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Danuta Z Loesch,
David E Godler,
Andrew Evans,
Quang M Bui,
Freya Gehling,
Katya E Kotschet,
Nicholas Trost,
Elsdon Storey,
Paige Stimpson,
Glynda Kinsella,
David Francis,
David R Thorburn,
Alison Venn,
Howard R Slater, Malcolm Horne
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ABSTRACT: Our previous results showed that both gray zone and lower end premutation range (40-85 repeats) fragile X mental retardation 1 (FMR1) alleles were more common among males with parkinsonism than in the general population. This study aimed to determine whether these alleles have a significant role in the manifestations and pathogenesis of parkinsonian disorders.
Detailed clinical assessment and genetic testing were performed in 14 male carriers of premutation and gray zone FMR1 alleles and in 24 noncarriers identified in a sample of males with parkinsonism.
The premutation + gray zone carriers presented with more severe symptoms than disease controls matched for age, diagnosis, disease duration, and treatment. The Parkinson disease (Unified Parkinson's Disease Rating Scale) motor score and the measures of cognitive decline (Mini-Mental State Examination and/or Addenbrooke's Cognitive Examination Final Revised Version A scores) were significantly correlated with the size of the CGG repeat and the (elevated) levels of antisense FMR1 and Cytochrome C1 mRNAs in blood leukocytes. In addition, the carriers showed a significant depletion of the nicotinamide adenine dinucleotide, reduced dehydrogenase subunit 1 mitochondrial gene in whole blood.
Small CGG expansion FMR1 alleles (gray zone and lower end premutation) play a significant role in the development of the parkinsonian phenotype, possibly through the cytotoxic effect of elevated sense and/or antisense FMR1 transcripts involving mitochondrial dysfunction and leading to progressive neurodegeneration.
Genetics in medicine: official journal of the American College of Medical Genetics 01/2011; 13(5):392-9. · 3.92 Impact Factor
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ABSTRACT: The cerebellar and spinocerebellar dysfunction seen in Friedreich ataxia (FRDA) has known effects on motor function. Recently, it was suggested that people with FRDA may also have impairment in motor planning, either because of cortical pathology or because of cerebello-cortical projections. Fifteen adults with FRDA and 15 matched controls completed a task requiring reciprocating movements between two buttons on a tapping board. Occasionally there was one of three "oddball" stimuli requiring reprogramming of movement. These were change in (1) direction, (2) extent or (3) direction and extent. We hypothesized that people with FRDA would have prolonged movement times due to their movement disorder, and that changes in preparation time would be affected in a way similar to controls, unless there was impairment in motor planning in FRDA. Movement execution and, to a lesser degree, movement preparation were impaired in individuals with FRDA. We argue this points to disturbed cortical function. There was a significant negative correlation between age of onset and all three reprogramming conditions, suggesting an impact of FRDA on developing motor planning. Future studies will be required to establish whether this dysfunction is due to cerebellar impairment interrupting cerebro-ponto-cerebello-thalamo-cerebral loops, primary cortical pathology or a combination of the two.
Journal of Neurology 12/2009; 257(5):782-91. · 3.47 Impact Factor
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Anusha Sritharan,
Gary F Egan,
Leigh Johnston, Malcolm Horne,
John L Bradshaw,
India Bohanna,
Hamed Asadi,
Ross Cunnington,
Andrew J Churchyard,
Phyllis Chua,
Maree Farrow,
Nellie Georgiou-Karistianis
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ABSTRACT: The striatum and its projections are thought to be the earliest sites of Huntington's disease (HD) pathology. This study aimed to investigate progression of striatal pathology in symptomatic HD using diffusion tensor imaging.
Diffusion weighted images were acquired in 18 HD patients and in 17 healthy controls twice, 1 year apart. Mean diffusivity (MD) was calculated in the caudate, putamen, thalamus and corpus callosum, and compared between groups. In addition, caudate width was measured using T1 high resolution images and correlated with caudate MD. Correlation analyses were also performed in HD between caudate/putamen MD and clinical measures.
MD was significantly higher in the caudate and putamen bilaterally for patients compared with controls at both time points although there were no significant MD differences in the thalamus or corpus callosum. For both groups, MD did not change significantly in any region from baseline to year 1. There was a significant negative correlation between caudate width and MD in patients at baseline but no correlation between these parameters in controls. There was also a significant negative correlation between Mini-Mental State Examination scores and caudate MD and putamen MD at both time points in HD.
It appears that microstructural changes influence cognitive status in HD. Although MD was significantly higher in HD compared with controls at both time points, there were no longitudinal changes in either group. This finding does not rule out the possibility that MD could be a sensitive biomarker for detecting early change in preclinical HD.
Journal of neurology, neurosurgery, and psychiatry 03/2009; 81(3):257-62. · 4.87 Impact Factor
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ABSTRACT: There is limited documentation regarding cognitive function in individuals with Friedreich ataxia (FRDA), possibly because FRDA is widely held to predominantly affect the spinal cord, peripheral sensory nerves and cerebellum and not to affect cognition. Traditionally, the cerebellum has been thought to coordinate voluntary movement and motor tone, posture and gait. However, recent studies have implicated the cerebellum in a range of cognitive functions including executive function, visuospatial organisation and memory. We review the available data on cognitive function and neuroimaging in FRDA and the role of the cerebellum in cognitive function. We conclude with recommendations for future research including correlating cognitive function in individuals with FRDA with possible determinants of disease severity, such as age of onset and the causative genetic mutation.
Brain Research Bulletin 08/2006; 70(3):197-202. · 2.82 Impact Factor
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Public health reports 02/1968; 83(1):90-94. · 1.33 Impact Factor
