- Email: [email protected]
O4-06-01 α-Internexin is present in the hallmark lesions of neuronal intermediate filament inclusion disease
Oral Session 04-06." Other Dementias - 1 associated fall in cognition was not seen. Alternatively, the reduction of cerebral volume in the treated group may be due to amyloid plaque removal, perhaps with associated fluid loss.
Oral Session 04-06: Other Dementias - 1 cl-INTERNEXIN IS PRESENT IN THE HALLMARK I O ] LESIONS 4 - OF0NEURONAL 6 -INTERMEDIATE 0 1 I
FILAMENT INCLUSION DISEASE Nigel J. Cairns* 1, Victoria Zhukareva 1, Kunihiro Uryu I, Eileen Bigio 2, Ian R. Makenzie 3 , Marla Geaing 4, Charles Duyckaerts 5, Hideaki Yokoo 6, Yoichi Nakazato 6, Evelyn Jaros 7, Robert H. Perry 7, Virginia M. Lee 1, John Q. Trojanowski 1. 1 University of Pennsylvania School of Medicine,
Philadelphia, PA, USA; 2Northwestern University Medical School, Chicago, IL, USA; 3Vancouver General Hospital, Vancouver, BC, Canada; 4Emory University School of Medicine, Atlanta, GA, USA; SH@ital de la Salp~trikre, Paris, France; 6Gunma University School of Medicine, Maebashi, Japan; 7Newcastle General Hospital, Newcastle-upon-Tyne, United Kingdom. Contact e-mail: cairns @mail. reed. upenn, edu Background: Neuronal intermediate filament (IF) inclusion disease (NIFID) is a novel neurological disease of early onset with a variable clinical phenotype including frontotemporal dementia, pyramidal, extrapyramidal, and upper motor neuron signs. Pathologically, in affected areas, there is neuronal loss, astrocytosis and neuronal intracytoplasmic aggregates of abnormal neuronal IFs which contain neither tan nor c~-synuclein. Objective: This study was undertaken to characterize the neuronal IF protein profile of inclusions in NIFID. Methods: Immunohistochemistry was performed on 10 cases of NIFID, 4 normal aged controls, and 4 cases of Alzheimer's disease using a panel of anti-neuronal IF proteins. Immunoelectron microscopy was performed on selected cases and frozen tissue from the frontal lobe of four cases was used for biochemical studies including sequential extractions and Western blotting. Results: Based on these studies, we report here for the first time that c~-internexin, a neuronal IF protein, is present within the inclusions of NIFID as are all three neurofilament subunits: heavy, medium, and light. Thus, all class IV neuronal IF proteins are present within the pathological inclusions of this disease. Biochemistry revealed that IF aggregates were soluble in sodium dodecyl sulfate and no posttranslational modification was detected when compared with Alzheimer's disease or aged control brains. Conclusions: NIFID is characterized by the pathological cytoplasmic aggregation of all class IV neuronal IF proteins in brain. The discovery of c~-internexin in the hallmark lesions implicates novel mechanisms of pathogenesis in NIFID and other neurological diseases with pathological accumulations of IFs.
fO4-06-02
] THE RELATIONSHIP BETWEEN SPECIFIC HISTOPATHOLOGY AND PATTERNS OF ATROPHY ON MRI IN FRONTOTEMPORAL LOBAR DEGENERATION
Jennifer L. Whitwell . I , Keith A. Josephs 1,2, Alison K. Godbolt 1, John M. Stevens 3, Nick C. Fox I, Martin N. Rossor 1,4.11nstitute of Neurology,
University College London, London, United Kingdom; 2Mayo Clinic, Rochester, MN, USA; 3Department of Radiology, Queen Square, London, United Kingdom; 4Division of Neuroscience and Psychological Medicine, Imperial College London, London, United Kingdom. Contact e-mail: jwhitwell @dementia.ion.ucI, ac. uk Background: Various pathological substrates underlie frontotemporal lobar degeneration (FTLD). These are difficult to predict in vivo based purely on clinical features. However, predicting pathology will become increasingly important when specific disease modifying treatments become available. Objective(s): To determine whether the different pathological substrates of FTLD have different patterns of atrophy on MRI and therefore whether MRI could be used to help predict final histopathology. Methods: We studied 17 post-mortem or biopsy-confirmed cases of FTLD with the following
$85
neuropathology: eight with dementia with ubiquitin-positive (tau and alphasynuclein negative) inclusions (DUI), five with Pick's disease (PiD) and four with frontotemporal dementia with parkinsonism linked to chromosome 17q (FTDP-17q). These were age and gender-matched to a group of 20 controls. Each subject had one volumetric MRI scan. Voxel-based morphometry, an automated unbiased technique, was used to assess the cross-sectional patterns of cerebral atrophy in each group. In addition, to corroborate findings each scan was also blindly visually assessed and graded by an experienced neuroradiologist in terms of regional atrophy. Results: Mean age (years) at scan was 63 5:6.8 in DUI, 51 4- 13.3 in PiD and 53 4- 4.2 in FTDP-17q; durations were 3.9 4- 2.7, 2.7 4- 1.3 and 5.7 4- 3.9 respectively, and CDR was 1.2 :t: 0.5, 1.8 4- 0.4 and 1.0 4- 0.0 respectively. A generalised pattern of atrophy was shown in DUI affecting frontal, temporal and parietal regions compared to controls (uncorrected, p < 0.0001). The PiD group showed a severe pattern of symmetrical frontal atrophy, with milder atrophy of the temporal lobes but also involvement of the parietal lobes~ with the FTDP-17q group showing a focal atrophy pattern affecting the anterior and medial temporal lobes, right>left, compared to controls (uncorrected, p < 0.0001). The right amygdala and hippocampus were more atrophied in FrDP-17q than PiD or DUI (uncorrected, p < 0.001). Visual assessments showed significantly more atrophy of the right amygdala in FTDP-17q than PiD (p = 0.01), and significantly more atrophy of the left frontal lobes, once corrected for global brain atrophy, in PiD than DUI (p = 0.02). Conclusions: Despite tremendous overlap between subjects with different histopathology, at least in terms of atrophy, these results suggest that the different pathological substrates of FTLD do present with different patterns of atrophy during life.
0 4 - 0 6 - 0 3 ] A N O V E L NR4A2 PROMOTER VARIATION
ASSOCIATED WITH PARKINSON'S DISEASE ALTERS GENE EXPRESSION Jessie Theuns*, Philippe Pals, Roos Rademakers, Marleen Van den Broeck, Ellen Corsmit, Krist'l Vennekens, Marc Cruts, Patrick Cras, Christine Van Broeckhoven. University of Antwerp, Antwerpen, Belgium. Contact e-mail:
jessie, theuns @ua. ac. be Background: Parkinson's disease (PD) is a frequent neurodegenerative disorder, characterized by dopaminergic cell loss in the mono-aminergic nuclei. A growing body of evidence indicates that PD is caused by genetic defects or by undefined environmental insults acting on predisposed individuals. Several studies have indicated that NR4A2, encoding a member of the nuclear receptor superfamily, may be a susceptibility gene for PD: NR4A2 is highly expressed in the midbraln dopaminergic neurons; NR4A2 depletion results in selective agenesis of mesencephalie dopaminergic neurons; and NR4A2 +/- mice show greater susceptibility to nigral injury and have features consistent with PD. Missense mutations in exons 1 and 3 have been reported in disorders related to dopaminergic dysfunction such as schizophrenia and manic depression. Two mutations were identified in exon 1 of NR4A2 in familial PD patients that cosegregated with the disease and were shown to have a dominant negative effect on NR4A2 expression. Methods and results: In this study, we carried out genetic analyses of the proximal promoter and 5'UTR in 186 individuals affected with Parkinson disease randomly recruited from patient support groups. All patients were prevalent and of Flemish origin (up to 3 generations). Patients were examined by a neurologist and strict criteria were used for inclusion (Pals et al., 2003). Direct sequencing of 1481 bp of the 5 r upstream regulatory region and the 51UTR exons 1 and 2 in 186 patients revealed 11 variations in the NR4A2 5 / regulatory region, 9 in the promoter region (-1336G/C, -1189C/G, - l 1 5 4 G / A , -811G/A, -785C/G, -784C/A, -401delC, +30C/G) and 2 in intron 2 (IVS2+107C/T and IVS2+224insG). One of these, +30C/G, is located in the core promoter of NR4A2 and affects one allele in 2 individuals with sporadic PD but not in controls (n = 300). The age at onset of disease and clinical features of these individuals were not different from those of individuals with typical PD. Preliminary reporter gene analysis in transfected cell lines and real-time PCR data in lymfocytes of affected individuals suggest an effect of this mutation on NR4A2 expression. Conclusions: These data suggest that mutations in NR4A2 can cause dopaminergic dysfunction, associated with PD.
Oral Session 04-06: Other Dementias - 1 cl-INTERNEXIN IS PRESENT IN THE HALLMARK I O ] LESIONS 4 - OF0NEURONAL 6 -INTERMEDIATE 0 1 I
FILAMENT INCLUSION DISEASE Nigel J. Cairns* 1, Victoria Zhukareva 1, Kunihiro Uryu I, Eileen Bigio 2, Ian R. Makenzie 3 , Marla Geaing 4, Charles Duyckaerts 5, Hideaki Yokoo 6, Yoichi Nakazato 6, Evelyn Jaros 7, Robert H. Perry 7, Virginia M. Lee 1, John Q. Trojanowski 1. 1 University of Pennsylvania School of Medicine,
Philadelphia, PA, USA; 2Northwestern University Medical School, Chicago, IL, USA; 3Vancouver General Hospital, Vancouver, BC, Canada; 4Emory University School of Medicine, Atlanta, GA, USA; SH@ital de la Salp~trikre, Paris, France; 6Gunma University School of Medicine, Maebashi, Japan; 7Newcastle General Hospital, Newcastle-upon-Tyne, United Kingdom. Contact e-mail: cairns @mail. reed. upenn, edu Background: Neuronal intermediate filament (IF) inclusion disease (NIFID) is a novel neurological disease of early onset with a variable clinical phenotype including frontotemporal dementia, pyramidal, extrapyramidal, and upper motor neuron signs. Pathologically, in affected areas, there is neuronal loss, astrocytosis and neuronal intracytoplasmic aggregates of abnormal neuronal IFs which contain neither tan nor c~-synuclein. Objective: This study was undertaken to characterize the neuronal IF protein profile of inclusions in NIFID. Methods: Immunohistochemistry was performed on 10 cases of NIFID, 4 normal aged controls, and 4 cases of Alzheimer's disease using a panel of anti-neuronal IF proteins. Immunoelectron microscopy was performed on selected cases and frozen tissue from the frontal lobe of four cases was used for biochemical studies including sequential extractions and Western blotting. Results: Based on these studies, we report here for the first time that c~-internexin, a neuronal IF protein, is present within the inclusions of NIFID as are all three neurofilament subunits: heavy, medium, and light. Thus, all class IV neuronal IF proteins are present within the pathological inclusions of this disease. Biochemistry revealed that IF aggregates were soluble in sodium dodecyl sulfate and no posttranslational modification was detected when compared with Alzheimer's disease or aged control brains. Conclusions: NIFID is characterized by the pathological cytoplasmic aggregation of all class IV neuronal IF proteins in brain. The discovery of c~-internexin in the hallmark lesions implicates novel mechanisms of pathogenesis in NIFID and other neurological diseases with pathological accumulations of IFs.
fO4-06-02
] THE RELATIONSHIP BETWEEN SPECIFIC HISTOPATHOLOGY AND PATTERNS OF ATROPHY ON MRI IN FRONTOTEMPORAL LOBAR DEGENERATION
Jennifer L. Whitwell . I , Keith A. Josephs 1,2, Alison K. Godbolt 1, John M. Stevens 3, Nick C. Fox I, Martin N. Rossor 1,4.11nstitute of Neurology,
University College London, London, United Kingdom; 2Mayo Clinic, Rochester, MN, USA; 3Department of Radiology, Queen Square, London, United Kingdom; 4Division of Neuroscience and Psychological Medicine, Imperial College London, London, United Kingdom. Contact e-mail: jwhitwell @dementia.ion.ucI, ac. uk Background: Various pathological substrates underlie frontotemporal lobar degeneration (FTLD). These are difficult to predict in vivo based purely on clinical features. However, predicting pathology will become increasingly important when specific disease modifying treatments become available. Objective(s): To determine whether the different pathological substrates of FTLD have different patterns of atrophy on MRI and therefore whether MRI could be used to help predict final histopathology. Methods: We studied 17 post-mortem or biopsy-confirmed cases of FTLD with the following
$85
neuropathology: eight with dementia with ubiquitin-positive (tau and alphasynuclein negative) inclusions (DUI), five with Pick's disease (PiD) and four with frontotemporal dementia with parkinsonism linked to chromosome 17q (FTDP-17q). These were age and gender-matched to a group of 20 controls. Each subject had one volumetric MRI scan. Voxel-based morphometry, an automated unbiased technique, was used to assess the cross-sectional patterns of cerebral atrophy in each group. In addition, to corroborate findings each scan was also blindly visually assessed and graded by an experienced neuroradiologist in terms of regional atrophy. Results: Mean age (years) at scan was 63 5:6.8 in DUI, 51 4- 13.3 in PiD and 53 4- 4.2 in FTDP-17q; durations were 3.9 4- 2.7, 2.7 4- 1.3 and 5.7 4- 3.9 respectively, and CDR was 1.2 :t: 0.5, 1.8 4- 0.4 and 1.0 4- 0.0 respectively. A generalised pattern of atrophy was shown in DUI affecting frontal, temporal and parietal regions compared to controls (uncorrected, p < 0.0001). The PiD group showed a severe pattern of symmetrical frontal atrophy, with milder atrophy of the temporal lobes but also involvement of the parietal lobes~ with the FTDP-17q group showing a focal atrophy pattern affecting the anterior and medial temporal lobes, right>left, compared to controls (uncorrected, p < 0.0001). The right amygdala and hippocampus were more atrophied in FrDP-17q than PiD or DUI (uncorrected, p < 0.001). Visual assessments showed significantly more atrophy of the right amygdala in FTDP-17q than PiD (p = 0.01), and significantly more atrophy of the left frontal lobes, once corrected for global brain atrophy, in PiD than DUI (p = 0.02). Conclusions: Despite tremendous overlap between subjects with different histopathology, at least in terms of atrophy, these results suggest that the different pathological substrates of FTLD do present with different patterns of atrophy during life.
0 4 - 0 6 - 0 3 ] A N O V E L NR4A2 PROMOTER VARIATION
ASSOCIATED WITH PARKINSON'S DISEASE ALTERS GENE EXPRESSION Jessie Theuns*, Philippe Pals, Roos Rademakers, Marleen Van den Broeck, Ellen Corsmit, Krist'l Vennekens, Marc Cruts, Patrick Cras, Christine Van Broeckhoven. University of Antwerp, Antwerpen, Belgium. Contact e-mail:
jessie, theuns @ua. ac. be Background: Parkinson's disease (PD) is a frequent neurodegenerative disorder, characterized by dopaminergic cell loss in the mono-aminergic nuclei. A growing body of evidence indicates that PD is caused by genetic defects or by undefined environmental insults acting on predisposed individuals. Several studies have indicated that NR4A2, encoding a member of the nuclear receptor superfamily, may be a susceptibility gene for PD: NR4A2 is highly expressed in the midbraln dopaminergic neurons; NR4A2 depletion results in selective agenesis of mesencephalie dopaminergic neurons; and NR4A2 +/- mice show greater susceptibility to nigral injury and have features consistent with PD. Missense mutations in exons 1 and 3 have been reported in disorders related to dopaminergic dysfunction such as schizophrenia and manic depression. Two mutations were identified in exon 1 of NR4A2 in familial PD patients that cosegregated with the disease and were shown to have a dominant negative effect on NR4A2 expression. Methods and results: In this study, we carried out genetic analyses of the proximal promoter and 5'UTR in 186 individuals affected with Parkinson disease randomly recruited from patient support groups. All patients were prevalent and of Flemish origin (up to 3 generations). Patients were examined by a neurologist and strict criteria were used for inclusion (Pals et al., 2003). Direct sequencing of 1481 bp of the 5 r upstream regulatory region and the 51UTR exons 1 and 2 in 186 patients revealed 11 variations in the NR4A2 5 / regulatory region, 9 in the promoter region (-1336G/C, -1189C/G, - l 1 5 4 G / A , -811G/A, -785C/G, -784C/A, -401delC, +30C/G) and 2 in intron 2 (IVS2+107C/T and IVS2+224insG). One of these, +30C/G, is located in the core promoter of NR4A2 and affects one allele in 2 individuals with sporadic PD but not in controls (n = 300). The age at onset of disease and clinical features of these individuals were not different from those of individuals with typical PD. Preliminary reporter gene analysis in transfected cell lines and real-time PCR data in lymfocytes of affected individuals suggest an effect of this mutation on NR4A2 expression. Conclusions: These data suggest that mutations in NR4A2 can cause dopaminergic dysfunction, associated with PD.