OBJECTIVE. To search for brain abnormalities in patients with Paget’s disease of the bone (PBD) carrying mutations in SQSTM1 gene using voxel-based morphometry.BACKGROUND. Recently, mutations in the sequestosome 1 (SQSTM1) gene, which encodes the autophagic p62 protein, have been described in patients with Frontotemporal Lobar Degeneration (FTLD) and/or Amyotrophic Lateral Sclerosis (ALS). SQSTM1 mutations have been described in approximately 25% of patients with familial PBD. Neurologic involvement in these patients have not yet been investigated.METHODS. 12 newly diagnosed patients with familial PBD (5 males, 7 females, mean age ± SD: 59 ± 8 yrs) carrying SQSTM1 gene mutations (E396X, M404V, G425R), and 12 healthy controls were recruited for the study. On examination, PDB patients show no signs of any neurological diseases and neuropsychological screening was normal. Structural MRI scans of all participants were acquired on a 1.0 T Impact Magnetom Imager scanner. Whole brain scans were obtained as high-resolution T1-weighted 3D MP-RAGE. Images were analyzed with FSL-VBM 4.1. All patients underwent clinical and neuropsychological assessment (MMSE, Semantic Fluency, Phonemic Fluency, Attentional Matrices, Corsi Span, Short Story Recall, Token test). Anxiety and depression were also evaluated with self-administered questionnaires (STAI-X1, STAI-X2, BDI).RESULTS. PDB patients carrying SQSTM1 gene mutations had significantly lesser (p<0.01) regional gray matter density in right middle temporal gyrus, right parahippocampal gyrus and left lingual gyrus, in comparison with controls. Age-related reduction in gray matter density was significantly (p<0.001) increased in PDB patients than in controls within a large brain network (including precuneus, cingulum and fronto-temporal lobes, especially on the left side).CONCLUSIONS. Our study shows that, in patients with PDB carrying SQSTM1 gene mutations, there is a significant gray matter decrease even in absence of neurologic symptoms. The clinical relevance our findings requires additional investigations.
Voxel-based Morphometry Reveals Gray Matter Loss in Patients with Paget's Disease of the Bone Carrying SQSTM1 Gene Mutations
RAINERO, Innocenzo;RUBINO, Elisa;D'AGATA, Federico;BERGUI, Mauro;PINESSI, Lorenzo;ISAIA, Giovanni Carlo;
2014-01-01
Abstract
OBJECTIVE. To search for brain abnormalities in patients with Paget’s disease of the bone (PBD) carrying mutations in SQSTM1 gene using voxel-based morphometry.BACKGROUND. Recently, mutations in the sequestosome 1 (SQSTM1) gene, which encodes the autophagic p62 protein, have been described in patients with Frontotemporal Lobar Degeneration (FTLD) and/or Amyotrophic Lateral Sclerosis (ALS). SQSTM1 mutations have been described in approximately 25% of patients with familial PBD. Neurologic involvement in these patients have not yet been investigated.METHODS. 12 newly diagnosed patients with familial PBD (5 males, 7 females, mean age ± SD: 59 ± 8 yrs) carrying SQSTM1 gene mutations (E396X, M404V, G425R), and 12 healthy controls were recruited for the study. On examination, PDB patients show no signs of any neurological diseases and neuropsychological screening was normal. Structural MRI scans of all participants were acquired on a 1.0 T Impact Magnetom Imager scanner. Whole brain scans were obtained as high-resolution T1-weighted 3D MP-RAGE. Images were analyzed with FSL-VBM 4.1. All patients underwent clinical and neuropsychological assessment (MMSE, Semantic Fluency, Phonemic Fluency, Attentional Matrices, Corsi Span, Short Story Recall, Token test). Anxiety and depression were also evaluated with self-administered questionnaires (STAI-X1, STAI-X2, BDI).RESULTS. PDB patients carrying SQSTM1 gene mutations had significantly lesser (p<0.01) regional gray matter density in right middle temporal gyrus, right parahippocampal gyrus and left lingual gyrus, in comparison with controls. Age-related reduction in gray matter density was significantly (p<0.001) increased in PDB patients than in controls within a large brain network (including precuneus, cingulum and fronto-temporal lobes, especially on the left side).CONCLUSIONS. Our study shows that, in patients with PDB carrying SQSTM1 gene mutations, there is a significant gray matter decrease even in absence of neurologic symptoms. The clinical relevance our findings requires additional investigations.
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