Modeling and Bioinformatics Identify Responders to G-CSF in Patients With Amyotrophic Lateral Sclerosis.

Objective: Developing an integrative approach to early treatment response classification using survival modeling and bioinformatics with various biomarkers for early assessment of filgrastim (granulocyte colony stimulating factor) treatment effects in amyotrophic lateral sclerosis (ALS) patients. Filgrastim, a hematopoietic growth factor with excellent safety, routinely applied in oncology and stem cell mobilization, had shown preliminary efficacy in ALS. Methods: We conducted individualized long-term filgrastim treatment in 36 ALS patients. The PRO-ACT database, with outcome data from 23 international clinical ALS trials, served as historical control and mathematical reference for survival modeling. Imaging data as well as cytokine and cellular data from stem cell analysis were processed as biomarkers in a non-linear principal component analysis (NLPCA) to identify individual response. Results: Cox proportional hazard and matched-pair analyses revealed a significant survival benefit for filgrastim-treated patients over PRO-ACT comparators. We generated a model for survival estimation based on patients in the PRO-ACT database and then applied the model to filgrastim-treated patients. Model-identified filgrastim responders displayed less functional decline and impressively longer survival than non-responders. Multimodal biomarkers were then analyzed by PCA in the context of model-defined treatment response, allowing identification of subsequent treatment response as early as within 3 months of therapy. Strong treatment response with a median survival of 3.8 years after start of therapy was associated with younger age, increased hematopoietic stem cell mobilization, less aggressive inflammatory cytokine plasma profiles, and preserved pattern of fractional anisotropy as determined by magnetic resonance diffusion tensor imaging (DTI-MRI). Conclusion: Long-term filgrastim is safe, is well-tolerated, and has significant positive effects on disease progression and survival in a small cohort of ALS patients. Developing and applying a model-based biomarker response classification allows use of multimodal biomarker patterns in full potential. This can identify strong individual treatment responders (here: filgrastim) at a very early stage of therapy and may pave the way to an effective individualized treatment option.

Clinical long-time course, novel mutations and genotype-phenotype correlation in a cohort of 27 families with POMT1-related disorders.

BACKGROUND: The protein O-mannosyltransferase 1, encoded by the POMT1 gene, is a key enzyme in the glycosylation of α-dystroglycan. POMT1-related disorders belong to the group of dystroglycanopathies characterized by a proximally pronounced muscular dystrophy with structural or functional involvement of the brain and/or the eyes. The phenotypic spectrum ranges from the severe Walker-Warburg syndrome (WWS) to milder forms of limb girdle muscular dystrophy (LGMD). The phenotypic severity of POMT1-related dystroglycanopathies depends on the residual enzyme activity. A genotype-phenotype correlation can be assumed. RESULTS: The clinical, neuroradiological, and genetic findings of 35 patients with biallelic POMT1 mutations (15 WWS, 1 MEB (muscle-eye-brain disease), 19 LGMD) from 27 independent families are reported. The representative clinical course of an infant with WWS and the long-term course of a 32 years old patient with LGMD are described in more detail. Specific features of 15 patients with the homozygous founder mutation p.Ala200Pro are defined as a distinct and mildly affected LGMD subgroup. Ten previously reported and 8 novel POMT1 mutations were identified. Type and location of each of the POMT1 mutations are evaluated in detail and a list of all POMT1 mutations reported by now is provided. Patients with two mutations leading to premature protein termination had a WWS phenotype, while the presence of at least one missense mutation was associated with milder phenotypes. In the patient with MEB-like phenotype two missense mutations were observed within the catalytic active domain of the enzyme. CONCLUSIONS: Our large cohort confirms the importance of type and location of each POMT1 mutation for the individual clinical manifestation and thereby expands the knowledge on the genotype-phenotype correlation in POMT1-related dystroglycanopathies. This genotype-phenotype correlation is further supported by the observation of an intrafamiliar analogous clinical manifestation observed in all affected 13 siblings from 5 independent families. Our data confirm the progressive nature of the disease also in milder LGMD phenotypes, ultimately resulting in loss of ambulation at a variable age. Our data define two major clinical POMT1 phenotypes, which should prompt genetic testing including the POMT1 gene: patients with a severe WWS manifestation predominantly present with profound neonatal muscular hypotonia and a severe and progressive hydrocephalus with involvement of brainstem and/or cerebellum. The presence of an occipital encephalocele in a WWS patient might point to POMT1 as causative gene within the different genes associated with WWS. The milder LGMD phenotypes constantly show markedly elevated creatine kinase values in combination with microcephaly and cognitive impairment.

Value of fluid-attenuated inversion recovery MRI data analyzed by the lesion segmentation toolbox in amyotrophic lateral sclerosis.

BACKGROUND: MRI fluid-attenuated inversion recovery (FLAIR) studies reported hyperintensity in the corticospinal tract and corpus callosum of patients with amyotrophic lateral sclerosis (ALS). PURPOSE: To evaluate the lesion segmentation toolbox (LST) for the objective quantification of FLAIR lesions in ALS patients. STUDY TYPE: Retrospective. POPULATION: Twenty-eight ALS patients (eight females, mean age: 50 range: 24-73, mean ALSFRS-R sum score: 36) were compared with 31 age-matched healthy controls (12 females, mean age: 45, range: 25-67). ALS patients were treated with riluzole and additional G-CSF (granulocyte-colony stimulating factor) on a named patient basis. FIELD STRENGTH/SEQUENCE: 1.5 T, FLAIR, T1 -weighted MRI. ASSESSMENT: The lesion prediction algorithm (LPA) of the LST enabled the extraction of individual binary lesion maps, total lesion volume (TLV), and number (TLN). Location and overlap of FLAIR lesions across patients were investigated by registration to FLAIR average space and an atlas. ALS-specific functional rating scale revised (ALSFRS-R), disease progression, and survival since diagnosis served as clinical correlates. STATISTICAL TESTS: Univariate analysis of variance (ANOVA), repeated-measures ANOVA, t-test, Bravais-Pearson correlation, Chi-square test of independence, Kaplan-Meier analysis, Cox-regression analysis. RESULTS: Both ALS patients and healthy controls exhibited FLAIR alterations. TLN significantly depended on age (F(1,54) = 24.659, P < 0.001) and sex (F(1,54) = 5.720, P = 0.020). ALS patients showed higher TLN than healthy controls depending on sex (F(1, 54) = 5.076, P = 0.028). FLAIR lesions were small and most pronounced in male ALS patients. FLAIR alterations were predominantly detected in the superior and posterior corona radiata, anterior capsula interna, and posterior thalamic radiation. Patients with pyramidal tract (PT) lesions exhibited significantly inferior survival than patients without PT lesions (P = 0.013). Covariate age exhibited strong prognostic value for survival (P = 0.015). DATA CONCLUSION: LST enables the objective quantification of FLAIR alterations and is a potential prognostic biomarker for ALS. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:552-559.

Information needs and requirements in patients with brain tumours and their relatives.

Patients with brain tumours face a number of medical and social challenges. Previous studies have shown that these patients and their relatives need a high level of patient-oriented information and counselling. However, these needs are often underestimated. In this single-centre cross-sectional study, we evaluated, for the first time, the information needs of patients with brain tumours and their relatives depending on diagnosis, age and level of education. The participants were interviewed using pre-specified questionnaires. Answers were evaluated descriptively using standard statistical methods. A total of 888 questionnaires were sent out. The return rate was 50.7%. The majority of patients (nP = 103; 59.9%) and a higher proportion of relatives (nR = 103; 72.5%; p = 0.019) wished to receive a maximum of information. The majority (79.7% of patients; 83.1% of relatives) also stated that they preferred a personal, face-to-face meeting as primary source of information. The need for information increased with education (p = 0.015), and decreased with tumour grade (p = 0.025) and age (p = 0.118). Our data indicate that patients with brain tumours and their relatives have high information needs throughout their disease and continuously require information and counselling. Optimal provision of information is based on personal preferences, which needs to be evaluated appropriately. Patient-oriented information and counselling are parts of a successful communication strategy that can improve cancer care significantly.

Side Effects of Long-Term Continuous Intra-arterial Nimodipine Infusion in Patients with Severe Refractory Cerebral Vasospasm after Subarachnoid Hemorrhage.

BACKGROUND: Long-term continuous intra-arterial nimodipine infusion (CIAN) is a rescue therapy option in cases of severe refractory cerebral vasospasm (CV) following acute non-traumatic subarachnoid hemorrhage (SAH). However, CIAN therapy can be associated with relevant side effects. Available studies focus on intracerebral complications, whereas extracerebral side effects are rarely examined. Aim of the present study was to generate descriptive data on the clinical course during CIAN therapy and expectable extracerebral side effects. METHODS: All patients treated with CIAN therapy for at least 5 days between May 2011 and December 2015 were included. We retrospectively extracted data from the patient data management system regarding the period between 2 days before the beginning and 5 days after the termination of CIAN therapy to analyze the course of ventilation parameters and pulmonary gas exchange, hemodynamic support, renal and liver function, integrity of the gastrointestinal tract, and the occurrence of infectious complications. In addition, we recorded the mean daily values of intracranial pressure (ICP) and intracerebral problems associated with CIAN therapy. RESULTS: Data from 28 patients meeting inclusion criteria were analyzed. The mean duration of long-term CIAN therapy was 10.5 ± 4.5 days. Seventeen patients (60.7%) reached a good outcome level (Glasgow Outcome Scale [GOS] 4-5) 6 months after SAH. An impairment of the pulmonary gas exchange occurred only at the very beginning of CIAN therapy. The required vasopressor support with norepinephrine was significantly higher on all days during and the first day after CIAN therapy compared to the situation before starting CIAN therapy. Two patients required short-time resuscitation due to cardiac arrest during CIAN therapy. Acute kidney injury was observed in four patients, and one of them required renal replacement therapy with sustained low-efficiency daily dialysis. During CIAN therapy, 23 patients (82.1%) needed the escalation of a previous antiinfective therapy or the onset of antibiotics which was in line with a significant increase of C-reactive protein and white blood cell count. Obstipation was observed in 22 patients (78.6%). Ten patients (35.7%) even showed insufficient defecation on at least seven consecutive days. Compared to the situation before, ICP was significantly higher during the whole period of CIAN therapy. CONCLUSIONS: Long-term CIAN therapy is associated with diverse side effects. The leading problems are an impairment of the hemodynamic situation and cardiac problems, an increase in infectious complications, a worsening of the motility of the gastrointestinal tract, and rising ICP values. Teams on neurointensive care units must be aware of these side effects to avoid that the beneficial effects of CIAN therapy on CV reported elsewhere are foiled by the problems this technique can be associated with.

Fulminant Acute Ascending Hemorrhagic Myelitis Treated with Eculizumab.

We describe an 18-year-old patient who developed back pain, rapidly ascending sensomotory deficits, bladder dysfunction, Lhermitte's sign, absent abdominal reflexes of all three levels, brisk tendon reflexes, and positive Babinski's sign. Magnetic resonance imaging of the spinal cord showed a long segment of cervical and thoracic intramedullary signal hyperintensity suggesting a longitudinally extensive transverse myelitis possibly within the course of a fast progressing ascending immune-mediated hemorrhagic myelopathy. Throughout his illness, the patient deteriorated with tetraplegia, cardiac arrest, and respiratory failure although he received, after exclusion of infective causes, therapy with steroids, immunoglobulins, plasmapheresis, and cyclophosphamide. Interestingly, treatment with the C5-inhibitor eculizumab to prevent complement-mediated spinal cord injury achieved an arrest of clinical deterioration. We propose eculizumab as treatment in fast progressive and potentially fatal immune-mediated spinal cord injury. Furthermore, this case raises awareness for the process of clinical decision-making in severe myelopathies.

Octreotide LAR and Prednisone as Neoadjuvant Treatment in Patients with Primary or Locally Recurrent Unresectable Thymic Tumors: A Phase II Study.

Therapeutic options to cure advanced, recurrent, and unresectable thymomas are limited. The most important factor for long-term survival of thymoma patients is complete resection (R0) of the tumor. We therefore evaluated the response to and the induction of resectability of primarily or locally recurrent unresectable thymomas and thymic carcinomas by octreotide Long-Acting Release (LAR) plus prednisone therapy in patients with positive octreotide scans. In this open label, single-arm phase II study, 17 patients with thymomas considered unresectable or locally recurrent thymoma (n = 15) and thymic carcinoma (n = 2) at Masaoka stage III were enrolled. Octreotide LAR (30 mg once every 2 weeks) was administered in combination with prednisone (0.6 mg/kg per day) for a maximum of 24 weeks (study design according to Fleming´s one sample multiple testing procedure for phase II clinical trials). Tumor size was evaluated by volumetric CT measurements, and a decrease in tumor volume of at least 20% at week 12 compared to baseline was considered as a response. We found that octreotide LAR plus prednisone elicited response in 15 of 17 patients (88%). Median reduction of tumor volume after 12 weeks of treatment was 51% (range 20%-86%). Subsequently, complete surgical resection was achieved in five (29%) and four patients (23%) after 12 and 24 weeks, respectively. Octreotide LAR plus prednisone treatment was discontinued in two patients before week 12 due to unsatisfactory therapeutic effects or adverse events. The most frequent adverse events were gastrointestinal (71%), infectious (65%), and hematological (41%) complications. In conclusion, octreotide LAR plus prednisone is efficacious in patients with primary or recurrent unresectable thymoma with respect to tumor regression. Octreotide LAR plus prednisone was well tolerated and adverse events were in line with the known safety profile of both agents.

GSK3ß-dependent dysregulation of neurodevelopment in SPG11-patient induced pluripotent stem cell model.

OBJECTIVE: Mutations in the spastic paraplegia gene 11 (SPG11), encoding spatacsin, cause the most frequent form of autosomal-recessive complex hereditary spastic paraplegia (HSP) and juvenile-onset amyotrophic lateral sclerosis (ALS5). When SPG11 is mutated, patients frequently present with spastic paraparesis, a thin corpus callosum, and cognitive impairment. We previously delineated a neurodegenerative phenotype in neurons of these patients. In the current study, we recapitulated early developmental phenotypes of SPG11 and outlined their cellular and molecular mechanisms in patient-specific induced pluripotent stem cell (iPSC)-derived cortical neural progenitor cells (NPCs). METHODS: We generated and characterized iPSC-derived NPCs and neurons from 3 SPG11 patients and 2 age-matched controls. RESULTS: Gene expression profiling of SPG11-NPCs revealed widespread transcriptional alterations in neurodevelopmental pathways. These include changes in cell-cycle, neurogenesis, cortical development pathways, in addition to autophagic deficits. More important, the GSK3ß-signaling pathway was found to be dysregulated in SPG11-NPCs. Impaired proliferation of SPG11-NPCs resulted in a significant diminution in the number of neural cells. The decrease in mitotically active SPG11-NPCs was rescued by GSK3 modulation. INTERPRETATION: This iPSC-derived NPC model provides the first evidence for an early neurodevelopmental phenotype in SPG11, with GSK3ß as a potential novel target to reverse the disease phenotype. Ann Neurol 2016;79:826-840.

LIS1-associated classic lissencephaly: A retrospective, multicenter survey of the epileptogenic phenotype and response to antiepileptic drugs.

BACKGROUND: Patients with LIS1-associated classic lissencephaly typically present with severe psychomotor retardation and drug-resistant epilepsy within the first year. AIM: To analyze the epileptogenic phenotype and response to antiepileptic therapy in LIS1-associated classic lissencephaly. METHOD: Retrospective evaluation of 22 patients (8 months-24 years) with genetically and radiologically confirmed LIS1-associated classic lissencephaly in 16 study centers. RESULTS: All patients in our cohort developed drug-resistant epilepsy. In 82% onset of seizures was noted within the first six months of life, most frequently with infantile spasms. Later in infancy the epileptogentic phenotype became more variable and included different forms of focal seizures as well generalized as tonic-clonic seizures, with generalized tonic-clonic seizures being the predominant type. Lamotrigine and valproate were rated most successful with good or partial response rates in 88-100% of the patients. Both were evaluated significantly better than levetiracetam (p<0.05) and sulthiame (p<0.01) in the neuropediatric assessment and better than levetiracetam, sulthiame (p<0.05) and topiramate (p<0.01) in the family survey. Phenobarbital and vigabatrin achieved good or partial response in 62-83% of the patients. CONCLUSION: Our findings suggest that patients with LIS1-associated lissencephaly might benefit most from lamotrigine, valproate, vigabatrin or phenobarbital.

47 patients with FLNA associated periventricular nodular heterotopia.

BACKGROUND: Heterozygous loss of function mutations within the Filamin A gene in Xq28 are the most frequent cause of bilateral neuronal periventricular nodular heterotopia (PVNH). Most affected females are reported to initially present with difficult to treat seizures at variable age of onset. Psychomotor development and cognition may be normal or mildly to moderately impaired. Distinct associated extracerebral findings have been observed and may help to establish the diagnosis including patent ductus arteriosus Botalli, progressive dystrophic cardiac valve disease and aortic dissection, chronic obstructive lung disease or chronic constipation. Genotype-phenotype correlations could not yet be established. METHODS: Sanger sequencing and MLPA was performed for a large cohort of 47 patients with Filamin A associated PVNH (age range 1 to 65 years). For 34 patients more detailed clinical information was available from a structured questionnaire and medical charts on family history, development, epileptologic findings, neurological examination, cognition and associated clinical findings. Available detailed cerebral MR imaging was assessed for 20 patients. RESULTS: Thirty-nine different FLNA mutations were observed, they are mainly truncating (37/39) and distributed throughout the entire coding region. No obvious correlation between the number and extend of PVNH and the severity of the individual clinical manifestation was observed. 10 of the mutation carriers so far are without seizures at a median age of 19.7 years. 22 of 24 patients with available educational data were able to attend regular school and obtain professional education according to age. CONCLUSIONS: We report the clinical and mutation spectrum as well as MR imaging for a large cohort of 47 patients with Filamin A associated PVNH including two adult males. Our data are reassuring in regard to psychomotor and cognitive development, which is within normal range for the majority of patients. However, a concerning median diagnostic latency of 17 to 20 years was noted between seizure onset and the genetic diagnosis, intensely delaying appropriate medical surveillance for potentially life threatening cardiovascular complications as well as genetic risk assessment and counseling prior to family planning for this X-linked dominant inherited disorder with high perinatal lethality in hemizygous males.

Continuous intra-arterial nimodipine infusion in patients with severe refractory cerebral vasospasm after aneurysmal subarachnoid hemorrhage: a feasibility study and outcome results.

BACKGROUND: Severe cerebral vasospasm is a major cause of death and disability in patients with aneurysmal subarachnoid hemorrhage. No causative treatment is yet available and hypertensive hypervolemic therapy (HHT) is often insufficient to avoid delayed cerebral ischemia and neurological deficits. We compared patients receiving continuous intra-arterial infusion of the calcium-antagonist nimodipine with a historical group treated with HHT and oral nimodipine alone. METHODS: Between 0.5 and 1.2 mg/h of nimodipine were continuously administered by intra-arterial infusion via microcatheters either into the internal carotid or vertebral artery or both, depending on the areas of vasospasm. The effect was controlled via multimodal neuromonitoring and transcranial Doppler sonography. Outcome was determined by means of the Glasgow Outcome Scale at discharge and 6 months after the hemorrhage and compared to a historical control group. RESULTS: Twenty-one patients received 28 intra-arterial nimodipine infusions. Six months after discharge, the occurrence of cerebral infarctions was significantly lower (42.6 %) in the nimodipine group than in the control group (75.0 %). This result was reflected by a significantly higher proportion (76.0 %) of patients with good outcome in the nimodipine-treated group, when compared to 10.0 % good outcome in the control group. Median GOS was 4 in the nimodipine group and 2 in the control group (p = 0.001). CONCLUSIONS: Continuous intra-arterial nimodipine infusion is an effective treatment for patients with severe cerebral vasospasm who fail to respond to HHT and oral nimodipine alone. Key to the effective administration of continuous intra-arterial nimodipine is multimodal neuromonitoring and the individual adaptation of dosage and time of infusion for each patient.

Intracranial hemorrhage: frequency, location, and risk factors identified in a TeleStroke network.

Intracranial hemorrhages are associated with high rates of disability and mortality. Telemedicine in general provides clinical healthcare at a distance by using videotelephony and teleradiology and is used particularly in acute stroke care medicine (TeleStroke). TeleStroke considerably improves quality of stroke care (for instance, by increasing thrombolysis) and may be valuable for the management of intracranial hemorrhages in rural hospitals and hospitals lacking neurosurgical departments, given that surgical/interventional therapy is only recommended for a subgroup of patients. The aim of this study was to analyze the frequency, anatomical locations of intracranial hemorrhage, risk factors, and the proportion of patients transferred to specialized hospitals. We evaluated teleconsultations conducted between 2008 and 2010 in a large cohort of patients consecutively enrolled in the Telemedical Project for Integrated Stroke Care (TEMPiS) network. In cases in which intracranial hemorrhage was detected, all images were re-examined and analyzed with a focus on frequency, location, risk factors, and further management. Overall, 6187 patients presented with stroke-like symptoms. Intracranial hemorrhages were identified in 631 patients (10.2%). Of these, intracerebral hemorrhages were found in 423 cases (67.0%), including 174 (41.1%) in atypical locations and 227 (53.7%) in typical sites among other locations. After 14 days of hospitalization in community facilities, the mortality rate in patients with intracranial hemorrhages was 15.1% (95/631). Two hundred and twenty-three patients (35.3%) were transferred to neurological/neurosurgical hospitals for diagnostic workup or additional treatment. Community hospitals are confronted with patients with intracranial hemorrhage, whose management requires specific neurosurgical and hematological expertise with respect to hemorrhage subtype and clinical presentation. TeleStroke networks help select patients who need advanced neurological and/or neurosurgical care. The relatively low proportion of interhospital transfers shown in this study reflects a differentiated decision process on the basis of both guidelines and standard operating procedures.

Hyperperfusion syndrome after MCA embolectomy - a rare complication?

PATIENT: Female, 78 FINAL DIAGNOSIS: Cerebral hyperperfusion syndrome Symptoms: - MEDICATION: - Clinical Procedure: Endovascular embolectomy Specialty: Neurology. OBJECTIVE: Unknown ethiology. BACKGROUND: Cerebral hyperperfusion syndrome (cHS) is a well known but rare complication after carotid endarterectomy, carotid angioplasty with stenting, and stenting of intracranial arterial stenosis. The clinical presentation may vary from acute onset of focal oedema (stroke-like presentation) and intracerbral hemorrhage to delayed (>24h hours after the procedure) presentation with seizures, focal motor weakness, or late intracerebral hemorrhage. The incidence of cHS after carotid endarterectomy ranges from 0-3% and defined as an increase of the ipsilateral cerebral blood flow up to 40% over baseline in ultrasound. CASE REPORT: We present a case of a 78-year-old woman with an acute ischemic stroke due to left side middle cerebral artery territory with right sided hemiparesis and aphasia (NIHSS 16). After systemic thrombolysis embolectomy using a retractable stent (Solitaire(®) device) was performed and resulted in complete and successful recanalization of MCA including its branches about 210 minutes after symptom onset but, partial dislocation of thrombotic material into the anterior cerebral artery (ACA). CONCLUSIONS: Cerebral hyperperfusion syndrome should be considered in patients with clinical deterioration after successful recanalisation and the early diagnosis and treatment may be important for neurological outcome after endovascular embolectomy.

Novel application of T1-weighted BLADE sequences with fat suppression compared to TSE in contrast-enhanced T1-weighted imaging of the neck: cutting-edge images?

PURPOSE: To evaluate if the use of BLADE sequences might overcome some limitations of magnetic resonance imaging (MRI) in the extracranial head and neck, which is a diagnostically challenging area with a variety of artifacts and a broad spectrum of potential lesions. MATERIALS AND METHODS: After informed consent and Institutional Review Board approval, two different BLADE sequences with (BLADE IR) and without inversion pulse (BLADE) were compared to turbo-spin echo (TSE) with fat saturation for coronal T1-weighted postcontrast imaging of the extracranial head and neck region in 40 individuals of a routine patient collective. Visual evaluation of image sharpness, motion artifacts, vessel pulsation, contrast of anatomic structures, contrast of pathologies to surrounding tissue as well as BLADE-specific artifacts was performed by two experienced, independent readers. Statistical evaluation was done by using the Wilcoxon test. RESULTS: Both BLADE and BLADE IR were significantly superior to TSE regarding pulsation artifacts and delineation of thoracic structures. TSE provided better results concerning contrast muscle/fat tissue and contrast lymph nodes/fat. More important, it showed significantly better contrast of several lesions, facilitating the detection of patient pathology. CONCLUSION: T1-weighted coronal imaging of the extracranial head and neck region is demanding. T1-weighted BLADE sequences still have drawbacks in anatomical contrast and lesion detection but offer possibilities to achieve reasonable image quality in difficult cases with a variety of artifacts.

Amyloid-ß contributes to blood-brain barrier leakage in transgenic human amyloid precursor protein mice and in humans with cerebral amyloid angiopathy.

BACKGROUND AND PURPOSE: Cerebral amyloid angiopathy (CAA) is a degenerative disorder characterized by amyloid-ß (Aß) deposition in the blood-brain barrier (BBB). CAA contributes to injuries of the neurovasculature including lobar hemorrhages, cortical microbleeds, ischemia, and superficial hemosiderosis. We postulate that CAA pathology is partially due to Aß compromising the BBB. METHODS: We characterized 19 patients with acute stroke with "probable CAA" for neurovascular pathology based on MRI and clinical findings. Also, we studied the effect of Aß on the expression of tight junction proteins and matrix metalloproteases (MMPs) in isolated rat brain microvessels. RESULTS: Two of 19 patients with CAA had asymptomatic BBB leakage and posterior reversible encephalopathic syndrome indicating increased BBB permeability. In addition to white matter changes, diffusion abnormality suggesting lacunar ischemia was found in 4 of 19 patients with CAA; superficial hemosiderosis was observed in 7 of 9 patients. Aß(40) decreased expression of the tight junction proteins claudin-1 and claudin-5 and increased expression of MMP-2 and MMP-9. Analysis of brain microvessels from transgenic mice overexpressing human amyloid precursor protein revealed the same expression pattern for tight junction and MMP proteins. Consistent with reduced tight junction and increased MMP expression and activity, permeability was increased in brain microvessels from human amyloid precursor protein mice compared with microvessels from wild-type controls. CONCLUSIONS: Our findings indicate that Aß contributes to changes in brain microvessel tight junction and MMP expression, which compromises BBB integrity. We conclude that Aß causes BBB leakage and that assessing BBB permeability could potentially help characterize CAA progression and be a surrogate marker for treatment response.

Mobilisation of hematopoietic CD34+ precursor cells in patients with acute stroke is safe--results of an open-labeled non randomized phase I/II trial.

BACKGROUND: Regenerative strategies in the treatment of acute stroke may have great potential. Hematopoietic growth factors mobilize hematopoietic stem cells and may convey neuroprotective effects. We examined the safety, potential functional and structural changes, and CD34(+) cell-mobilization characteristics of G-CSF treatment in patients with acute ischemic stroke. METHODS AND RESULTS: Three cohorts of patients (8, 6, and 6 patients per cohort) were treated subcutaneously with 2.5, 5, or 10 µg/kg body weight rhG-CSF for 5 consecutive days within 12 hrs of onset of acute stroke. Standard treatment included i.v. thrombolysis. Safety monitoring consisted of obtaining standardized clinical assessment scores, monitoring of CD34(+) stem cells, blood chemistry, serial neuroradiology, and neuropsychology. Voxel-guided morphometry (VGM) enabled an assessment of changes in the patients' structural parenchyma. 20 patients (mean age 55 yrs) were enrolled in this study, 5 of whom received routine thrombolytic therapy with r-tPA. G-CSF treatment was discontinued in 4 patients because of unrelated adverse events. Mobilization of CD34(+) cells was observed with no concomitant changes in blood chemistry, except for an increase in the leukocyte count up to 75,500/µl. Neuroradiological and neuropsychological follow-up studies did not disclose any specific G-CSF toxicity. VGM findings indicated substantial atrophy of related hemispheres, a substantial increase in the CSF space, and a localized increase in parenchyma within the ischemic area in 2 patients. CONCLUSIONS: We demonstrate a good safety profile for daily administration of G-CSF when begun within 12 hours after onset of ischemic stroke and, in part in combination with routine i.v. thrombolysis. Additional analyses using VGM and a battery of neuropsychological tests indicated a positive functional and potentially structural effect of G-CSF treatment in some of our patients. TRIAL REGISTRATION: German Clinical Trial Register DRKS 00000723.

Comprehensive small animal imaging strategies on a clinical 3 T dedicated head MR-scanner; adapted methods and sequence protocols in CNS pathologies.

BACKGROUND: Small animal models of human diseases are an indispensable aspect of pre-clinical research. Being dynamic, most pathologies demand extensive longitudinal monitoring to understand disease mechanisms, drug efficacy and side effects. These considerations often demand the concomitant development of monitoring systems with sufficient temporal and spatial resolution. METHODOLOGY AND RESULTS: This study attempts to configure and optimize a clinical 3 Tesla magnetic resonance scanner to facilitate imaging of small animal central nervous system pathologies. The hardware of the scanner was complemented by a custom-built, 4-channel phased array coil system. Extensive modification of standard sequence protocols was carried out based on tissue relaxometric calculations. Proton density differences between the gray and white matter of the rodent spinal cord along with transverse relaxation due to magnetic susceptibility differences at the cortex and striatum of both rats and mice demonstrated statistically significant differences. The employed parallel imaging reconstruction algorithms had distinct properties dependent on the sequence type and in the presence of the contrast agent. The attempt to morphologically phenotype a normal healthy rat brain in multiple planes delineated a number of anatomical regions, and all the clinically relevant sequels following acute cerebral ischemia could be adequately characterized. Changes in blood-brain-barrier permeability following ischemia-reperfusion were also apparent at a later time. Typical characteristics of intra-cerebral haemorrhage at acute and chronic stages were also visualized up to one month. Two models of rodent spinal cord injury were adequately characterized and closely mimicked the results of histological studies. In the employed rodent animal handling system a mouse model of glioblastoma was also studied with unequivocal results. CONCLUSIONS: The implemented customizations including extensive sequence protocol modifications resulted in images of high diagnostic quality. These results prove that lack of dedicated animal scanners shouldn't discourage conventional small animal imaging studies.