Putative neuroprotective agents in Huntington's disease may have particular application before brain pathology becomes manifest clinically. If these agents were to be tested in clinical trials, a reliable marker of the burden and rate of progression of pathological change in the pre-clinical group would be needed. The present study investigates whether the Huntington's disease genotype is associated with regional differences in brain structure, particularly differences that could not be predicted from clinical or neuropsychological assessment. A secondary aim is to seek indirect evidence of pathological progression in the form of changes in local tissue volume with age, specific to the Huntington's disease genotype. Formal motor examination, neuropsychological assessment, and T(1)-weighted cerebral MRI were performed in 34 subjects who had undergone predictive genetic testing for Huntington's disease. Clinical and cognitive testing were performed blinded to gene status. A linear discriminant analysis revealed the combination of test scores (the 'optimal clinical score') which best differentiated 18 subjects carrying the Huntington's disease gene mutation (the 'gene-positive' group). Voxel-based morphometry (VBM) was used to identify regions of significant main effect of Huntington's disease gene status on grey and white matter volume and regions of significant interaction of gene status with age. In the gene-positive group, there was significant reduction in grey matter volume in the left striatum, bilateral insula, dorsal midbrain and bilateral intra-parietal sulcus relative to 'gene-negative' controls. There was a significant reduction of periventricular white matter volume with age bilaterally in the gene-positive relative to the gene-negative group. Changes remained significant when controlled for differences in optimal clinical score between subjects. This study provides evidence of distributed grey matter pathology and progressive white matter atrophy with age before clinical onset of Huntington's disease. This suggests that VBM may be useful in monitoring cross-sectional and longitudinal changes in brain structure in pre-clinical Huntington's disease and for determining the efficacy of neuroprotective agents.
Background and objectives: Regional cerebral atrophy occurs in carriers of the Huntington's disease (HD) gene mutation before clinical diagnosis is possible. The current inability to reliably measure progression of pathology in this preclinical phase impedes development of therapies to delay clinical onset. We hypothesised that longitudinal statistical imaging would detect progression of structural pathology in preclinical carriers of the HD gene mutation, in the absence of measurable clinical change. Methods: Thirty subjects (17 preclinical mutation positive, 13 mutation negative) underwent serial clinical and magnetic resonance imaging (MRI) assessments over an interval of 2 years. Statistically significant changes in regional grey and white matter volume on MRI were analysed using tensor based morphometry (TBM). This technique derives a voxel-wise estimation of regional tissue volume change from the deformation field required to warp a subject's early to late T1 images. Results: Over 2 years, there was progressive regional grey matter atrophy in mutation-positive relative to negative subjects, without significant clinical progression of disease. Significant grey matter volume loss was limited to bilateral putamen and globus pallidus externa (GPe), left caudate nucleus, and left ventral midbrain in the region of the substantia nigra. Conclusions: While these results are consistent with previous cross sectional pathologic and morphometric studies, significant progression of atrophy in HD before the onset of significant clinical decline is now demonstrable with longitudinal statistical imaging. Such measures could be used to assess the efficacy of potential disease modifying drugs in slowing the progression of pathology before confirmed clinical onset of HD.
Skull-base osteomyelitis (SBO) occurs secondary to invasive bacterial and fungal infection. Distinguishing between fungal and bacterial aetiologies of SBO has significant therapeutic implications. An 18-year (1990-2007) retrospective review of patients with SBO presenting to Westmead Hospital was performed. Epidemiological, clinical, laboratory and radiology data were collated. Twenty-one patients (median age 58 years) with SBO were identified: ten (48%) had bacterial and 11 (52%) had fungal SBO. Diabetes mellitus (57%) and chronic otitis externa (33%) were the most frequent co-morbidities; immunosuppression was present in five cases (24%). Cranial nerve deficits occurred in ten (48%) patients. The commonest pathogens were Pseudomonas aeruginosa (50% bacterial SBO) and a zygomycete (55% fungal SBO). Compared to bacterial SBO, fungal SBO was more frequently associated with underlying chronic sinusitis, sinonasal pain, facial/periorbital swelling and nasal stuffiness or discharge and the absence of purulent ear discharge (all p <0.05). Bacterial SBO was more frequently associated with deafness, ear pain or ear discharge (all p <0.05). Median time to presentation was longer in patients with bacterial SBO (26.3 weeks vs. 8.1 weeks, p 0.08). Overall 6-month survival was 88% (14/18 patients). All four deaths occurred in patients with fungal SBO. Immunosuppression was a risk factor for death (p <0.05). Early diagnostic sampling is recommended in patients at increased risk of fungal SBO to enable optimal antimicrobial and surgical management.
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