Publications (94) View all
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Article: Cognitive changes predict functional decline in ALS: A population-based longitudinal study.
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ABSTRACT: OBJECTIVE: To determine whether cognitive status in patients with amyotrophic lateral sclerosis (ALS) is a useful predictor of attrition and motor and cognitive decline. METHODS: Cognitive testing was undertaken in a large population-based cohort of incident ALS patients using a longitudinal, case-control study design. Normative data for neuropsychological tests were generated using age-, sex-, and education-matched healthy controls who also underwent repeated assessments. Data were analyzed to generate models for progression/spread. RESULTS: One hundred eighty-six patients with ALS who had no evidence of C9orf72 hexanucleotide repeat expansion were enrolled. A second and third assessment were undertaken in 98 and 46 of the patients with ALS, respectively. Executive impairment at the initial visit was associated with significantly higher rates of attrition due to disability or death and faster rates of motor functional decline, particularly decline in bulbar function. Decline in cognitive function was faster in patients who were cognitively impaired at baseline. Normal cognition at baseline was associated with tendency to remain cognitively intact, and with slower motor and cognitive progression. CONCLUSIONS: Non-C9orf72-associated ALS is characterized by nonoverlapping cognitive subgroups with different disease trajectories. These findings have important implications for models of ALS pathogenesis, and for future clinical trial design.Neurology 04/2013; · 8.31 Impact Factor -
Article: Controversies and priorities in amyotrophic lateral sclerosis.
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ABSTRACT: Two decades after the discovery that 20% of familial amyotrophic lateral sclerosis (ALS) cases were linked to mutations in the superoxide dismutase-1 (SOD1) gene, a substantial proportion of the remainder of cases of familial ALS have now been traced to an expansion of the intronic hexanucleotide repeat sequence in C9orf72. This breakthrough provides an opportunity to re-evaluate longstanding concepts regarding the cause and natural history of ALS, coming soon after the pathological unification of ALS with frontotemporal dementia through a shared pathological signature of cytoplasmic inclusions of the ubiquitinated protein TDP-43. However, with profound clinical, prognostic, neuropathological, and now genetic heterogeneity, the concept of ALS as one disease appears increasingly untenable. This background calls for the development of a more sophisticated taxonomy, and an appreciation of ALS as the breakdown of a wider network rather than a discrete vulnerable population of specialised motor neurons. Identification of C9orf72 repeat expansions in patients without a family history of ALS challenges the traditional division between familial and sporadic disease. By contrast, the 90% of apparently sporadic cases and incomplete penetrance of several genes linked to familial cases suggest that at least some forms of ALS arise from the interplay of multiple genes, poorly understood developmental, environmental, and age-related factors, as well as stochastic events.The Lancet Neurology 03/2013; 12(3):310-22. · 23.46 Impact Factor -
Article: Using Reference Databases of Genetic Variation to Evaluate the Potential Pathogenicity of Candidate Disease Variants.
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ABSTRACT: The potential pathogenicity of genetic variants identified in disease based resequencing studies is often overlooked where variants have previously been reported in dbSNP, the 1000 genomes project or the NHLBI exome sequencing project (ESP). In this work we estimate that collectively, these databases capture ∼52% of mutations (dbSNP 50.4%; 1000 genomes 4.8%; ESP 10.2%) reported as disease-causing within phenotype based locus specific databases (LSDBs). To investigate whether these mutations may simply represent benign population variants, we evaluated whether the carrier frequencies associated with mutations implicated in amyotrophic lateral sclerosis (ALS) were higher than could be accounted for by high penetrance disease models. In doing so we have questioned the veracity of 51 mutations but also demonstrated that each of the 3 databases included credible disease variants. Our results demonstrate the benefits of using databases like dbSNP, the 1000 genomes project and the ESP to evaluate the pathogenicity of putative disease variants and suggest that many disease mutations reported across LSDBs may not actually be pathogenic. However they also demonstrate that even in the context of rare Mendelian disorders, the potential pathogenicity of variants reported by these databases should not be overlooked without proper evaluation.Human Mutation 02/2013; · 5.69 Impact Factor -
Article: Grey matter correlates of clinical variables in amyotrophic lateral sclerosis (ALS): a neuroimaging study of ALS motor phenotype heterogeneity and cortical focality.
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ABSTRACT: BACKGROUND: Body region of onset and functional disability are key components of disease heterogeneity in amyotrophic lateral sclerosis (ALS). OBJECTIVES: To evaluate patterns of grey matter pathology in the motor cortex and correlate focal structural changes with functional disability. METHODS: We conducted a single-centre neuroimaging study of a cohort of 33 cognitively normal patients with amyotrophic lateral sclerosis (ALS) and 44 healthy controls. A voxel-wise generalised linear model was used to investigate the distribution of disease burden within the motor cortex in relation to clinical disability. RESULTS: Patients with bulbar onset have bilateral focal atrophy in the bulbar segment of the motor homunculus compared with patients with limb onset who have focal cortical changes in the limb segment of their motor strip. Furthermore, the extent to which different body regions are affected in ALS corresponds to the extent of focal grey matter loss in the primary motor cortex. Cortical ALS pathology also extends beyond the motor cortex affecting frontal, occipital and temporal regions. CONCLUSIONS: Focal grey matter atrophy within the motor homunculus corresponds with functional disability in ALS. The findings support the existing concepts of cortical focality and motor phenotype heterogeneity in ALS.Journal of neurology, neurosurgery, and psychiatry 10/2012; · 4.87 Impact Factor -
Article: H63D polymorphism in HFE is not associated with amyotrophic lateral sclerosis.
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ABSTRACT: The H63D polymorphism in HFE has frequently been associated with susceptibility to amyotrophic lateral sclerosis (ALS). Regarding the role of HFE in iron homeostasis, iron accumulation is considered an important process in ALS. Furthermore, novel therapeutic strategies are being developed targeting this process. Evidence for this genetic association is, however, limited to several small studies. For this reason we studied the H63D polymorphism in a large European cohort including 3962 ALS patients and 5072 control subjects from 7 countries. After meta-analysis of previous studies and current findings we conclude that the H63D polymorphism in HFE is not associated with susceptibility to ALS, age at disease onset, or survival.Neurobiology of aging 10/2012; · 5.94 Impact Factor
