Francesca Brett

Evolution of Neuropathologic Abnormalities Associated with Blood-Brain Barrier Breakdown in Transgenic Mice Expressing Interleukin-6 in Astrocytes

Abstract. As both astrocytes and cytokines modulate the permeability of cerebral endothelial cells, transgenic animal models which overexpress cytokines, such as interleukin-6 (IL-6), may provide insight into the neuropathological consequences of increased BBB permeability. In this study, a GFAP-IL6 transgenic mouse model and horseradish peroxidase (HRP) were used to investigate BBB permeability and associated neuropathologic changes. In the cerebellum of control mice, the BBB developed between postnatal days 7 and 14. In transgenic mice, the BBB never developed and extensive breakdown was evident in both high- and low-expressor animals by 1 month after birth. Vascular proliferation was apparent from birth in association with development and retention of normal cerebellar architecture until 3 and 6 months in high- and low-expressor animals, respectively. At these times, a leptomeningeal inflammatory infiltrate, vacuolated astrocytic foot processes and endothelial abnormalities were apparent in the cerebellum. At 6 months in high-expressor and 12 months in low-expressor animals, parenchymal inflammation, gliosis, spongiform change, axonal degeneration and macrophage accumulation were evident. The findings suggest that increased production of IL-6 can influence the development and physiologic function of the BBB as well as contribute to parenchymal central nervous system injury.

Rapid-onset dystonia-parkinsonism : A clinical and genetic analysis of a new kindred

Background: Rapid-onset dystonia-parkinsonism (RDP) is an autosomal dominant disorder linked to chromosome 19q13 that is characterized by sudden onset of primarily bulbar and upper limb dystonia with parkinsonism. Methods: The authors evaluated 12 individuals from three generations of an Irish family and obtained detailed medical records on a deceased member. The authors describe the clinical, psychiatric, and genetic features of the affected individuals. Results: Five of eight affected members developed sudden-onset (several hours to days) dystonia with postural instability. Four of the five also had bulbar symptoms. Two have stable focal or segmental limb dystonia. One has intermittent hemidystonia with dysarthria that comes on abruptly in times of stress or anxiety. Three had a history of profound difficulty socializing, and at presentation two developed depression. Three patients had a trial of dopamine agonists without benefit. Genetic analysis suggests linkage to chromosome 19 with lod score of 2.1 at zero recombination. Conclusion: This is the third reported family with chromosome 19q13 rapid-onset dystonia-parkinsonism. Psychiatric morbidity appeared common in affected members of this family and may be part of the RDP phenotype.

“True” sporadic ALS associated with a novel SOD-1 mutation

Mutations in the Cu/Zn superoxide dismutase gene (SOD‐1) are reported in 20% of familial amyotrophic lateral sclerosis (ALS) cases, but no definite report of a mutation in a “truly” sporadic case of ALS has been proved. We present the first case of a novel SOD‐1 mutation in a patient with genetically proven sporadic ALS. This mutation (H80A) is believed to alter zinc ligand binding, and its functional significance correlates well with the aggressive clinical course and postmortem findings observed in this patient.

Parkin disease: A clinicopathologic entity?

IMPORTANCE Mutations in the gene encoding parkin (PARK2) are the most common cause of autosomal recessive juvenile-onset and young-onset parkinsonism. The few available detailed neuropathologic reports suggest that homozygous and compound heterozygous parkin mutations are characterized by severe substantia nigra pars compacta neuronal loss. OBJECTIVE To investigate whether parkin-linked parkinsonism is a different clinicopathologic entity to Parkinson disease (PD). DESIGN, SETTING, AND PARTICIPANTS We describe the clinical, genetic, and neuropathologic findings of 5 unrelated cases of parkin disease and compare them with 5 pathologically confirmed PD cases and 4 control subjects. The PD control cases and normal control subjects were matched first for age at death then disease duration (PD only) for comparison. RESULTS Presenting signs in the parkin disease cases were hand or leg tremor often combined with dystonia. Mean age at onset was 34 years; all cases were compound heterozygous for mutations of parkin. Freezing of gait, postural deformity, and motor fluctuations were common late features. No patients had any evidence of cognitive impairment or dementia. Neuronal counts in the substantia nigra pars compacta revealed that neuronal loss in the parkin cases was as severe as that seen in PD, but relative preservation of the dorsal tier was seen in comparison with PD (P = .04). Mild neuronal loss was identified in the locus coeruleus and dorsal motor nucleus of the vagus, but not in the nucleus basalis of Meynert, raphe nucleus, or other brain regions. Sparse Lewy bodies were identified in 2 cases (brainstem and cortex). CONCLUSIONS AND RELEVANCE These findings support the notion that parkin disease is characterized by a more restricted morphologic abnormality than is found in PD, with predominantly ventral nigral degeneration and absent or rare Lewy bodies.

Response of Glia, Mast Cells and the Blood Brain Barrier, in Transgenic Mice Expressing Interleukin-3 in Astrocytes, an Experimental Model for CNS Demyelination

Transgenic mice overexpressing cytokines facilitate analysis of the effects of these immunomodulators on indigenous cells of the central nervous system. This study examines morphological aspects of demyelination and permeability changes, in a recently described transgenic model (termed GFAP‐IL3). GFAP‐IL3 mice develop progressive motor disease at approximately 5 months. Lesions identified after disease onset, showed activation of microglia, astroglial proliferation with phagocytosis of lipids, and immigration of macrophages and mast cells into neural parenchyma. Lymphocytes failed to appear until the later stages of the disease. Later, cerebellar and brain stem white matter contained focal demyelinating lesions with intense macrophage infiltration and a proliferative astrocytosis. Dystrophic axonal changes were noted, in addition to demyelination in heavily infiltrated lesions. Mast cells, variably present in the thalamus and meninges of wild type mice, were greatly increased at these sites in GFAP‐IL3 mice. Blood‐brain barrier (BBB) defects were documented with leakage of intravenously injected horseradish peroxidase. Mast cell infiltration into the CNS and their degranulation at the site of injury, may represent initial events in a spontaneous process of macrophage mediated demyelination in which glial cells and macrophages are both involved in the phagocytic process.

Autoregulated paracellular clearance of amyloid-β across the blood-brain barrier

Size-selective and passive paracellular diffusion of amyloid-β across tight junctions of the blood-brain barrier in Alzheimer’s disease. The blood-brain barrier (BBB) is essential for maintaining brain homeostasis and protecting neural tissue from damaging blood-borne agents. The barrier is characterized by endothelial tight junctions that limit passive paracellular diffusion of polar solutes and macromolecules from blood to brain. Decreased brain clearance of the neurotoxic amyloid-β (Aβ) peptide is a central event in the pathogenesis of Alzheimer’s disease (AD). Whereas transport of Aβ across the BBB can occur via transcellular endothelial receptors, the paracellular movement of Aβ has not been described. We show that soluble human Aβ(1–40) monomers can diffuse across the paracellular pathway of the BBB in tandem with a decrease in the tight junction proteins claudin-5 and occludin in the cerebral vascular endothelium. In a murine model of AD (Tg2576), plasma Aβ(1–40) levels were significantly increased, brain Aβ(1–40) levels were decreased, and cognitive function was enhanced when both claudin-5 and occludin were suppressed. Furthermore, Aβ can cause a transient down-regulation of claudin-5 and occludin, allowing for its own paracellular clearance across the BBB. Our results show, for the first time, the involvement of the paracellular pathway in autoregulated Aβ movement across the BBB and identify both claudin-5 and occludin as potential therapeutic targets for AD. These findings also indicate that controlled modulation of tight junction components at the BBB can enhance the clearance of Aβ from the brain.

Loss of Chromosome 1p/19q in Oligodendroglial Tumors: Refinement of Chromosomal Critical Regions and Evaluation of Internexin Immunostaining as a Surrogate Marker

Loss of chromosome 1p/19q in oligodendrogliomas represents a powerful predictor of good prognosis. Expression of internexin (INA), a neuronal specific intermediate filament protein, has recently been proposed as a surrogate marker for 1p/19q deletion based on the high degree of correlation between both parameters in oligodendrogliomas. The aim of this study was to assess further the diagnostic utility of INA expression in a set of genetically well-characterized oligodendrogliomas. On the basis of a conservative approach for copy number determination, using both comparative genomic hybridization and fluorescent in situ hybridization, INA expression as a surrogate marker for 1p/19q loss had both reduced specificity (80%) and sensitivity (79%) compared with respective values of 86% and 96% reported in the previous report. The histologic interpretation and diagnostic value of INA expression in oligodendrogliomas should therefore be assessed with greater caution when compared with 1p/19q DNA copy number analysis. In addition, DNA copy number aberrations of chromosomes 10, 16, and 17 were detected exclusively in 1p/19q codeleted samples, suggesting that other regions of the genome may contribute to the 1p/19q-deleted tumor phenotype inthese samples.

Inflammatory myopathy in thyrotoxicosis

Article abstract-A 45-year-old man with a 3-month history of episodic muscle weakness, MRC grade 4/5 symmetric hip flexor weakness, elevated CK, and an inflammatory myopathy was found to have elevated free thyroxine and T3. Treatment with carbimazole resulted in complete resolution of symptoms and return of muscle power to normal. A repeat biopsy revealed resolution of the inflammatory endomysial infiltrate and an absence of necrosis. Complete clinical and pathologic resolution of a thyrotoxicosis-associated inflammatory myopathy without steroid therapy has not been previously described. The favorable outcome experienced by this patient indicates that steroids may not be necessary in thyrotoxicosis-associated inflammatory myopathy. NEUROLOGY 1997;48: 339-341

Headaches that kill: A retrospective study of incidence, etiology and clinical features in cases of sudden death

Objective: The study objective was to analyze cases of sudden death that presented to the National Deptartment of Clinical Neurosciences, Ireland, over a 10-year period (1997–2006) where headache was the presenting symptom. Background: Headache is a common yet challenging presentation in clinical neurology. In the vast majority of cases, the cause is trivial and reversible—however, in a few patients it may be indicative of a more sinister intracranial process. Recognizing associated “red flag” features and identifying possible life-threatening causes are crucial in ensuring prompt and appropriate intervention. Design/methods: A retrospective study/database of all autopsy cases presenting to the Neuropathology Department in Beaumont Hospital, Dublin, was carried out for the period 1997–2006. Cases were selected with headache as the presenting clinical feature. Traumatic head injuries or known central nervous system (CNS) disorders were excluded. Autopsy and medical reports were reviewed to identify associated red flag features at initial presentation according to the International Classification of Headache Diseases, second edition (ICHD-II) criteria. Results: Fifty-five autopsy cases out of a total of 499 complying with selection criteria were reviewed. Over the 10-year-study period, the number of cases of fatal headaches over time were negatively correlated. The most commonly associated red flag symptoms included age over 50: loss of consciousness and collapse, and worst/thunderclap character of headache. Cause of death at autopsy comprised vascular events 60.4% (N = 29), primary brain tumours/cysts 16.7% (N = 8) and meningitis 6.25% (N = 3). Aneurysms accounted for the majority of vascular cases 22.9% (N = 11), with loss of consciousness, occipital headache, neck pain and a focal neurological deficit seen more commonly in this subset of cases. Conclusions: Sudden-onset headache is a common and often alarming presentation. The majority of cases are of a benign nature; however, a small proportion may be indicative of a catastrophic etiology. Documenting “red flags” on initial presentation is crucial to acutely identify and treat those at highest risk. The results demonstrate an improving trend among clinicians in recognizing and initiating appropriate interventions in these patients, and highlights particular red flag features common in cases of fatal headaches.

Cavernous angioma of the internal auditory canal

Cavernous angiomas of the internal auditory canal are rare lesions. The authors present a case of a 29-year-old lady with multiple infratentorial cavernous angiomas, whose sister had previously undergone surgery for a similar supratentorial lesion. She initially presented with an acute brainstem haematoma, secondary to a pontine cavernous angioma. Three years later she developed progressive right-sided sensorineural hearing loss and facial nerve paresis due to an internal auditory canal lesion. This was removed via the translabyrinthine approach and was found to be a cavernous angioma. This report underlines the multiple and dynamic nature of familial cavernous angiomas, as well as the importance of follow up to determine whether new symptoms are due to the enlargement of known angiomas or the development of new ones. As far as the authors are aware, this is the first report describing a cavernous angioma of the internal auditory canal in the context of familial and multiple infratentorial angiomas.