Stress and Tissue Injury Following Small-Bowel Autotransplantation

Tissue injury caused by cold preservation and reperfusion remains an unsolved problem during small-bowel transplantation. Pituitary adenylate cyclase-activating polypeptide (PACAP) is present and plays a central role in the intestinal physiology. This study investigated effect of PACAP-38 on the oxidative stress and tissue damage in autotransplanted intestine. Sham-operated, ischemia/reperfusion, and autotransplanted groups were established in Wistar rats. In ischemia/reperfusion groups, 1 h (group A), 2 h (group B), and 3 h (group C) ischemia followed by 3 h of reperfusion was applied. In autotransplanted groups, total orthotopic intestinal autotransplantation was performed. Grafts were preserved in University of Wisconsin (UW) solution and in UW containing 30 μg PACAP-38 for 1, 2, 3, and 6 h. Reperfusion lasted 3 h in all groups. Endogenous PACAP-38 concentration was measured by radioimmunoassay. To determine oxidative stress parameters, malondialdehyde, reduced glutathione, and superoxide dismutase were measured in tissue samples. Tissue damage was analyzed by qualitative and quantitative methods on hematoxylin/eosin-stained sections. Concentration of endogenous PACAP-38 significantly decreased in groups B and C compared to sham-operated group. Preservation solution containing PACAP-38 ameliorated bowel tissue oxidative injury induced by cold ischemia and reperfusion. Histological results showed that preservation caused destruction of the mucous, submucous, and muscular layers, which were further deteriorated by the end of reperfusion. In contrast, PACAP-38 significantly protected the intestinal structure. Ischemia/reperfusion decreased the endogenous PACAP-38 concentration in the intestinal tissue. Administration of PACAP-38 mitigated the oxidative injury and histological lesions in small-bowel autotransplantation model.     

Alternative Splicing of the Pituitary Adenylate Cyclase-activating Polypetide (PACAP) Receptor Contributes to Function of PACAP-27

Pituitary adenylate cyclase-activating polypeptide (PACAP)-27 and PACAP-38 are neuropeptides performing a variety of physiological functions. The PACAP-specific receptor PAC1 has several variants that result mainly from alternative splicing in the mRNA region encoding the first extracellular (EC1) domain and the third intracellular cytoplasmic (IC3) loop. To characterize the molecular forms of alternative splicing variants of PAC1, we examined the binding affinity and activation of two major second messenger pathways (cAMP production and changes in [Ca²⁺] _i ) by PACAP-27. Activation of cAMP was influenced by the variant in both of the EC1 domain and IC3 loops. In the N form in the EC1 domain, the suppressive effect of the HOP1 form in the IC3 loop was enhanced. Regarding the intracellular calcium mobilization assay, the rank order of the potency of PACAP-27 for the different PAC1 isoforms was S/HOP1 >> N/R ≅ S/R >> N/HOP1. In particular, PACAP-27 exhibited remarkable potency of calcium mobilization in the S/HOP1-expressing cells at sub-picomolar concentrations even though the affinities of PACAP-27 to the four PAC1 isoforms were not significantly different. This suggests the specific functions of PACAP-27 due to PACAP-27 preferring PAC1 activation, and leads in clarification of the pleiotoropic function of PACAP.     

Cerebrospinal fluid levels of interleukin-6 and interleukin-12 in children with meningitis

Purpose  Certain cytokines play important roles in the pathophysiology of meningitis. The main purpose of this study was to investigate if the levels of interleukin-6 (IL-6) and interleukin-12 (IL-12) in cerebrospinal fluid (CSF) could be diagnostic predictors of bacterial meningitis in children. Methods  CSF was obtained from 95 patients suspected with meningitis. These cases were classified to the bacterial meningitis (n = 12), aseptic meningitis (n = 41), and nonmeningitis (n = 42) groups. The levels of IL-6 and IL-12 in CSF were measured using the enzyme-linked immmunosorbent assays test. Results  The CSF IL-6 levels in the bacterial meningitis group (45.2 ± 50.0 pg/ml) were significantly higher than those in the aseptic meningitis group (12.9 ± 10.2 pg/ml) and the nonmeningitis group (6.5 ± 7.8 pg/ml; p < 0.05). The CSF IL-12 levels in the bacterial meningitis group (69.8 ± 67.1 pg/ml) were significantly higher than those in the aseptic meningitis group (22.9 ± 10.8 pg/ml) and the nonmeningitis group (15.3 ± 11.2 pg/ml; p < 0.05). With regard to diagnosis, the measurement of CSF IL-6 and IL-12 levels showed sensitivities of 96% and 96%, respectively, and specificities of 51% and 75%, respectively. Conclusion  It is suggested that the CSF IL-6 and IL-12 levels are useful markers for distinguishing bacterial meningitis from aseptic meningitis.     

Neurological grading,survival, MR imaging,and histological evaluation in the rat brainstem glioma model

Objective  Convection-enhanced delivery using carboplatin in brainstem glioma models was reported to prolong survival. Functional impairment is of additional importance to evaluate the value of local chemotherapy. We established a neurological scoring system for the rat brainstem glioma model. Material and methods  In 46 male Fisher rats stereotactically 10⁵ F-98 cells were implanted at 1.4-mm lateral to midline and at the lambdoid suture using guided screws. Following 4 days local delivery was performed using Alzet^TM pumps (1 μl/h over 7 days) with either vehicle (5% dextrose) or carboplatin via one or two cannulas, respectively. All rats were subsequently tested neurologically using a specified neurological score. In 38 animals survival time was recorded. Representative MR imaging were acquired in eight rats, respectively, at day 12 after implantation. HE staining was used to evaluate tumor extension. Results  Neurological scoring showed significantly higher impairment in the high dose carboplatin group during the treatment period. Survival was significantly prolonged compared to control animals in the high dose carboplatin-one cannula group as well as in both low dose carboplatin groups (18.6 ± 3 versus 26.3 ± 9, 22.8 ± 2, 23.6 ± 2 days; p < 0.05). Overall neurological grading correlated with survival time. MR imaging showed a focal contrast enhancing mass in the pontine brainstem, which was less exaggerated after local chemotherapy. Histological slices visualized decreased cellular density in treatment animals versus controls. Conclusion  Local chemotherapy in the brainstem glioma model showed significant efficacy for histological changes and survival. Our neurological grading enables quantification of drug and tumor-related morbidity as an important factor for functional performance during therapy.     

Outcome of teenagers and young adults with ependymoma: The Royal Marsden experience

Background  The outcome and clinical characteristics of teenagers and young adults (TYA) with ependymoma have not been well documented. We report the Royal Marsden Hospital experience treating TYA with ependymoma. Materials and methods  Sixteen TYA were treated for ependymoma from 1971 to 2004 and are compared to 24 children (not infants) treated in the same period. Results  Twelve TYA (75%) received treatment in a neuro-oncology unit. Average time from symptoms to diagnosis was 183 days for TYA vs. 61.2 for children (p = 0.005). Two TYA (12.5% vs. 41.6% for children, p = 0.08) were enrolled in a clinical trial. Only 25% of TYA achieved gross total resection, all of them received radiotherapy and five of them received chemotherapy. There were five relapses; all of them were local. Five-year overall survival was 84.6% ± 10 for TYA vs. 78.1% ± 8.7 for children (p = 0.15), and 5-year progression-free survival was 66.6% ± 12.3 for TYA vs. 44.4% ± 10.3 for children (p = 0.08). Up to 56% of patients treated in the paediatric unit received psychosocial support vs. 42.9% of patients treated in the adult unit. Discussion  Ependymoma in adolescents and young adults is an infrequent entity, with perhaps better outcome compared to children. The extent of surgical resection as seen in children is an important prognostic factor. Providing adolescents with ependymoma the appropriate neuro-oncologic care, including access to multidisciplinary teams, full access to clinical trials and age-appropriate neuro-oncologic ancillary support services, remains a challenge.     

The Neuropathology of Late-Onset Friedreich��s Ataxia

Friedreich’s ataxia (FRDA) affects very young persons. In a large series, the mean ages of onset and death were 11 and 38 years, respectively. The clinical spectrum of FRDA has expanded after genetic confirmation of the mutation became a routine laboratory test. The main cause of death in juvenile-onset FRDA is cardiomyopathy whereas patients with late-onset are more likely to succumb to neurological disability or an intercurrent illness. Many patients with early onset now survive for 20 years or longer. This study made a systematic comparison of the neuropathology in 14 patients with juvenile onset and long survival, and five patients with late onset and long survival. Mean ages of onset (± standard deviation) were 10 ± 5 and 28 ± 13 years, respectively. Disease durations were 33 ± 11 and 47 ± 11 years, respectively. Cross-sectional areas of the thoracic spinal cord were greatly reduced from the normal state but did not differ between the two groups. Similarly, the neurons of dorsal root ganglia were significantly reduced in size in both juvenile- and late-onset cases of FRDA. The dentate nucleus showed severe loss of neurons as well as modification and destruction of corticonuclear terminals in all FRDA patients. Delayed atrophy of the dentate nucleus is the likely cause of the ataxic phenotype of FRDA in late-onset cases, but the reason for the delay is unknown. Frataxin levels in the dentate nucleus of two patients with late onset were similar to those of seven patients with juvenile onset.     

Unfavorable lipoprotein profile in childhood cancer survivors with suprasellar brain tumors—a high Apo B level and increased small dense LDL-cholesterol

Objective  The purpose of this study is to evaluate atherosclerotic potency among childhood cancer survivors (CCS) with suprasellar tumors. Study design  Patients with remitted suprasellar tumors were recruited. A total of 17 subjects with simple obesity of similar ages served as obese controls. Fasting sera were subjected to determination of lipids and apolipoproteins (Apo), including small dense LDL-cholesterol (sdLDL-C). Results  Twenty-three patients (4–22 years old) were enrolled. Patients, 12/23, had a body mass index (BMI) above the 90th percentile and were designated as ‘obese patients’. Obese patients had lower BMI scores (mean 26.4 kg/m², p < 0.01) compared to obese controls (mean 31.5 kg/m²). Both groups had identical levels of total cholesterol, triglycerides, LDL-C, and HDL-C. However, obese patients were found to have a higher incidence of Apo B/Apo A1 ratio elevation (6/12) than obese controls (0/17, p < 0.01). In addition, obese patients had higher sdLDL-C level (47.6 ± 14.8 mg/dL) than obese controls (28.3 ± 7.1 mg/dL, p < 0.01). BMI showed strong correlations with both the Apo B/Apo A1 ratio (r = 0.663, p < 0.001) and sdLDL-C (r = 0.606, p < 0.01). Conclusion  CCS with suprasellar tumors, especially patients with a high BMI, had an unfavorable lipoprotein profile characterized by increased Apo B and sdLDL-C.     

Measurements of burr-hole localization for endoscopic procedures in the third ventricle in children

Objective  In a retrospective study, we measured the localization for the burr hole for neuroendoscopic procedures in the third ventricle, which are determined by anatomical landmarks like the foramen of Monro (FM) and the respective targets. Patients and methods  In 48 children, thin-sliced T2-weighted magnetic resonance images were analyzed within an imaging software tool to determine the trajectory between the FM to the floor of the third ventricle (F3V) or the entrance of the sylvian aqueduct (SA). The crossing point at the skull convexity defined the entry points. Coordinates are given relative to nasion and midline. A mean virtual entry point to reach both targets was compared to the burr-hole localization used in the respective surgeries. The tissue shift at the FM was quantified for the trajectories. Results  The entry point to reach the F3V or the SA measured 119.7 ± 26.4 mm (to nasion)–20.5 ± 11.5 mm (to midline) and 57.4 ± 26.5–18.8 ± 8.3 mm, respectively. The virtual mean entry point to reach both targets was located at 86.5 ± 25.3–20.9 ± 9.8 mm. There was a statistical difference in the entry point localization relative to nasion of the virtual mean trajectory compared with the burr-hole localization used in these patients. The tissue shift at the level of the FM using the mean virtual trajectory was significantly lower than by using the actual burr hole to the SA. Conclusions  Planning an optimal burr-hole localization is important in neuroendoscopic procedures in children, especially where the target is located around the sylvian aqueduct.     

Neurocognitive and psychological profiles in pediatric arachnoid cyst

Objective  This study aims to investigate whether intracranial arachnoid cysts (AC) compromise neurocognitive function and psychological profiles in pediatric patients, depending on various clinical factors. Methods  We assessed neurocognitive functions and psychological tests in 35 AC patients and 35 healthy control subjects between October 2007 and April 2008. AC patients ranged in age from 3 to 15 (7.94 ± 3.12) years old and control patients from 5 to 13 (8.84 ± 2.17) years old. The location of the AC were temporal (n = 22), frontal (n = 6), suprasellar (n = 4), and posterior fossa (n = 3). Patients underwent neurocognitive and psychological assessments before surgery. To investigate which AC impair neurocognitive function and psychological profile, we assessed intelligence, memory, attention, executive function, behavioral problems, emotional distress, and parenting stress. Results  AC caused some demonstrated impairment by both neurocognitive function and psychological assessments. Left hemisphere AC tended to have more anxiety; mood changes can be detected depending on cyst grade. An incidental finding of AC after trauma is more intelligent, well-reserved executive function. Frontal locations tended to cause more anxiety than temporal locations. Conclusions  Our results imply that intracranial AC impairs some neurocognitive and psychological functions. An incidental finding of AC after trauma was a more intelligent, well-reserved executive function. AC in the left hemisphere, frontal location tended to cause more anxiety. The AC itself did not cause differences in neurocognitive function from the control group. However, parenting stress in the AC group was much higher than in the control group.     

Automatic Segmentation of Ventricular Cerebrospinal Fluid from Ischemic Stroke CT Images

Accurate segmentation of ventricular cerebrospinal fluid (CSF) regions in stroke CT images is important in assessing stroke patients. Manual segmentation is subjective, time consuming and error prone. There are currently no methods dedicated to extracting ventricular CSF regions in stroke CT images. 102 ischemic stroke CT scans (slice thickness between 3 and 6 mm, voxel size in the axial plane between 0.390 and 0.498 mm) were acquired. An automated template-based algorithm is proposed to extract ventricular CSF regions which accounts for the presence of ischemic infarct regions, image noise, and variations in orientation. First, template VT₂ is registered to the scan using landmark-based piecewise linear scaling and then template VT₁ is used to further refine the registration by partial segmentation of the fourth ventricle. A region of interest (ROI) is found using the registered VT₂. Automated thresholding is then applied to the ROI and the artifacts are removed in the final phase. Sensitivity, dice similarity coefficient, volume error, conformity and sensibility of segmentation results were 0.74 ± 0.12, 0.8 ± 0.09, 0.16 ± 0.11, 0.45 ± 0.39, 0.88 ± 0.09, respectively. The processing time for a 512 × 512 × 30 CT scan takes less than 30 s on a 2.49 GHz dual core processor PC with 4 GB RAM. Experiments with clinical stroke CT scans showed that the proposed algorithm can generate acceptable results in the presence of noise, size variations and orientation differences of ventricular systems and in the presence of ischemic infarcts.     

Hemodynamic responses to visual stimulation in children with sickle cell anemia

Blood oxygenation level-dependent (BOLD) and cerebral blood flow (CBF)-based functional magnetic resonance imaging (fMRI) were used to measure primary visual cortex responses to photic stimulation in 23 children (12.4 ± 0.7 years old) with sickle cell anemia (SCA) and 21 clinical controls (11 ± 1.0 years old). The objectives were to investigate the effect of SCA on detection of brain activation with fMRI and to explore the relationship between fMRI responses and global cognitive function. The BOLD responses were diminished in children with SCA. Clinical indicators of disease severity were greatest in patients without detectable visual cortex activation, but blood hemoglobin concentration and resting CBF were not predictive of BOLD signal amplitude in the SCA patients. Unexpectedly, the BOLD signal amplitude was positively associated (r_s ≥ 0.8, p ≤ 0.05) with Wechsler Abbreviated Scale of Intelligence scores, suggesting that fMRI may help clarify medical, hemodynamic, and neural factors that mediate adverse effects of SCA on neurocognitive function.     

Oxidative stress induced by loss of Cu,Zn-superoxide dismutase (SOD1) or superoxide-generating herbicides causes axonal degeneration in mouse DRG cultures

Axonal degeneration is a common pathologic feature in peripheral neuropathy, neurodegenerative disease, and normal aging. Oxidative stress may be an important mechanism of axonal degeneration, but is underrepresented among current experimental models. To test the effects of loss of the antioxidant enzyme Cu,Zn-superoxide dismutase (SOD1) on axon survival, we cultured dorsal root ganglion (DRG) neurons from SOD1 knockout mice. Beginning as early as 48–72 h, we observed striking degeneration of Sod1−/− axons that was prevented by introduction of human SOD1 and was attenuated by antioxidant treatment. To test susceptibility to increased superoxide production, we exposed wild-type DRGs to the redox-cycling herbicides paraquat and diquat (DQ). Dose-dependent axon degeneration was observed, and toxicity of DQ was exacerbated by SOD1 deficiency. MTT staining suggested that DRG axons are more susceptible to injury than their parent cell bodies in both paradigms. Taken together, these data demonstrate susceptibility of DRG axons to oxidative stress-mediated injury due to loss of SOD1 or excess superoxide production. These in vitro models provide a novel means of investigating oxidative stress-mediated injury to axons, to improve our understanding of axonal redox control and dysfunction in peripheral neuropathy.     

Neuronal Conditioning Medium and Nerve Growth Factor Induce Neuronal Differentiation of Collagen-Adherent Progenitors Derived from Human Umbilical Cord Blood

The aim of the study was to isolate and characterize a population of neuronal progenitors in the human umbilical cord blood (HUCB) mononuclear cell (MNC) fraction, for in vitro manipulation towards neuronal differentiation. Selection of the HUCB neuronal progenitors (HUCBNPs) was based on the neuronal prerequisite for adherence to collagen. Populations of collagen-adherent, nestin-positive (94.8 ± 2.9%) progenitors expressing α1/2 integrin receptors, as revealed by Western blot and adhesion assay using selective antagonists, were isolated and survived for more than 14 days. In vitro differentiation of the HUCBNPs was achieved by treatment with 10% human SH-SY5Y neuroblastoma cell-conditioning media (CM) supplemented with 10 ng/ml nerve growth factor (NGF). Some 83 ± 8.2% of the surviving progenitors acquired a neuronal-like morphology, expressed by cellular outgrowths of different lengths. About 35 ± 6% of the HUCBNPs had long outgrowths with a length/cell diameter ratio greater than 2, typical of developing neurons. The majority of these progenitors, analyzed by immunocytochemistry and/or RT-PCR, expressed common neuronal markers such as microtubule-associated protein 2 (MAP-2; 98.5 ± 2%), neurotrophin receptor (TrkA; 98.5 ± 0.06%), neurofillament-160 (NF-160; 94.2 ± 1%), beta-tubulin III (89.8 ± 4.2%) and neuron specific enolase (NSE). Combined CM and NGF treatment induced constitutive activation of the mitogen-activated protein kinases ERK2 (36-fold vs control), p38α (nine-fold vs control) and p38beta (23-fold vs control), most likely related to survival and/or differentiation. The results point to operationally defined conditions for activating neuronal differentiation of HUCBNPs ex vivo and emphasize the crucial role of neuronal CM and NGF in this process. This study is part of a PhD thesis to be submitted to the Hebrew University of Jerusalem by H.A.Z.     

Changes of PACAP Immunoreactivities and Cytokine Levels After PACAP-38 Containing Intestinal Preservation and Autotransplantation

Small bowel is one of the most sensitive organs to ischemia–reperfusion injury, which is a significant problem during transplantation. Pituitary adenylate cyclase-activating polypeptide (PACAP) has cytoprotective effect in ischemic injuries of various tissues. The aim of our study was to measure changes of PACAP-38 and PACAP-27 immunoreactivities and cytokine levels in intestinal grafts stored in PACAP-38-containing preservation solution. Small bowel autotransplantation was performed on male Wistar rats. Grafts were stored in University of Wisconsin (UW) solution at 4 °C for 1 h (group (G)I), for 3 h (GII), and for 6 h (GIII) and in PACAP-38-containing UW solution for 1 h (GIV), for 3 h (GV), and for 6 h (GVI). After preservation, performing vessel anastomosis reperfusion began, which lasted 3 h in each group. Tissue biopsies were collected after laparotomy (control) and at the end of the reperfusion periods. Intestinal PACAP-38 and PACAP-27 immunoreactivities were measured by radioimmunoassay. To measure cytokines from tissue homogenates, we used rat cytokine array and Luminex Multiplex Immunoassay. Levels of PACAP-38 and PACAP-27 immunoreactivity decreased after 1 and 3 h preservation compared to control levels. This decrease was significant following 6 h cold storage (p?<?0.05). Values remained significantly higher in grafts stored in PACAP-38-containing UW. Cytokine array revealed that expression of the soluble intercellular adhesion molecule-1 (CD54) and L-selectin (CD62L/LECAM-1) was increased in GIII. Both 6 h cold storage in PACAP-38-containing UW solution and 3 h reperfusion caused strong reduction in these cytokines activation in GVI. RANTES (CCL5) levels were increased in all groups. Strong activation of the tissue inhibitor of metalloproteinase-1 was in GIII. However, PACAP-38-containing cold storage could decrease its activation in GVI. Furthermore, strong activation of the tissue inhibitor of metalloproteinase-1 was detected in 6 h preserved grafts without PACAP-38 (GIII). PACAP-38-containing cold storage could decrease its activation in GVI. Our present study showed that PACAP-38 and PACAP-27 immunoreactivities decreased in a time-dependent manner during intestinal cold preservation, which could be ameliorated by administration of exogenous PACAP-38 to the preservation solution. Moreover, PACAP-38 could attenuate tissue cold ischemic injury-induced changes in cytokine expression.     

Down-regulation Synaptic Vesicle Protein 2A in the Anterior Temporal Neocortex of Patients with Intractable Epilepsy

Synaptic vesicle protein 2A (SV2A) involvement has been reported in the animal models of epilepsy. The aim of this study was to investigate the expression of SV2A in human intractable epilepsy (IE) brain tissue. Using immunohistochemistry, immunofluorescence, and Western blot, we detected SV2A expression in tissue samples from the anterior temporal neocortex of 33 patients who had been surgically treated for IE. We compared these tissues with nine histologically normal anterior temporal lobe samples from controls. SV2A immunoreactive staining was 0.1651 ± 0.0564 in patient group and 0.2347 ± 0.0187 in the control group (p < 0.05) using immunohistochemistry, and this finding was consistently observed with Western blot analysis (0.1727 ± 0.0471 versus 0.3976 ± 0.0983, p < 0.05). Immunofluorescence staining showed that SV2A was mainly accumulated in neurons. Our findings demonstrate that down-regulation of SV2A is present in patients with temporal lobe epilepsy.     

A fMRI Study of Verbal Working Memory, Cardiac Output, and Ejection Fraction in Elderly Patients with Cardiovascular Disease

Cardiovascular disease (CVD) is associated with cognitive deficits even in the absence of stroke. We examined the relationship between cardiac performance, as measured by cardiac output (CO) and ejection fraction (EF), and brain activity during a verbal working memory (VWM) task in elderly CVD patients who tend to be at increased risk for vascular cognitive impairments. Seventeen patients were recruited from a cohort participating in an ongoing prospective study examining the effects of CVD on cognitive function in the elderly. Participants were diagnosed with CVD (age 68 ± 8) and completed a 2-back VWM task in a 1.5T fMRI paradigm. CO and EF were calculated from echocardiogram measures. Task-related activation was averaged in a priori regions of interest. The relationship between CO, EF, and 2-back-related activity was modeled using partial correlations (two-tailed p < .05) controlling for age and 2-back accuracy. All participants were globally cognitively intact as indicated by Mini-Mental Status Exam and Dementia Rating Scale scores. Mean accuracy on the 2-back was 78 ± 9% while reaction time averaged 1,027 ± 192 ms. Mean CO and EF values showed a large range (CO: 3.55 to 6.31; EF: 0.36 to 0.76) but average values were within the normal range. After controlling for age and 2-back accuracy, lower EF was related to decrease in left insula activity (r = 0.61, p = 0.03). There were trends for EF to be related to accuracy (r = 0.47, p = 0.09) and reaction time (r = −0.48, p = 0.09). CO was also related to insula activity (r = 0.60, p = 0.04) and activity in the supplementary motor area activity (r = 0.66, p = 0.01). Cardiac performance was related to decreased efficiency in task related brain areas and tended to be related to performance on a VWM task in elderly patients with CVD. Results have implications for a line of investigation indicating that cardiac and systemic vascular indices could be used as proxy measures to examine mechanisms of cerebrovascular dysfunction in the elderly.     

Severity and Progression Rate of Cerebellar Ataxia in 16q-linked Autosomal Dominant Cerebellar Ataxia (16q-ADCA) in the Endemic Nagano Area of Japan

16q22.1-linked autosomal dominant cerebellar ataxia (16q-ADCA) is a recently defined subtype of ADCA identified by a disease-specific C/T substitution in the 5′ untranslated region of the puratrophin-1 gene. In Nagano, the central mountainous district of the main island of Japan, 16q-ADCA and spinocerebellar ataxia type 6 (SCA6) are the most and second most prevalent subtypes of ADCA, respectively. Both subtypes are classified into Harding’s ADCA III, but little attention has been given to the differences in the severity and progression rate of cerebellar ataxia between 16q-ADCA and SCA6. We investigated the clinical severity and progression rate of cerebellar ataxia of 16q-ADCA patients using international cooperative ataxia rating scale and scale for the assessment and rating of ataxia and compared them with those of SCA6 patients. The age at onset was much higher in 16q-ADCA patients (60.1 ± 9.8 years, n = 66) than in SCA6 patients (41.1 ± 8.7 years, n = 35). Clinical features of 16q-ADCA were basically consistent with pure cerebellar ataxia, as well as in SCA6, but gaze-evoked nystagmus was observed less frequently in 16q-ADCA patients than in SCA6 patients. When compared at almost the same disease duration after onset, the severity of cerebellar ataxia was a little higher, and the progression rate seemed more rapid in 16q-ADCA patients than in SCA6 patients, but the differences were not significant. The authors report no conflicts of interest.     

Torpedoes in the Cerebellar Vermis in Essential Tremor Cases vs. Controls

The study of the postmortem changes in essential tremor (ET) is in its infancy, although recent evidence points to a central role of the cerebellum, where Purkinje cell axonal swellings (“torpedoes”) are significantly more common in ET than control brains. Yet, all existing studies have been confined to the cerebellar hemispheres, and whether there is a more widely distributed cerebellar problem is presently unknown. Our aims were to address whether: (1) ET cases have greater numbers of torpedoes in the vermis than controls, (2) there a correlation between the extent of vermal torpedo pathology and hemispheric torpedo pathology, and (3) vermal torpedo pathology is correlated with clinical features of the disease. A parasagittal neocerebellar block and a vermal block were harvested from 24 ET and 10 control brains. Paraffin sections (7 μm) were stained with Luxol fast blue/hematoxylin and eosin, and torpedoes were quantified. All torpedo counts were corrected for Purkinje cell layer length. Vermal corrected torpedo count (VermTc) was higher in ET cases than controls (7.1 ± 6.8 [median, 4.3] vs. 2.6 ± 2.5 [median, 2]), p = 0.002). The VermTc and the hemispheric corrected torpedo count (HemTc) were correlated with one another (Spearman’s r = 0.54, p = 0.002). ET cases with neck, voice, and jaw tremors had the highest VermTc (p = 0.046). The abundance of torpedoes in the ET brain is not confined to the ponto- or neocerebellum but is more broadly distributed, also involving the spino- or paleocerebellum. These data further confirm the central role of the cerebellum in the underlying pathophysiology of this common neurological disorder.     

The plasma alpha-synuclein levels in patients with Parkinson’s disease and multiple system atrophy

Summary. α-Synuclein, a synaptic protein of unknown function, is a major component of Lewy bodies and may play a role in the pathophysiological process of Parkinson’s disease (PD). In this study, we measured the plasma α-synuclein levels in 105 patients with PD, 38 patients with multiple system atrophy (MSA), and 51 age-matched controls. The α-synuclein level was significantly elevated in patients with PD (79.9 ± 4.0 pg/ml, p < 0.001) and in those with MSA (78.1 ± 3.5 pg/ml, p = 0.019) compared with the level in controls (76.1 ± 3.9 pg/ml). The α-synuclein level was higher in patients with PD than in those with MSA (79.9 ± 4.0 vs 78.1 ± 3.5, p = 0.016). Our study demonstrated that the α-synuclein level in plasma is elevated in patients with PD and MSA.