Feasibility and acceptance of simultaneous amyloid PET/MRI.

PURPOSE: Established Alzheimer's disease (AD) biomarker concepts classify into amyloid pathology and neuronal injury biomarkers, while recent alternative concepts classify into diagnostic and progression AD biomarkers. However, combined amyloid positron emission tomography/magnetic resonance imaging (PET/MRI) offers the chance to obtain both biomarker category read-outs within one imaging session, with increased patient as well as referrer convenience. The aim of this pilot study was to investigate this matter for the first time. METHODS: 100 subjects (age 70 ± 10 yrs, 46 female), n = 51 with clinically defined mild cognitive impairment (MCI), n = 44 with possible/probable AD dementia, and n = 5 with frontotemporal lobe degeneration, underwent simultaneous [18F]florbetaben or [11C]PIB PET/MRI (3 Tesla Siemens mMR). Brain amyloid load, mesial temporal lobe atrophy (MTLA) by means of the Scheltens scale, and other morphological brain pathologies were scored by respective experts. The patients/caregivers as well as the referrers were asked to assess on a five-point scale the convenience related to the one-stop-shop PET and MRI approach. RESULTS: In three subjects, MRI revealed temporal lobe abnormalities other than MTLA. According to the National Institute on Aging-Alzheimer's Association classification, the combined amyloid-beta PET/MRI evaluation resulted in 31 %, 45 %, and 24 % of the MCI subjects being categorized as "MCI-unlikely due to AD", "MCI due to AD-intermediate likelihood", and "MCI due to AD-high likelihood", respectively. 50 % of the probable AD dementia patients were categorized as "High level of evidence of AD pathophysiological process", and 56 % of the possible AD dementia patients as "Possible AD dementia - with evidence of AD pathophysiological process". With regard to the International Working Group 2 classification, 36 subjects had both positive diagnostic and progression biomarkers. The patient/caregiver survey revealed a gain of convenience in 88 % of responders as compared to a theoretically separate PET and MR imaging. In the referrer survey, an influence of the combined amyloid-beta PET/MRI on the final diagnosis was reported by 82 % of responders, with a referrer acceptance score of 3.7 ± 1.0 on a 5-point scale. CONCLUSION: Simultaneous amyloid PET/MRI is feasible and provides imaging biomarkers of all categories which are able to supplement the clinical diagnosis of MCI due to AD and that of AD dementia. Further, patient and referrer convenience is improved by this one-stop-shop imaging approach.

Clinical Presentation and Multi-Parametric Screening Surrogates of Ischemic Stroke Patients Suffering from Infective Endocarditis.

BACKGROUND: Infective endocarditis (IE) represents a life-threatening condition due to complications like cardiac failure and thromboembolism. In ischemic stroke, IE formally excludes patients from approaches addressing the recanalization of occluded vessels, challenging decision-making in the early phase of hospitalization. This study aimed at the rate and clinical course of stroke patients with IE and explored clinical, imaging-based and serum parameters, which would allow early identification. METHODS: A hospital-based registry containing 1,531 ischemic stroke patients was screened for IE identified by echocardiography. In addition to clinical parameters, patterns of cerebral manifestation as well as a variety of inflammatory serum and myocardial markers were analyzed concerning their predictive impact for identifying affected patients. RESULTS: IE was found in 26 patients (1.7%) and was associated with an increased body temperature and cardiac murmurs. Patients suffering from IE demonstrated a more severe clinical affection at hospital discharge and an impaired symptom decline during hospitalization, further deteriorated by the use of systemic thrombolysis. Distribution of cerebral infarction patterns did not differ between the groups. C-reactive protein (CRP) and leukocyte count as well as troponin and myoglobin, taken at hospital admission, were found to be significantly associated with IE. CONCLUSIONS: IE in stroke patients is associated with worse clinical outcome, complicated by intravenously applied thrombolysis, and therefore needs to be screened during the early phase of hospitalization. Increased serum levels of CRP and leukocyte count in combination with an increased body temperature or abnormal cardiac murmurs should entail rapid initiation of further diagnostics, that is, transoesophageal echocardiography.

Three gangliogliomas: results of GTG-banding, SKY, genome-wide high resolution SNP-array, gene expression and review of the literature.

According to the World Health Organization gangliogliomas are classified as well-differentiated and slowly growing neuroepithelial tumors, composed of neoplastic mature ganglion and glial cells. It is the most frequent tumor entity observed in patients with long-term epilepsy. Comprehensive cytogenetic and molecular cytogenetic data including high-resolution genomic profiling (single nucleotide polymorphism (SNP)-array) of gangliogliomas are scarce but necessary for a better oncological understanding of this tumor entity. For a detailed characterization at the single cell and cell population levels, we analyzed genomic alterations of three gangliogliomas using trypsin-Giemsa banding (GTG-banding) and by spectral karyotyping (SKY) in combination with SNP-array and gene expression array experiments. By GTG and SKY, we could confirm frequently detected chromosomal aberrations (losses within chromosomes 10, 13 and 22; gains within chromosomes 5, 7, 8 and 12), and identify so far unknown genetic aberrations like the unbalanced non-reciprocal translocation t(1;18)(q21;q21). Interestingly, we report on the second so far detected ganglioglioma with ring chromosome 1. Analyses of SNP-array data from two of the tumors and respective germline DNA (peripheral blood) identified few small gains and losses and a number of copy-neutral regions with loss of heterozygosity (LOH) in germline and in tumor tissue. In comparison to germline DNA, tumor tissues did not show substantial regions with significant loss or gain or with newly developed LOH. Gene expression analyses of tumor-specific genes revealed similarities in the profile of the analyzed samples regarding different relevant pathways. Taken together, we describe overlapping but also distinct and novel genetic aberrations of three gangliogliomas.

Mechanical thrombectomy in patients with acute vertebrobasilar occlusion using the Trevo device: a single-centre experience.

INTRODUCTION: The purpose of this study is to investigate the efficacy and safety of mechanical thrombectomy in patients with acute vertebrobasilar artery occlusion (VBAO) using the Trevo Stentriever™ device. METHODS: Twenty patients diagnosed with VBAO underwent digital subtraction angiography (DSA) with the intention to perform mechanical thrombectomy with stent-retrievers between August 2011 and October 2013. Two patients were excluded because another device was primarily used; in two other patients, thrombectomy was not possible. RESULTS: Thrombectomy with the Trevo device was performed in 16 patients. The Stentriever™ was used either as the sole device (56.3 %) or in conjunction with up to four additional devices or techniques. Thirty-three clot retrieval manoeuvres were performed (mean 2.1 ± 1.3, range 1-5); the device could be deployed and retrieved in all manoeuvres (100 %). No device-related complications occurred. Mean duration of the endovascular intervention was 71.8 min (±39.9; range 22-144). Complete or near complete recanalization (thrombolysis in cerebral infarction (TICI) ≥2b) was achieved in 13 patients (81.3 %). Eleven patients (68.8 %) survived and seven patients (43.8 %) showed a good clinical outcome at discharge, defined as modified Rankin Scale (mRS) 0-2 or National Institute of Health Stroke Scale (NIHSS) improvement ≥10 points. Including the two patients in whom thrombectomy was not possible, successful recanalization, good clinical outcome and survival were achieved in 72.2, 38.9 and 61.1 %, respectively. CONCLUSIONS: Thrombectomy in patients with acute VBAO using the Trevo Stentriever™-either as the sole device or in conjunction with other devices-is feasible and seems to be similarly effective and safe as in the anterior circulation compared to reported data in the literature.

Integrated PET/MRI for planning navigated biopsies in pediatric brain tumors.

INTRODUCTION: An integrated PET/MRI scanner has been used in selected cases of pediatric brain tumor patients to obtain additional metabolic information about lesions for preoperative biopsy planning and navigation. PATIENTS AND METHODS: Four patients, age 9-16 years, received PET/MRI scans employing [(11)C]methionine positron emission tomography (PET) and contrast-enhanced 3D-MR sequences for neuronavigation. PET and MR sequences have been matched for neurosurgical guidance. An infrared camera-based neuronavigation system was employed with co-registered MR and PET images fused to hybrid images for preoperative planning, stereotactic biopsy planning, and/or intraoperative guidance. RESULTS: All patients showed hot spots of increased amino acid transport in PET and contrast-enhancing lesions in MRI. In three of the four patients, PET hot spots were congruent with contrast-enhancing areas in MRI. In two patients, frame-based stereotactic biopsies were taken from thalamo-mesencephalic lesions. One patient underwent second-look surgery for the suspicion of recurrent malignant glioma of the posterior fossa. One incidental frontal mass lesion was subtotally resected. No complications occurred. Hybrid imaging was helpful during the procedures to obtain representative histopathologic specimens and for surgical guidance during resection. Co-registered images did match with intraoperative landmarks, tumor borders, and histopathologic specimens. CONCLUSION: The integrated PET/MRI scanner offers co-registered multimodal, high-resolution data for neuronavigation with reduced radiation exposure compared to PET/CT scans. One examination session provides all necessary data for neuronavigation and preoperative planning, avoiding additional anesthesia in the small patients. Hybrid multimodality imaging may improve safety and yield additional information when obtaining representative histopathologic specimens of brain tumors.

The influence of lumbar spinal drainage on diffusion parameters in patients with suspected normal pressure hydrocephalus using 3T MRI.

BACKGROUND: Normal pressure hydrocephalus (NPH) has been an ongoing and challenging field of research for the past decades because two main issues are still not fully understood: the pathophysiologic mechanisms underlying ventricular enlargement and prediction of outcome after surgery. PURPOSE: To evaluate changes in diffusion tensor imaging (DTI) derived parameters in patients with suspected normal pressure hydrocephalus before and after withdrawal of cerebrospinal fluid (CSF). MATERIAL AND METHODS: Twenty-four consecutive patients with clinical and radiological suspicion of NPH and 14 age-matched control subjects were examined with DTI on a clinical 3T scanner. Patients were examined before and 6-36 h after CSF drainage (interval between scans, 5 days). Fifteen patients were finally included in data analysis. Fractional anisotropy (FA) and mean, parallel, and radial diffusivity (MD, PD, RD) were evaluated using a combination of a ROI-based approach and a whole-brain voxel-by-voxel analysis. RESULTS: Alteration of DTI parameters in patients with suspected NPH is regionally different. Compared to the control group, we found an elevation of FA in the subcortical white matter (SCWM) and corpus callosum, whereas the other diffusion parameters showed an increase throughout the brain in variable extent. We also found a slight normalization of RD in the SCWM in patients after lumbar drainage. CONCLUSION: Our results show that DWI parameters are regionally dependent and reflect multifactorial (patho-) physiological mechanisms, which need to be interpreted carefully. It seems that improvement of gait is caused by a decrease of interstitial water deposition in the SCWM.

Implementing conventional Zamorano Dujovny frames versus individually manufactured microTargeting platforms--a comparative study on deep brain stimulation in Parkinson patients.

BACKGROUND AND OBJECTIVES: Individually manufactured microTargeting™ platforms (MT) provide a novel generation of stereotactic systems based on preoperatively implanted bone markers and screws. The feasibility and reliability of these frames were evaluated for bilateral deep brain stimulation (DBS) in patients with idiopathic Parkinson's disease (IPD). Surgical and clinical results were compared to conventional Zamorano Dujovny frames (ZD) in this prospective study. MATERIALS AND METHODS: Twenty-six IPD patients undergoing surgery for DBS were divided into 2 groups. In group I, electrode implantation was accomplished using conventional ZD. Group II underwent electrode implantation using MT. Microrecording and macrostimulation were performed and surgery time was measured. The clinical outcome was determined using the Unified Parkinson's Disease Rating Scale Part III (UPDRS III) and L-dopa-equivalent doses for a 12-month follow-up postoperatively. RESULTS: Clinical evaluation confirmed comparable outcomes for both targeting procedures and electrode positioning. Surgical time was lower in group II than in group I. Significant improvements were determined for both groups in UPDRS III and L-dopa-equivalent dose. CONCLUSIONS: Both systems allow for reliable and safe neurosurgical procedures, yielding comparable clinical results. MT improved handling and automatic adjustment of frame coordinates. Surgery time was reduced markedly compared to conventional frames.

Improvement of SNR and acquisition acceleration using a 32-channel head coil compared to a 12-channel head coil at 3T.

BACKGROUND: Magnetic resonance imaging (MRI) techniques continue to improve in manifold ways. Besides field strength and sequence optimization, technical advances in coil design and sensitivity yield to increase the signal detection and therefore improve image quality. PURPOSE: To evaluate the performance of signal-to-noise ratio (SNR) and parallel acquisition technique (PAT) acceleration of a dedicated 32-channel head coil compared with a standard 12-channel head coil. MATERIAL AND METHODS: In a clinical 3T setting, spatial resolved SNR values for unaccelerated imaging and PAT with acceleration factors of 2-6 of a 32-channel head coil were evaluated in relation to a 12-channel head coil. SNR was determined quantitatively using proton-density-weighted in-vivo examinations in five healthy volunteers. Quantitative SNR maps for unaccelerated and PAT imaging were calculated using unfiltered MR raw data. RESULTS: Up to three-fold higher SNR values were achieved with the 32-channel head coil, which diminished towards the center to an increase of 40% compared with the 12-channel head coil. When using PAT, the 32-channel head coil resulted in a lower spatial-dependent quantitative noise enhancement, varying between 0% at R = 2 and 33% at R = 5. CONCLUSION: The 32-channel head coil provided superior SNR both with and without PAT compared with a 12-channel head coil, especially close to the brain surface. Using PAT, the unavoidable noise enhancement is diminished up to acceleration factors of 6 for the 32-channel head coil. Therefore, the 32-channel head coil is considered as a preferable tool for high-resolution neuroradiological imaging.

Mechanical thrombectomy versus systemic thrombolysis in MCA stroke: a distance to thrombus-based outcome analysis.

BACKGROUND: Acute ischemic stroke due to occlusion of the middle cerebral artery (MCA) has a poor outcome. The distance to thrombus (DT) from the carotid T can predict the outcome after intravenous thrombolysis (IVT). With a DT <16 mm, fewer than 50% of patients treated with IVT have a favorable outcome. OBJECTIVE: To compare stent retriever-based endovascular mechanical thrombectomy (MT) plus additional IVT (IVT-MT) with IVT alone. MATERIALS AND METHODS: Patients with MCA occlusion proved by CT angiography with a DT <16 mm, treated with either IVT alone or with stent retriever-based endovascular IVT-MT, were included in this study. Changes in National Institutes of Health Stroke Scale (NIHSS), the 7-day NIHSS, and the 90-day modified Rankin Scale (mRS) scores were analyzed by treatment modality. RESULTS: Of 621 patients, 87 fulfilled all inclusion criteria. Fifty-nine patients were treated with IVT and 28 with IVT-MT. Although patients treated with IVT-MT had had significantly more severe strokes than those treated with IVT alone (initial NIHSS 16 (7-18) vs 14 (5-22); p=0.032), both the short- and long-term outcomes were significantly better in this patient group (NIHSS improvement on day 7: 10.9±6.3 vs 6.7±6.7; p=0.008/90-day mRS: 2 (0.75-2.5) vs 4 (2-6); p=0.003). CONCLUSIONS: In patients with an acute MCA occlusion and a DT <16 mm, IVT-MT leads to a significantly better outcome than in patients treated with IVT alone.

A comparison of two surgical approaches in functional neurosurgery: individualized versus conventional stereotactic frames.

OBJECT: The individualized Starfix® miniframe belongs to a new generation of stereotactic systems enabling high-precision electrode placement with considerably better time-efficiency in deep brain stimulation (DBS). We evaluated the usability and reliability of this novel technique in patients with idiopathic Parkinson's disease (IPD) and compared surgical and clinical results with those obtained in a historical group in which a conventional stereotactic frame was employed. METHODS: Sixty patients underwent surgery for implantation of DBS electrodes in the subthalamic nucleus. In 31 of them (group I) a conventional Zamorano-Dujovny frame was used and in 29 of them (group II) a Starfix® miniframe was used. Image fusion of preoperatively acquired 3D T1w and T2w 1.5 T MR-image series was used for the targeting procedure. Placement of the test electrodes and permanent electrodes corresponded to standard functional neurosurgery and included microelectrode recording and macrostimulation. Clinical (L-Dopa equivalent dose, United Parkinson's disease rating scale part III) and time for surgical electrode implantation were evaluated postoperatively in a 3-, 6- and 12-month follow-up. RESULTS: Twelve months postoperatively, L-Dopa dose was significantly reduced from 685.19 to 205.88 mg/day and from 757.92 to 314.42 mg/day in groups I and II, respectively. A comparable reduction of the LED could be observed 1 year after surgery. Motor function has improved in a significant and identical manner with 59% (group I) and 61% (group II). Besides clinical effects by stimulation therapy there was a significantly reduced surgery time required for electrode implantation using the Starfix® miniframe (group I: 234.1 min, group II: 173.6 min; p < 0.001). CONCLUSIONS: Individualized miniframes such as the Starfix® miniframe allow implantation of DBS electrodes in IPD that is equally effective as conventional systems. The time efficiency achieved in surgery using of the Starfix® system helps to minimize patients' discomfort during DBS surgery.

Simultaneous PET/MRI in stroke: a case series.

Prospective studies on magnetic resonance imaging (MRI)-guided systemic thrombolysis >4.5 hours after stroke onset did not reach their primary end points. It was discussed and observed in post hoc data re-assessment that this was partly because of limited MRI accuracy to measure critical hypoperfusion. We report the first cases of simultaneous [(15)O]H2O-positron emission tomography (PET)/MRI in stroke patients and an ovine model. Discrepancies between simultaneously obtained PET and MRI readouts were observed that might explain the above current limitations of stroke MRI. By offering highly complementary information, [(15)O]H2O-PET/MRI might help to identify critically hypoperfused tissue resulting in an improved patient stratification in thrombolysis trials.

Seven-tesla magnetic resonance imaging in Wilson disease using quantitative susceptibility mapping for measurement of copper accumulation.

OBJECTIVES: In Wilson disease (WD), the copper content of cerebral tissue is increased, particularly in the basal ganglia. This study investigated whether a change in magnetic susceptibility can be detected using quantitative susceptibility mapping of the brain in patients with WD compared with healthy controls. MATERIALS AND METHODS: Eleven patients with WD (6 with the neurological form, 5 with the hepatic form) and 10 age-matched healthy controls who gave informed consent were examined at 7 T in a whole-body scanner (MAGNETOM; Siemens Medical Solutions, Erlangen, Germany) using a 24-channel phased array coil (Nova Medical). For imaging, a 3-dimensional spoiled gradient multiecho sequence (repetition time, 40 milliseconds; echo time, 9.76/19.19/28.62 milliseconds; bandwidth, 150 hertz per pixel; voxel size, 0.6 × 0.6 × 0.8 mm) was used. The susceptibility of selected regions (substantia nigra, red nucleus, pallidum, putamen, caudate nucleus) was analyzed in susceptibility maps. RESULTS: The patients with WD showed significantly increased susceptibility (P value, 0.001-0.05) in all analyzed regions compared with healthy controls. This was evident not only in patients with a neurological syndrome but also, with lower values, in patients with isolated hepatic manifestations. The distribution patterns of copper accumulation were different between the patients with neurological and non-neurological manifestations of the disease. CONCLUSIONS: In neurologically symptomatic and asymptomatic patients with WD, we found increased magnetic susceptibility in the brain tissue using quantitative susceptibility mapping.

Abdominal fat distribution and its relationship to brain changes: the differential effects of age on cerebellar structure and function: a cross-sectional, exploratory study.

OBJECTIVES: To investigate whether the metabolically important visceral adipose tissue (VAT) relates differently to structural and functional brain changes in comparison with body weight measured as body mass index (BMI). Moreover, we aimed to investigate whether these effects change with age. DESIGN: Cross-sectional, exploratory. SETTING: University Clinic, Integrative Research and Treatment Centre. PARTICIPANTS: We included 100 (mean BMI=26.0 kg/m², 42 women) out of 202 volunteers randomly invited by the city's registration office, subdivided into two age groups: young-to-mid-age (n=51, 20-45 years of age, mean BMI=24.9, 24 women) versus old (n=49, 65-70 years of age, mean BMI=27.0, 18 women). MAIN OUTCOME MEASURES: VAT, BMI, subcutaneous abdominal adipose tissue, brain structure (grey matter density), functional brain architecture (eigenvector centrality, EC). RESULTS: We discovered a loss of cerebellar structure with increasing VAT in the younger participants, most significantly in regions involved in motor processing. This negative correlation disappeared in the elderly. Investigating functional brain architecture showed again inverse VAT-cerebellum correlations, whereas now regions involved in cognitive and emotional processing were significant. Although we detected similar results for EC using BMI, significant age interaction for both brain structure and functional architecture was only found using VAT. CONCLUSIONS: Visceral adiposity is associated with cerebellar changes of both structure and function, whereas the regions involved contribute to motor, cognitive and emotional processes. Furthermore, these associations seem to be age dependent, with younger adults' brains being adversely affected.

Giant intradiploic epidermoid cyst with large osteolytic lesions of the skull: a case report.

INTRODUCTION: We report a case of tumor growth over a period of four decades, presenting with large multicentric lytic lesions of the skull and a profound mass effect, without neurological deficits. Clinical and radiological features of a patient with a giant intradiploic epidermoid and its impact on the choice of treatments are discussed. CASE PRESENTATION: An 81-year-old Caucasian man, who had first noticed a painless subcutaneous swelling over the left frontal scalp about 40 years ago, presented after a short episode of dizziness, which he experienced after treatment of focal retinal detachment. Computed tomography (CT) and magnetic resonance imaging (MRI) examinations revealed an exceptionally large tumor involving major parts of the skull with extensive destruction of the bone and distinct deformation of the brain. Considering his age and the absence of neurological deficits or pain, the patient refused the option of tumor removal and cranioplasty, yet agreed to a biopsy, which confirmed the suspected diagnosis. CONCLUSIONS: The course of the disease demonstrates that even patients with large tumors, inducing distinct pathomorphological changes, do not necessarily experience significant impairment of their quality of life without surgery. This is an impressive example of the chance to lead a long and satisfying life without specific medical treatment, avoiding the inherent risks of these procedures. Yet, there is a clear indication for surgery of intradiploic epidermoids in most cases described in the literature.

Detection of novel genomic aberrations in anaplastic astrocytomas by GTG-banding, SKY, locus-specific FISH, and high density SNP-array.

Astrocytomas represent the largest and most common subgroup of brain tumors. Anaplastic astrocytoma (WHO grade III) may arise from low-grade diffuse astrocytoma (WHO grade II) or as primary tumors without any precursor lesion. Comprehensive analyses of anaplastic astrocytomas combining both cytogenetic and molecular cytogenetic techniques are rare. Therefore, we analyzed genomic alterations of five anaplastic astrocytomas using high-density single nucleotide polymorphism arrays combined with GTG-banding and FISH-techniques. By cytogenetics, we found 169 structural chromosomal aberrations most frequently involving chromosomes 1, 2, 3, 4, 10, and 12, including two not previously described alterations, a nonreciprocal translocation t(3;11)(p12;q13), and one interstitial chromosomal deletion del(2)(q21q31). Additionally, we detected previously not documented loss of heterozygosity (LOH) without copy number changes in 4/5 anaplastic astrocytomas on chromosome regions 5q11.2, 5q22.1, 6q21, 7q21.11, 7q31.33, 8q11.22, 14q21.1, 17q21.31, and 17q22, suggesting segmental uniparental disomy (UPD), applying high-density single nucleotide polymorphism arrays. UPDs are currently considered to play an important role in the initiation and progression of different malignancies. The significance of previously not described genetic alterations in anaplastic astrocytomas presented here needs to be confirmed in a larger series.

Intracranial hemangiopericytoma: Case study with cytogenetics and genome wide SNP-A analysis.

The tumor entity of hemangiopericytoma is not universally recognized as a nosological entity by pathologists, and there is a trend toward reassigning it to other categories gradually. However, hemangiopericytomas occurring in the nervous system are included in the new WHO classification of brain tumors, and are distinguished from both meningioma and fibrous tumors. Since there are few genetic studies, we performed a comprehensive cytogenetic analysis of an infratentorial hemangiopericytoma in a 55-year-old female. It was originally classified as a grade II tumor but recurred as a grade III tumor with a proliferation index of 20%. Using trypsin-Giemsa staining (GTG-banding) and multicolor fluorescence in situ hybridization (M-FISH), we could confirm the loss of chromosomal material 10q, which has been previously described in hemangiopericytoma, and we identified de novo chromosomal aberrations on chromosome 8. Applying genome-wide high-density single nucleotide polymorphism array (SNP-A) analysis, we detected segments with loss or gain, as well as clonal deletions or regions suggestive of segmental uniparental disomy. These findings, together with the results of conventional histological and immunohistochemical characterization, provide additional evidence for the nosological separation of hemangiopericytoma in the central nervous system as a biologically different entity.