Beth J. Synek

Opsoclonus, myoclonus, ataxia, and encephalopathy in adults with cancer : a distinct paraneoplastic syndrome

The clinical and pathological findings in 4 adults with cancer and opsoclonus were compared with those of 15 other patients described elsewhere. The clinical syndrome of paraneoplastic opsoclonus is characterized by the acute onset of opsoclonus and truncal ataxia, often accompanied by encephalopathy, myoclonus and a cerebrospinal fluid pleocytosis. Unlike most other paraneoplastic syndromes, the course is often remitting and relapsing. Neuropathological examination in 3 of our patients showed lymphocytic cuffing of occasional blood vessels throughout the central nervous system, associated with a mild, diffuse proliferation of microglia in 1 patient. Apart from a mild, patchy loss of Purkinje cells in 1 patient, there was no loss of neurons from the cerebellum, brainstem, cerebral hemispheres, or spinal cord. These patients differ from those with the more common paraneoplastic cerebellar degeneration by the predominance of truncal over limb ataxia, the presence of myoclonus, the absence of severe dysarthria, a tendency for remission, and the preservation of Purkinje cells.

Cell loss in the motor and cingulate cortex correlates with symptomatology in Huntington’s disease

Huntingtons disease is an autosomal dominant inherited neurodegenerative disease with motor symptoms that are variably co-expressed with mood and cognitive symptoms, and in which variable neuronal degeneration is also observed in the basal ganglia and the cerebral cortex. We have recently shown that the variable symptomatology in Huntingtons disease correlates with the variable compartmental pattern of GABAA receptor and cell loss in the striatum. To determine whether the phenotypic variability in Huntingtons disease is also related to variable neuronal degeneration in the cerebral cortex, we undertook a double-blind study using unbiased stereological cell counting methods to determine the pattern of cell loss in the primary motor and anterior cingulate cortices in the brains of 12 cases of Huntingtons disease and 15 controls, and collected detailed data on the clinical symptomatology of the patients with Huntingtons disease from family members and clinical records. The results showed a significant association between: (i) pronounced motor dysfunction and cell loss in the primary motor cortex; and (ii) major mood symptomatology and cell loss in the anterior cingulate cortex. This association held for both total neuronal loss (neuronal N staining) and pyramidal cell loss (SMI32 staining), and also correlated with marked dystrophic changes in the remaining cortical neurons. There was also an association between cortical cell loss and striatal neuropathological grade, but no significant association with CAG repeat length in the Huntingtons disease gene. These findings suggest that the heterogeneity in clinical symptomatology that characterizes Huntingtons disease is associated with variation in the extent of cell loss in the corresponding functional regions of the cerebral cortex whereby motor dysfunction correlates with primary motor cortex cell loss and mood symptomatology is associated with cell loss in the cingulate cortex.

A fatal case of ovarian hyperstimulation syndrome with cerebral infarction

&NA; The ovarian hyperstimulation syndrome (OHSS) as a cause of death in infertile patients involved in in vitro fertilization is an extremely rare phenomenon. Reported here are the clinical and pathological features of just such a case together with a discussion of the pathophysiology thought to be involved.

Chapter 7 The distribution of GABAA-benzodiazepine receptors in the basal ganglia in Huntington's disease and in the quinolinic acid-lesioned rat

Publisher Summary Although the gene for Huntingtons disease has been localized to the short arm of chromosome 4, the pathogenesis of the disease still remains unknown. Over the recent years, however, excitotoxic mechanisms have been suggested as a possible factor in the neurodegenerative process and the excitotoxin quinolinic acid has been specifically implicated in the pathogenesis of Huntingtons disease. Quinolinic acid is an endogenous metabolite in the brain that produces axon-sparing lesions and neurochemical changes in the rat striatum similar to those in Huntingtons disease. In particular, intrastriatal injections of quinolinic acid in the rat brain result in a marked depletion of GABAergic efferent neurons with the apparent selective sparing of somato-statin-neuropeptide-Y–NADPH, diaphorase neurons. Others have shown, however, that somatostatin- neuropeptide Y cells are not spared in quinolinic acid lesions of the striatum and have questioned the validity of the proposed model. In order to further investigate the validity of the quinolinic acid animal model of Huntingtons disease, this chapter documents the GABAA-benzodiazepine receptor changes in the striatum and globus pallidus in Huntingtons disease and then investigates whether the same pattern of receptor changes occurs in the basal ganglia of the quinolinic acid-lesioned rat model of the disease. In both the human and animal studies, the distribution of GABAA-benzodiazepine receptors is investigated using receptor autoradiography following in vitro labelling of cryostat sections with a tritiated GABAA-benzodiazepine receptor ligand ([3H]flunitrazepam) and immunohistochemical techniques with a monoclonal antibody (bd-17) to the β 2,3 subunits of the GABAA-benzodiazepine receptor complex.

A histochemical and immunohistochemical analysis of the subependymal layer in the normal and Huntington's disease brain

Previous studies in the rodent brain have characterised the cell types present in the subependymal layer, however the general organisation and cellular morphology of the adult human subependymal layer has not been demonstrated previously. In this study, we have demonstrated that the normal human brain subependymal layer contains three morphologically distinct types of cells, A, B and C type cells. The type A cells resembling migrating neuroblasts were located in the superficial part of the subependymal layer, type B cells resembling glial cells were evenly distributed throughout the subependymal layer and caudate nucleus, and type C cells that resembled progenitor cells were located in the deeper regions of the subependymal layer close to the caudate nucleus. We also examined the subependymal layer in the Huntingtons disease brain to determine whether neurodegenerative pathology of the caudate nucleus (adjacent to the subependymal layer) altered the cellular composition of the subependymal layer. In the Huntingtons disease subependymal layer there was a significant increase in the thickness of the subependymal layer compared with the normal subependymal layer (p < 0.01) and there was a 2.8-fold increase in the number of cells present in the Huntingtons disease subependymal layer compared with the normal subependymal layer but the density of cells remained unchanged. As the grade of Huntingtons disease increased, so did the overall number of cells in the subependymal layer. An increase in the number of type B cells was responsible for most of the increase demonstrated, however there was also an increase in the numbers of type A and C cells. To further characterise the human normal and Huntingtons disease subependymal layer we used immunohistochemistry and antibodies against a range of projection neuron markers, interneuron markers, glial cell markers and GABAA receptor subunits. The results demonstrated the presence of increased numbers of neuropeptide Y positive cells in the Huntingtons disease subependymal layer compared with the normal subependymal layer, suggesting that neuropeptide Y neurons may play a role in progenitor cell proliferation. Also there was an increased level of the developmentally active GABAA receptor subunit gamma 2 that indicates that the adult subependymal layer still retains the ability to proliferate. Taken together our results give a detailed description of the adult human subependymal layer and also demonstrate the plasticity of the human subependymal layer in response to Huntingtons disease.

The collection and processing of human brain tissue for research

To further understand the neuroanatomy, neurochemistry and neuropathology of the normal and diseased human brain, it is essential to have access to human brain tissue where the biological and chemical nature of the tissue is optimally preserved. We have established a human brain bank where brain tissue is optimally processed and stored in order to provide a resource to facilitate neuroscience research of the human brain in health and disease. A donor programme has been established in consultation with the community to provide for the post-mortem donation of brain tissue to the brain bank. We are using this resource of human brain tissue to further investigate the basis of normal neuronal functioning in the human brain as well as the mechanisms of neuronal dysfunction and degeneration in neurodegenerative diseases. We have established a protocol for the preservation of post-mortem adult human brain tissue firstly by snap-freezing unfixed brain tissue and secondly by chemical fixation and then storage of this tissue at −80°C in a human brain bank. Several research techniques such as receptor autoradiography, DNA and RNA analysis, are carried out on the unfixed tissue and immunohistochemical and histological analysis is carried out on the fixed human tissue. Comparison of tissue from normal control cases and from cases with neurodegenerative disorders is carried out in order to document the changes that occur in the brain in these disorders and to further investigate the underlying pathogenesis of these devastating neurological diseases.

Cortical Interneuron Loss and Symptom Heterogeneity in Huntington Disease

The cellular basis of variable symptoms in Huntington disease (HD) is unclear. One important possibility is that degeneration of the interneurons in the cerebral cortex, which play a critical role in modulating cortical output to the basal ganglia, might play a significant role in the development of variable symptomatology in HD. This study aimed to examine whether symptom variability in HD is specifically associated with variable degeneration of cortical interneurons.

Widespread Heterogeneous Neuronal Loss Across the Cerebral Cortex in Huntington's Disease

Huntingtons disease is an autosomal dominant neurodegenerative disease characterized by neuronal degeneration in the basal ganglia and cerebral cortex, and a variable symptom profile. Although progressive striatal degeneration is known to occur and is related to symptom profile, little is known about the cellular basis of symptom heterogeneity across the entire cerebral cortex. To investigate this, we have undertaken a double blind study using unbiased stereological cell counting techniques to determine the pattern of cell loss in six representative cortical regions from the frontal, parietal, temporal, and occipital lobes in the brains of 14 Huntingtons disease cases and 15 controls. The results clearly demonstrate a widespread loss of total neurons and pyramidal cells across all cortical regions studied, except for the primary visual cortex. Importantly, the results show that cell loss is remarkably variable both within and between Huntingtons disease cases. The results also show that neuronal loss in the primary sensory and secondary visual cortices relate to Huntingtons disease motor symptom profiles, and neuronal loss across the associational cortices in the frontal, parietal and temporal lobes is related to both Huntingtons disease motor and to mood symptom profiles. This finding considerably extends a previous study (Thu et al., Brain, 2010; 133:1094-1110) which showed that neuronal loss in the primary motor cortex was related specifically to the motor symptom profiles while neuronal loss in the anterior cingulate cortex was related specifically to mood symptom profiles. The extent of cortical cell loss in the current study was generally related to the striatal neuropathological grade, but not to CAG repeat length on the HTT gene. Overall our findings show that Huntingtons disease is characterized by a heterogeneous pattern of neuronal cell loss across the entire cerebrum which varies with symptom profile.

Elevation of brain glucose and polyol-pathway intermediates with accompanying brain-copper deficiency in patients with Alzheimer’s disease: metabolic basis for dementia

Impairment of brain-glucose uptake and brain-copper regulation occurs in Alzheimer’s disease (AD). Here we sought to further elucidate the processes that cause neurodegeneration in AD by measuring levels of metabolites and metals in brain regions that undergo different degrees of damage. We employed mass spectrometry (MS) to measure metabolites and metals in seven post-mortem brain regions of nine AD patients and nine controls, and plasma-glucose and plasma-copper levels in an ante-mortem case-control study. Glucose, sorbitol and fructose were markedly elevated in all AD brain regions, whereas copper was correspondingly deficient throughout (all P < 0.0001). In the ante-mortem case-control study, by contrast, plasma-glucose and plasma-copper levels did not differ between patients and controls. There were pervasive defects in regulation of glucose and copper in AD brain but no evidence for corresponding systemic abnormalities in plasma. Elevation of brain glucose and deficient brain copper potentially contribute to the pathogenesis of neurodegeneration in AD.

String Vessel Formation is Increased in the Brain of Parkinson Disease

BACKGROUND String vessels are collapsed basement membrane without endothelium and have no function in circulation. String vessel formation contributes to vascular degeneration in Alzheimer disease. By comparing to age-matched control cases we have recently reported endothelial degeneration in brain capillaries of human Parkinson disease (PD). OBJECTIVE Current study evaluated changes of basement membrane of capillaries, string vessel formation and their association with astrocytes, blood-brain-barrier integrity and neuronal degeneration in PD. METHODS Brain tissue from human cases of PD and age-matched controls was used. Immunohistochemical staining for collagen IV, GFAP, NeuN, tyrosine hydroxylase, fibrinogen and Factor VIII was evaluated by image analysis in the substantia nigra, caudate nucleus and middle frontal gyrus. RESULTS While the basement-membrane-associated vessel density was similar between the two groups, the density of string vessels was significantly increased in the PD cases, particularly in the substantia nigra. Neuronal degeneration was found in all brain regions. Astrocytes and fibrinogen were increased in the caudate nuclei of PD cases compared with control cases. CONCLUSIONS Endothelial degeneration and preservation of basement membrane result in an increase of string vessel formation in PD. The data may suggest a possible role for cerebral hypoperfusion in the neuronal degeneration characteristic of PD, which needs further investigation. Elevated astrocytosis in the caudate nucleus of PD cases could be associated with disruption of the blood-brain barrier in this brain region.