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Objectives: To characterize the nature and extent of basal ganglia involvement in amyotrophic lateral sclerosis (ALS) genotypes in vivo. Methods: Forty-four healthy controls and 39 patients with ALS were included in the study. Thirty patients with ALS had a negative C9orf72 status and 9 patients with ALS carried the C9orf72 hexanucleotide repeat expansion. High-resolution T1-weighted MRI data were used for model-based subcortical registration and segmentation. Fifteen subcortical structures were studied with both volumetric and vertex-wise approaches. Changes in basal ganglia diffusivity parameters were also assessed. Results: Using age as a covariate, patients with ALS who were C9orf72 repeat negative showed significant volume reductions in the left caudate nucleus ( p = 0.01), left hippocampus ( p = 0.007), and right accumbens nucleus ( p = 0.001) compared with healthy controls. Vertex-wise shape analyses revealed changes affecting the superior and inferior aspects of the bilateral thalami, the lateral and inferior portion of the left hippocampus, and the medial and superior aspect of the left caudate. Basal ganglia pathology was more extensive in patients with ALS carrying the C9orf72 hexanucleotide repeat expansion. Conclusions: ALS is associated with widespread basal ganglia involvement. Caudate nucleus, hippocampus, and nucleus accumbens atrophy are key features of ALS. Dysfunction of frontostriatal networks is likely to contribute to the unique neuropsychological profile of ALS, dominated by executive dysfunction, apathy, and deficits in social cognition. Our quantitative imaging findings are consistent with postmortem studies and indicate that subcortical gray matter structures should be included in future biomarker studies of ALS.

Objective: To look at the clinical phenotype of Irish ALS patients testing positive for hexanucelotide repeat on chromosome nine. Background Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that overlaps with frontotemporal dementia. A hexanucleotide repeat on chromosome 9p21 has been associated with ALS and FTD. The population based frequency of this repeat and the cognitive phenotype in familial and sporadic ALS, has not been established. Design/Methods: 600 population-based samples from the Irish ALS DNA bank were tested using a combination of reverse prime PCR and capillary electrophoresis. 200 of these patients had undergone full neurocognitive profiling and 25% of these had undergone extensive neuroimaging with 3-T MRI. Results: 9.9% of the Irish ALS population had an expanded hexanucleotide repeat of greater than 30. 60% had a strong family history of ALS or FTD, and all had evidence of cognitive or behaviour impairment. A distinctive imaging signal could be identified in those with the repeat. The negative predictive value for patients with normal cognition and no family history was 100%. Patients with ALS/FTD and a family history had a positive predictive value of 80%. Conclusions: The 9p21 hexanucleotide repeat account for 40% of familial ALS in Ireland. The repeat does not associate with cognitively normal sporadic ALS. Supported by: HRB research grant. Disclosure: Dr. Byrne has nothing to disclose. Dr. Byrne has nothing to disclose. Dr. Bede has nothing to disclose. Dr. Elamin has nothing to disclose. Dr. Byrne has nothing to disclose. Dr. Byrne has nothing to disclose. Dr. McLaughlin has nothing to disclose. Dr. Pender has nothing to disclose. Dr. Byrne has nothing to disclose. Dr. Al-Chalabi has nothing to disclose. Dr. Hardiman has received personal compensation for activities with Ono Pharmaceuticals, Sanofi Aventis Pharmaceuticals, Inc., and Biogen Idec, Merck Serono and Schering AG as a committee member and/or serving on advisory panels.2. Dr. Hardiman has received personal compensation in an editorial capacity for the Amyotrophic Lateral Sclerosis Journal.