Lee-Cyn Ang

Brain serotonin transporter in human methamphetamine users

RationaleResearch on methamphetamine (MA) toxicity primarily focuses on the possibility that some of the behavioural problems in human MA users might be caused by damage to brain dopamine neurones. However, animal data also indicate that MA can damage brain serotonin neurones, and it has been suggested that cognitive problems and aggression in MA users might be explained by serotonergic damage. As information on the brain serotonin system in human MA users is fragmentary, our objective was to determine whether protein levels of serotonin transporter (SERT), a key marker of serotonin neurones, are decreased in brain of chronic MA users.MethodsSERT immunoreactivity was measured using an immunoblotting procedure in autopsied brain of 16 chronic MA users testing positive for the drug in blood and brain and matched controls.ResultsSERT levels were non-significantly decreased (−14% to −33%) in caudate, putamen and thalamus (normal in hippocampus), and, unlike the robust striatal dopamine reduction, there was marked overlap between control and MA user ranges. Concentrations of SERT were significantly decreased (−23% to −39%) in orbitofrontal and occipital cortices (normal in frontopolar and temporal cortices).ConclusionsOur data suggest that MA might modestly damage brain serotonin neurones and/or inhibit SERT protein expression, with cerebral cortex being more affected than sub-cortical regions. The SERT reduction in orbitofrontal cortex complements other data suggesting involvement of this area in MA-related behaviour. Decreased brain SERT could also be related to the clinical finding that treatment with a selective serotonin re-uptake inhibitor might increase relapse to MA.

Low levels of astroglial markers in Parkinson’s disease: relationship to α-synuclein accumulation

Although gliosis is a normal response to brain injury, reports on the extent of astrogliosis in the degenerating substantia nigra in Parkinsons disease (PD) are conflicting. It has also been recently suggested that accumulation of nigral α-synuclein in this disorder might suppress astrocyte activation which in turn could exacerbate the degenerative process. This study examined brain protein levels (intact protein, fragments, and aggregates, if any) of astroglial markers and their relationship to α-synuclein in PD and in the positive control parkinson-plus conditions multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Autopsied brain homogenates of patients with PD (n=10), MSA (n=11), PSP (n=11) and matched controls (n=10) were examined for the astroglial markers glial fibrillary acidic protein (GFAP), vimentin, and heat shock protein-27 (Hsp27) by quantitative immunoblotting. As expected, both MSA (putamen>substantia nigra>caudate>frontal cortex) and PSP (substantia nigra>caudate>putamen, frontal cortex) showed widespread but regionally specific pattern of increased immunoreactivity of the markers, in particular for the partially proteolyzed fragments (all three) and aggregates (GFAP). In contrast, immunoreactivity of the three markers was largely normal in PD in brain regions examined with the exception of trends for variably increased levels of cleaved vimentin in substantia nigra and frontal cortex. In patients with PD, GFAP levels in the substantia nigra correlated inversely with α-synuclein accumulation whereas the opposite was true for MSA. Our biochemical findings of generally normal protein levels of astroglial markers in substantia nigra of PD, and negative correlation with α-synuclein concentration, are consistent with some recent neuropathology reports of mild astroglial response and with the speculation that astrogliosis might be suppressed in this disorder by excessive α-synuclein accumulation. Should astrogliosis protect, to some extent, the degenerating substantia nigra from damage, therapeutics aimed at normalization of astrocyte reaction in PD could be helpful.

Neuropathology of heart transplantation

The neuropathology of 18 cardiac transplant recipients was reviewed with the clinical findings. Pathological changes were noted in the central nervous system (CNS) in 94% of the patients, the most frequent being cerebral vascular in origin (72%). Eight patients (44%) had multiple cerebral infarcts and morphologically, a large number of these antedated the transplantation. In addition 4 patients had acute focal ischemic changes which occurred after transplantation. Intracranial hemorrhage was noted in 5 patients (28%), including one case of fatal intracerebral hemorrhage following an acute hypertensive episode after the transplantation. While systemic infection was common (10 patients), there were only 5 cases of intracranial infection; including 3 cases of cytomegalovirus infection, one of candidiasis and one of aspergillosis. Post-transplant seizures, occurring in a third of the patients, were related to a variety of causative factors such as sepsis, intracranial hemorrhage, cerebral ischemia, metabolic encephalopathy and cyclosporin neurotoxicity. Of note in this series was the absence of CNS lymphoma or other systemic lymphoproliferative disorder.

Intraparenchymal supratentorial neurenteric cyst.

BACKGROUND Neurenteric cysts are congenital cysts of the central nervous system that are believed to be of endodermal origin. In this report we present the unique case of a supratentorial neurenteric cyst that is contained entirely within the brain parenchyma. METHODS A patient presented with an intraparenchymal cystic lesion that was subsequently identified as a neurenteric cyst. This lesion is reviewed in light of the available literature. CASE REPORT A 35-year-old female presented with a one year history of progressive headaches and seizure-like episodes. Her examination revealed no deficits. Magnetic resonance imaging showed a 4 cm x 4 cm x 4 cm cystic lesion within the parenchyma of the right frontal lobe. A right frontal craniotomy and complete excision of the cystic lesion was performed. Pathologic examination confirmed that it was a neurenteric cyst. Postoperatively the patients symptoms improved. CONCLUSION Review of the literature revealed this to be the first case of a surgically excised, pathologically confirmed supratentorial neurenteric cyst, contained entirely within the brain parenchyma.

Severe cerebellar degeneration in a patient with T-cell lymphoma.

SummaryA 53-year-old man with an aggressive T-cell lymphoma was found at autopsy to have severe cerebellar degeneration, presumably as a ‘remote’ effect of malignancy. The degree of cerebellar atrophy was unusually pronounced and widespread, involving both Purkinje cell and granule cell layers, although patches of preserved and essentially normal cerebellar cortex were identified. This case is of particular interest in view of data which indicate that cerebellar Purkinje cells and T-lymphocytes share antigenic surface markers.

Catheter based selective hypothermia reduces stroke volume during focal cerebral ischemia in swine

Background Total body hypothermia is an established neuroprotectant in global cerebral ischemia. The role of hypothermia in acute ischemic stroke remains uncertain. Selective application of hypothermia to a region of focal ischemia may provide similar protection with more rapid cooling and elimination of systemic side effects. We studied the effect of selective endovascular cooling in a focal stroke model in adult domestic swine. Methods After craniotomy under general anesthesia, a proximal middle cerebral artery branch was occluded for 3 h, followed by 3 h of reperfusion. In half of the animals, selective hypothermia was induced during reperfusion using a dual lumen balloon occlusion catheter placed in the ipsilateral common carotid artery. Following reperfusion, the animals were sacrificed. Brain MRI and histology were evaluated by experts who were blinded to the intervention. Results 25 animals were available for analysis. Using selective hypothermia, hemicranial temperature was successfully cooled to a mean of 26.5°C. Average time from start of perfusion to attainment of moderate hypothermia (<30°C) was 25 min. Mean MRI stroke volumes were significantly reduced by selective cooling (0.050±0.059 control, 0.005±0.011 hypothermia (ratio stroke:hemisphere volume) (p=0.046). Stroke pathology volumes were reduced by 42% compared with controls (p=0.256). Conclusions Selective moderate hypothermia was rapidly induced using endovascular techniques in a clinically realistic swine stroke model. A significant reduction in stroke volume on MRI was observed. Endovascular selective hypothermia can provide neuroprotection within time frames relevant to acute ischemic stroke treatment.

Intracranial segmental arterial mediolysis: report of 2 cases and review of the literature.

Extensive nontraumatic subarachnoid hemorrhage is an important cause of unexpected death in young adults. Segmental arterial mediolysis (SAM) represents an uncommon pathologic finding in the intracranial blood vessels associated with this type of hemorrhage. Segmental arterial mediolysis is a pathologic entity with putative vasospastic etiology, which recently has been reported to be associated with Ehlers-Danlos syndrome type 4. We describe 2 additional cases of ruptured intracranial vertebral artery with features of SAM that resulted in fatal subarachnoid hemorrhage. We also review the literature on vessels with features of SAM that are either intracranial or affecting the internal carotid artery with major direct effects (ie, stroke or transient ischemic attack) on the central nervous system.

Adult-Onset Leukodystrophy: Review of 3 Clinicopathologic Phenotypes and a Proposed Classification

Adult-onset leukodystrophies are clinically and pathologically heterogeneous diseases, and the overlapping morphologic features among these disorders can lead to confusion in pathologic classification. We report 3 recent autopsy cases that illustrate the clinicopathologic distinction between the 3 entities. The first, autosomal dominant leukodystrophy, is characterized clinically by early autonomic dysfunction and genetically by LMNB1 (lamin B1 gene) duplication. Recently, another clinical subtype emerged without the early autonomic dysfunction but with a similar genetic abnormality documented in 1 family. We reviewed the reported autopsy cases and show that both clinical subtypes share distinctive pathologic features. Other forms of adult-onset leukodystrophy can be classified based on the histologic evidence of the primary pathologic processes. A case of axonopathy with secondary demyelination serves as a prototype for adult-onset leukoencephalopathy/leukodystrophy with axonal spheroids; the genetic mutation of CSF1R (colony stimulating factor 1R) was recently discovered in patients with this disorder. A case of a primary demyelinating disease with no other distinctive pathologic features is designated as orthochromatic leukodystrophy. Pigmented glia can be present in both of the latter two categories and should not be used as a differentiating diagnostic feature. Based on the observations of our cases and literature review, we propose an algorithm for a practical diagnostic approach to adult-onset leukodystrophies.

Emergence of Primary CNS Lymphoma in a Patient with Findings of CLIPPERS

We report the case of a patient who had clinical, radiological, and neuropathological features initially suggestive of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) but who ultimately succumbed to autopsy-proven primary central nervous system lymphoma (PCNSL). This case emphasizes the need for close follow-up of patients who are suspected to have CLIPPERS, and the importance of maintaining a continued high index of suspicion for an alternative diagnosis, particularly when such patients develop steroid-resistance. CLIPPERS is a recently described inflammatory disease1-3 centred in the pons with common features including: (1) episodic brainstem symptoms responsive to corticosteroids and immunotherapy; (2) characteristic punctate and curvilinear gadolinium-enhancing lesions predominantly in the pons with variable involvement of other structures including the cerebellum, cerebral white matter, and spinal cord on magnetic resonance imaging (MRI); and (3) T-lymphocytic infiltrate with perivascular predominance in the brain biopsy specimens2. The original paper on CLIPPERS, by Pittock et al in 2010, described eight patients with common clinical, radiological, and pathological features. Since that time, two other case series2,3 described an additional 17 patients with similar features. Followup periods ranged from 6 to 408 months. It has been suggested that the combination of clinical and radiological features in CLIPPERS may be sufficiently distinctive that the disease could be diagnosed and treated without pathological examination, if alternative diagnoses are rigorously excluded1. However, making a definitive diagnosis remains challenging due to the lack of specific biomarkers and overlap in imaging features with a number of other disease entities, such as neurosarcoidosis, central nervous system (CNS) lymphoma, lymphomatoid granulomatosis, CNS vasculitis, chronic perivascular infectious process, Behçet disease, glioma, demyelinating disease, and histiocytosis1.

Hemangioblastoma Stromal Cells Show Committed Stem Cell Phenotype

BACKGROUND Hemangioblastomas are benign vascular tumors of the central nervous system that occur sporadically or in association with von Hippel-Lindau disease. These tumors are characteristically composed of a dense capillary network with intervening stromal/interstitial cells. To date, the histogenesis of hemangioblastoma remains unclear. We hypothesize that hemangioblastomas arise from a defective mesodermal stem cell, which gives rise to the atypical vasculature. METHODS To test our hypothesis, we have characterized the cellular composition of hemangioblastomas by immunophenotyping pluripotent and committed stem cells and vascular endothelial cells. RESULTS Our findings show that hemangioblastoma endothelial cells are positive for CD133, a stem and progenitor cell marker. Vascular endothelial cells also expressed nuclear Oct4. In addition to the endothelium, both CD133 and Oct4 were present in stromal and perivascular cells. Interestingly, neither the endothelium nor the stromal cells expressed Sox2 or Nanog suggesting a committed stem cell phenotype. CONCLUSIONS From these findings, we believe that hemangioblastoma stromal cells are committed stem cells producing both vascular cell types. The findings also show an unusual CD133-positive endothelial phenotype in hemangioblastoma.