- Email: [email protected]
BRAINSTEM MICROBLEEDS AFFECT MOTOR DEFICITS IN SUBCORTICAL VASCULAR COGNITIVE IMPAIRMENT
P842
Poster Presentations: P4
diencephalon, suggesting the importance of the parahippocampal and hippocampal cortices, which play a crucial role in the retention of shortmemory. P4-145
BRAINSTEM MICROBLEEDS AFFECT MOTOR DEFICITS IN SUBCORTICAL VASCULAR COGNITIVE IMPAIRMENT
Yeo Jin Kim1, Sang Won Seo2, Hanna Cho3, Byoung Seok Ye4, Hee Jin Kim4, Jung-Hyun Kim4, Sung Tae Kim4, Chang-Seok Ki4, Jong Min Lee5, Juhee Chin4, Yun Joong Kim6, Duk L. Na2, 1Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; 2Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; 3Departments of Neurology, Samsung Medical Center, Seoul, South Korea; 4Samsung Medical Center, Seoul, South Korea; 5Hanyang University, Seoul, South Korea; 6Ilsong Institute of Life Science, Hallym University, Anyang, South Korea. Contact e-mail: [email protected] Background: Subcortical vascular cognitive impairment (SVCI) manifests as cognitive, behavioral and motor deficits. Microbleeds (MB) are commonly found in SVCI patients, but their clinical implication has been debatable. Especially, to my knowledge, there were no studies evaluating the regional effects of MB on motor deficits. Therefore, we aim to determine whether MB in the lobar, deep or brainstem are associated with motor deficts. Methods: A total of 129 SVCI individuals were included in this study. All of them underwent MRI and Pyramidal and extrapyramidal scale (PEPS). MB were divided into lobar MB, deep MB or brainstem MB according to their location. The PEPS is composed of five subsets: corticospinal, corticobulbar, extrapyramidal, gait abnormality, and gait severity. Multiple linear regression were performed after controlling for demographic, vascular risk factors, WMH volume and lacunes. Results: Of the 129 patients with SVCI, 85 (65.9%) had CMBs. The mean total PEPS was 11.9 69.5. Brainstem MB were associated with bulbar (unstandardized beta coefficient; b¼ 0.139, p value 0.028), gait abnormality (b ¼0.009, p value 0.009) gait severity (b ¼0.216, p value 0.003) and total PEPS (b ¼1.488, p value 0.008). However, lobar or deep MB were not associated with PEPS sores. Conclusions: Our finding suggested that brainstem MB predict bulbar and gait abnormalities in SVCI patients. P4-146
POSTERIOR CEREBRAL ATROPHY ASSOCIATED WITH THE PSEN1 I229F MUTATION
Kathy L. Newell1, Jill R. Murrell2, Adrian L. Oblak2, Francine Epperson3, Barbara-Jean Ottley4, Frederick W. Unverzagt2, Martin R. Farlow5, Shannon Leigh Risacher2, Andrew J. Saykin6, John C. Morris7, Nigel J. Cairns7, Bernardino Francesco Ghetti2, 1University of Kansas School of Medicine, Kansas City, Kansas, United States; 2Indiana University School of Medicine, Indianapolis, Indiana, United States; 3 Indiana School of Medicine, Indianapolis, Indiana, United States; 4Ottley Neurology Center, Hays, Kansas, United States; 5Indiana Universitty School of Medicine, Indianapolis, Indiana, United States; 6Indiana University School of Medicine, Indianapolis, Indiana, United States; 7 Washington University School of Medicine, St. Louis, Missouri, United States. Contact e-mail: [email protected] Background: Mutations in the Presenilin 1 (PSEN1) gene are associated with autosomal dominant early onset Alzheimer disease (EOAD). Posterior cerebral atrophy (PCA), a progressive neurodegenerative syndrome affecting visual processing accompanied by atrophy and hypometabolism in the parieto-occipital brain, has been associated with AD and certain PSEN1 gene mutations. Methods: Clinical, neuropsychological, and neuroimaging studies were performed. Postmortem neuropathologic studies of the brain were carried out. Histological methods included hematoxylinand eosin-Luxol fast blue and Thioflavin S. For immunohistochemistry, antibodies against b-amyloid, tau, and a-synuclein were used. DNA was extracted from brain or blood for gene sequencing. Results: At 47, the proband developed memory loss, unsteady gait, pyramidal signs, and visual disturbance (loss of depth perception, intermittent visual loss suggestive of a visual apraxia, eventual blindness.) MRI revealed greater atrophy in parietal
than frontal lobes. DNA sequencing revealed an ATT to TTT nucleotide mutation, resulting in a phenylalanine for isoleucine substitution (I229F) in the PSEN1 gene. The proband’s daughters enrolled in the Dominantly Inherited Alzheimer Network. At 39, one daughter developed memory loss, unsteady gait, and visual disturbance. DNA sequencing confirmed a PSEN1 I229F mutation. Neuropsychological evaluation revealed inability to copy a simple geometric design, recall visual information, and a WAIS-R Block Design raw score of 0/51, indicating markedly impaired visuospatial abilities. Structural MRI revealed greater bilateral parieto-occipital lobe gray matter volume loss relative to frontal gray matter. FDG-PET confirmed notable hypometabolism in bilateral parietal lobes. PIB-PET showed high signal consistent with amyloid deposition throughout cortex, including parieto-occipital lobes. She died at 44. Histological and immunohistochemical studies confirmed AD in both brains. The proband’s brain showed severe cerebral atrophy of parieto-occipital lobes relative to the frontal and temporal lobes. The daughter’s brain showed disproportionate thinning of occipital cortex relative to other lobes and reduction of occipital white matter. In both brains, b-amyloid and tau burdens were severe in occipital cortex. The proband also had corticospinal tract degeneration. Conclusions: Prominent visual disturbances in EOAD may suggest the PCA syndrome. Our findings suggest that PCA may be associated with the PSEN1 I229F mutation. (Grants: P30AG35982, P30AG 010133, U19AG032438.) P4-147
PHENOTYPIC CHARACTERIZATION OF EARLY ONSET FAMILIAL AD ASSOCIATED WITH A PSEN1 L418F MUTATION
Kathy Newell1, Jean Paul Vonsattel2, Jill Murrell3, Bernardino Francesco Ghetti4, Pierluigi Gambetti5, Richard Dubinsky6, Russell H. Swerdlow7, 1University of Kansas School Of Medicine, Kansas City, Kansas, United States; 2Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, New York, New York, United States; 3Indiana University, Indianapolis, Indiana, United States; 4Indiana University School of Medicine, Indianapolis, Indiana, United States; 5Case Western Reserve University, Cleveland, Ohio, United States; 6University of Kansas School of Medicine, Kansas City, Kansas, United States; 7University of Kansas, Kansas City, Kansas, United States. Contact e-mail: knewell@ kumc.edu Background: The phenotype of early-onset Alzheimer Disease, associated with Presenilin 1 (PSEN1) gene mutations, may present with clinical and neuropathological heterogeneity. In some instances, the clinical presentation and evolution of the disorder may suggest other neurodegenerative disorders. Methods: The proband has been followed clinically during the past two years; magnetic resonance imaging (MRI) studies were carried out. Family history indicates that the proband’s mother died at 39 with a neurodegenerative disease. The proband’s DNA was isolated, and the Huntingtin and Prion Protein genes were sequenced. Archival brain tissue from the proband’s mother was traced and reexamined by histology and immunohistochemistry. For histology, hematoxylin and eosin-Luxol fast blue and Thioflavin S methods were used; for immunohistochemistry, sections were labeled with antibodies against tau, b-amyloid, and a-synuclein. Following the brain studies, the PSEN1 gene was sequenced. Results: The proband, a 38 year-old woman, presented with impaired memory and lack of insight. Neurological evaluation showed dysarthria, truncal myoclonus, increased muscle tone, and ataxia with a wide-based gait. MRI revealed marked cerebral atrophy with hydrocephalus. Review of records documented early onset dementia, suspected to be Huntington disease (HD), affecting the proband’s mother and grandmother. Genetic analysis at the National Prion Disease Pathology Surveillance Center ruled out familial prion disease. HD had been ruled out previously. Review of the mother’s brain autopsy revealed cerebral atrophy. Histologically, the cerebral cortex showed numerous amyloid plaques and neurofibrillary tangles. Lewy bodies were noted in amygdala. Ab and tau deposits were numerous in cerebral cortex, amygdala, hippocampus, and entorhinal cortex. Ab-immunolabeled plaques without cores (“cotton wool plaques”) were present. Amyloid angiopathy was observed. DNA analysis revealed a TTG to TTT nucleotide mutation, resulting in leucine to phenylalanine substitution (L418F) in the
Poster Presentations: P4
diencephalon, suggesting the importance of the parahippocampal and hippocampal cortices, which play a crucial role in the retention of shortmemory. P4-145
BRAINSTEM MICROBLEEDS AFFECT MOTOR DEFICITS IN SUBCORTICAL VASCULAR COGNITIVE IMPAIRMENT
Yeo Jin Kim1, Sang Won Seo2, Hanna Cho3, Byoung Seok Ye4, Hee Jin Kim4, Jung-Hyun Kim4, Sung Tae Kim4, Chang-Seok Ki4, Jong Min Lee5, Juhee Chin4, Yun Joong Kim6, Duk L. Na2, 1Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; 2Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; 3Departments of Neurology, Samsung Medical Center, Seoul, South Korea; 4Samsung Medical Center, Seoul, South Korea; 5Hanyang University, Seoul, South Korea; 6Ilsong Institute of Life Science, Hallym University, Anyang, South Korea. Contact e-mail: [email protected] Background: Subcortical vascular cognitive impairment (SVCI) manifests as cognitive, behavioral and motor deficits. Microbleeds (MB) are commonly found in SVCI patients, but their clinical implication has been debatable. Especially, to my knowledge, there were no studies evaluating the regional effects of MB on motor deficits. Therefore, we aim to determine whether MB in the lobar, deep or brainstem are associated with motor deficts. Methods: A total of 129 SVCI individuals were included in this study. All of them underwent MRI and Pyramidal and extrapyramidal scale (PEPS). MB were divided into lobar MB, deep MB or brainstem MB according to their location. The PEPS is composed of five subsets: corticospinal, corticobulbar, extrapyramidal, gait abnormality, and gait severity. Multiple linear regression were performed after controlling for demographic, vascular risk factors, WMH volume and lacunes. Results: Of the 129 patients with SVCI, 85 (65.9%) had CMBs. The mean total PEPS was 11.9 69.5. Brainstem MB were associated with bulbar (unstandardized beta coefficient; b¼ 0.139, p value 0.028), gait abnormality (b ¼0.009, p value 0.009) gait severity (b ¼0.216, p value 0.003) and total PEPS (b ¼1.488, p value 0.008). However, lobar or deep MB were not associated with PEPS sores. Conclusions: Our finding suggested that brainstem MB predict bulbar and gait abnormalities in SVCI patients. P4-146
POSTERIOR CEREBRAL ATROPHY ASSOCIATED WITH THE PSEN1 I229F MUTATION
Kathy L. Newell1, Jill R. Murrell2, Adrian L. Oblak2, Francine Epperson3, Barbara-Jean Ottley4, Frederick W. Unverzagt2, Martin R. Farlow5, Shannon Leigh Risacher2, Andrew J. Saykin6, John C. Morris7, Nigel J. Cairns7, Bernardino Francesco Ghetti2, 1University of Kansas School of Medicine, Kansas City, Kansas, United States; 2Indiana University School of Medicine, Indianapolis, Indiana, United States; 3 Indiana School of Medicine, Indianapolis, Indiana, United States; 4Ottley Neurology Center, Hays, Kansas, United States; 5Indiana Universitty School of Medicine, Indianapolis, Indiana, United States; 6Indiana University School of Medicine, Indianapolis, Indiana, United States; 7 Washington University School of Medicine, St. Louis, Missouri, United States. Contact e-mail: [email protected] Background: Mutations in the Presenilin 1 (PSEN1) gene are associated with autosomal dominant early onset Alzheimer disease (EOAD). Posterior cerebral atrophy (PCA), a progressive neurodegenerative syndrome affecting visual processing accompanied by atrophy and hypometabolism in the parieto-occipital brain, has been associated with AD and certain PSEN1 gene mutations. Methods: Clinical, neuropsychological, and neuroimaging studies were performed. Postmortem neuropathologic studies of the brain were carried out. Histological methods included hematoxylinand eosin-Luxol fast blue and Thioflavin S. For immunohistochemistry, antibodies against b-amyloid, tau, and a-synuclein were used. DNA was extracted from brain or blood for gene sequencing. Results: At 47, the proband developed memory loss, unsteady gait, pyramidal signs, and visual disturbance (loss of depth perception, intermittent visual loss suggestive of a visual apraxia, eventual blindness.) MRI revealed greater atrophy in parietal
than frontal lobes. DNA sequencing revealed an ATT to TTT nucleotide mutation, resulting in a phenylalanine for isoleucine substitution (I229F) in the PSEN1 gene. The proband’s daughters enrolled in the Dominantly Inherited Alzheimer Network. At 39, one daughter developed memory loss, unsteady gait, and visual disturbance. DNA sequencing confirmed a PSEN1 I229F mutation. Neuropsychological evaluation revealed inability to copy a simple geometric design, recall visual information, and a WAIS-R Block Design raw score of 0/51, indicating markedly impaired visuospatial abilities. Structural MRI revealed greater bilateral parieto-occipital lobe gray matter volume loss relative to frontal gray matter. FDG-PET confirmed notable hypometabolism in bilateral parietal lobes. PIB-PET showed high signal consistent with amyloid deposition throughout cortex, including parieto-occipital lobes. She died at 44. Histological and immunohistochemical studies confirmed AD in both brains. The proband’s brain showed severe cerebral atrophy of parieto-occipital lobes relative to the frontal and temporal lobes. The daughter’s brain showed disproportionate thinning of occipital cortex relative to other lobes and reduction of occipital white matter. In both brains, b-amyloid and tau burdens were severe in occipital cortex. The proband also had corticospinal tract degeneration. Conclusions: Prominent visual disturbances in EOAD may suggest the PCA syndrome. Our findings suggest that PCA may be associated with the PSEN1 I229F mutation. (Grants: P30AG35982, P30AG 010133, U19AG032438.) P4-147
PHENOTYPIC CHARACTERIZATION OF EARLY ONSET FAMILIAL AD ASSOCIATED WITH A PSEN1 L418F MUTATION
Kathy Newell1, Jean Paul Vonsattel2, Jill Murrell3, Bernardino Francesco Ghetti4, Pierluigi Gambetti5, Richard Dubinsky6, Russell H. Swerdlow7, 1University of Kansas School Of Medicine, Kansas City, Kansas, United States; 2Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, New York, New York, United States; 3Indiana University, Indianapolis, Indiana, United States; 4Indiana University School of Medicine, Indianapolis, Indiana, United States; 5Case Western Reserve University, Cleveland, Ohio, United States; 6University of Kansas School of Medicine, Kansas City, Kansas, United States; 7University of Kansas, Kansas City, Kansas, United States. Contact e-mail: knewell@ kumc.edu Background: The phenotype of early-onset Alzheimer Disease, associated with Presenilin 1 (PSEN1) gene mutations, may present with clinical and neuropathological heterogeneity. In some instances, the clinical presentation and evolution of the disorder may suggest other neurodegenerative disorders. Methods: The proband has been followed clinically during the past two years; magnetic resonance imaging (MRI) studies were carried out. Family history indicates that the proband’s mother died at 39 with a neurodegenerative disease. The proband’s DNA was isolated, and the Huntingtin and Prion Protein genes were sequenced. Archival brain tissue from the proband’s mother was traced and reexamined by histology and immunohistochemistry. For histology, hematoxylin and eosin-Luxol fast blue and Thioflavin S methods were used; for immunohistochemistry, sections were labeled with antibodies against tau, b-amyloid, and a-synuclein. Following the brain studies, the PSEN1 gene was sequenced. Results: The proband, a 38 year-old woman, presented with impaired memory and lack of insight. Neurological evaluation showed dysarthria, truncal myoclonus, increased muscle tone, and ataxia with a wide-based gait. MRI revealed marked cerebral atrophy with hydrocephalus. Review of records documented early onset dementia, suspected to be Huntington disease (HD), affecting the proband’s mother and grandmother. Genetic analysis at the National Prion Disease Pathology Surveillance Center ruled out familial prion disease. HD had been ruled out previously. Review of the mother’s brain autopsy revealed cerebral atrophy. Histologically, the cerebral cortex showed numerous amyloid plaques and neurofibrillary tangles. Lewy bodies were noted in amygdala. Ab and tau deposits were numerous in cerebral cortex, amygdala, hippocampus, and entorhinal cortex. Ab-immunolabeled plaques without cores (“cotton wool plaques”) were present. Amyloid angiopathy was observed. DNA analysis revealed a TTG to TTT nucleotide mutation, resulting in leucine to phenylalanine substitution (L418F) in the