- Email: [email protected]
P3-338 Mutant tau expression increases β-catenin levels in affected CNS regions of transgenic mice
Poster Session P3: Related Neurodegenerative Conditions - Frontotemporal Dementias, FTDP-17 decreased comprehension of words, prosopagnosia and object visual agnosia. Objective(s): To identify the location of glucose hypometabolism using Statistical Parametric Mapping (SPM) methods. Methods: We report FDG-PET findings of 6 patients with SD that was analyzed by SPM. Six patients fulfilled the diagnostic criteria of SD proposed by consensus on PTLD diagnostic criteria. Brain MRI showed asymmetric temporal atrophies, mainly left antero-inferior temporal cortices in all patients. We performed FDG-PET scan in these patients and l 1 normal controls and conducted an SPM analysis to identify brain regions with glucose hypometabolism in SD patients Results: Visually, FDG-PET images of the six patients showed hypometabolism in bilateral anterior temporal lobes, more severe in the left. Hypometablic brain regions analyzed by SPM method were left fusiform gyms, middle, inferior temporal gyri and right superior temporal gyms. Conclusions: Our results suggest that SD is a degenerative dementia that primarily affects anterior and basal temporal area especially of left hemisphere.
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FRONTOTEMPORAL DEMENTIA: RELATIONS BETWEEN REGIONAL CEREBRAL GLUCOSE METABOLISM AND C L I N I C A L AND N E U R O P S Y C H O L O G I C A L FINDINGS
Lena Kilander* 1, Maria Lindau 1, Henry Engler 2. 1Uppsala University,
Uppsala, Sweden; 2Uppsala Imanet AB, Uppsala, Sweden. Contact e-mail: lena.kilander @akademiska.se Background: Frontotemporal dementia (FTD) is a clinically heterogenous syndrome, dominated by changes in personality and social behaviour, and language disturbances. Objectives: To study the relation between clinical symptoms and signs, neuropsychological deficits and regional cerebral glucose hypometabolism measured by PET (positron emission tomography). Methods: Five patients who were clinically diagnosed as FTD (mean age 66 years, MMSE 10-28 p, duration 1.5-6 years) were examined with PET scan (18-fluorodeoxy-glucose) and an extensive neuropsychological testing, including an evaluation of self-image. The presence or absence of frontotemporal deficit symptoms during the course of the disease were recorded in a semi-structured interview with the patients and their spouses. Results: PET imaging showed an asymmetrical frontotemporal hypometabolism in all patients; predominantly right-sided in three cases and left-sided in two cases. The neuropsychological test profile was virtually similar in all patients, with impaired performance in tests on verbal fluency, naming and abstract thinking, executive function, and delayed memory. Both patients with predominantly left-sided hypometabolism had language disturbances as first symptoms, such as less fluent speech or difficulties in word finding. Two patients had prosopagnosia as their earliest symptom and later developed signs of frontal involvement, eg. disinhibition. They had similar patterns of hypometabolism, with predominantly right temporal reductions. One patient presenting with florid frontal symptoms had marked, wide-spread metabolic reductions in the right cortex, and hypermetabolism in the left fronto-parietai cortex. Three patients with mild cognitive impairment had hypometabolic areas extending into the parietal cortex. PET was repeated after approximately two years in two patients, confirming a further reduced and more wide-spread cortical hypometabolism, extending also into the posterior cortex, Conclusions: These preliminary descriptive results from a small sample of FTD patients confirm that clinical and neuropsychological signs of frontotemporal engagement is reflected in frontotemporal hypometabolisrn as measured by PET. The study also confirms that there is an overlapping between the three subtypes described earlier: the frontal variant, semantic dementia and progressive nonfluent aphasia. Further research is needed in order to study the relation between the regional distribution of neurodegeneration and how it manifests clinically, along the course of the disease.
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$451
MUTANT TAU E X P R E S S I O N INCREASES ~-CATENIN L E V E L S IN A F F E C T E D CNS R E G I O N S OF TRANSGENIC M I C E
Martina H. Wiedau-Pazos*. UCLA, Los Angeles, CA, USA. Contact e-mail:
mwiedau @mednet, ucla.edu Background: : Mutations of the microtubule-associated protein tan are the only known cause of frontotemporal dementia (FTD). The mechanisms, by which mutant tau causes degeneration of the affected CNS regions remains unknown. Our previous research in a Drosophila model of tan expression has pointed to potential roles of components of the Wnt signaling pathway in tan-induced neuronal loss. Objective(s): To test the hypothesis that mutant tau induces neuronal death in a transgenic mouse model expressing the most common tall mutation P301L via activation of beta-catenin. Methods: Six-month old JNPL3 female mice expressing human P301L tau and wild type control mice were used. Sections for immunohistochemistry of fixed mouse CNS and protein extracts for immunoblotting from fresh mouse CNS were prepared and probed with antibodies against total beta-catenin, total tan, hyperphosphorylated tau and glycogen synthase kinase-3beta (GSK3beta, kinase of tan and beta-catenin). Results: JNPL3 mice that display early changes, such as hyperphosphorylated tau deposits, in CNS regions undergoing degeneration, exhibit increased beta-catenin expression in those CNS regions. This finding was confirmed using Western blotting and immunohistochemical studies. Results are pending of studies investigating the expression of beta-catenin-related transcription factors in the affected CNS regions. Conclusions: Evidence is presented that beta-catenin may be misregulated in YNPL3 mice overexpressing the P301L tan mutation. Further studies are executed to investigate the expression of cell deathrelated transcription factors that are regulated by beta-catenin. Further correlation with GSK-3beta is planned to investigate the hypothesis that abnormal phosphorylation of beta-catenin by GSK-3beta in the presence of mutant tau occurs.
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L O N G I T U D I N A L C H A R A C T E R I Z A T I O N O F TWO SIBLINGS WITH FRONTOTEMPORAL D E M E N T I A ASSOCIATED W I T H THE $305N TAU MUTATION
Bradley F. Boeve* 1, Ivo W. Tremont 2, Andrew J. Waclawik 3, Jill Murrell 4, Brace Hermann 3, Clifford R. Jack 1, Glenn E. Smith I, David S. Knopman 1, Anil R. Nair 1, Noralane Lindor ~, Vinaya Koppikar s, Bernardino Ghetti 4 .
1Mayo Clinic, Rochester, MN, USA; 2Medical University of South Carolina, Charlston, SC, USA; 3University of Wisconsin, Madison, WI, USA; 41ndiana University School of Medicine, Indianapolis, IN, USA; 5Monroe Clinic, Monroe, W1, USA. Contact e-mail: [email protected] Background: Two Japanese kindreds with the $305N tau mutation have been reported. Although the pathologic findings in the autopsied cases were well-characterized, only limited antemortern data was presented. Objective(s): To characterize the longitudinal antemortem features in two Caucasian siblings with the $305N tan mutation. Methods: Longitudinal characterization was carried out in two siblings of European ancestry with frontotemporal dementia (FTD) through comprehensive neurobehavioral examinations and other scales at approximate six month intervals. Scales included the Clinical Dementia Rating scale, Global Deterioration Scale, Record of Independent Living, Mini-Mental State Examination (MMSE), Short Test of Mental Status (STMS), motor subtest of the Unified Parkinson's Disease Rating Scale, detailed neuropsychological testing, Neuropsychiatric Inventory (NPI), and magnetic resonance imaging (MRI) of the brain. Results: The missense mutation in tan, $305N, was detected in the proband who developed features typical of FTD at age 31, and she has undergone serial evaluations for over 3 years. Her older sister, who also has the $305N mutation, developed similar symptoms at age 36 and has undergone serial evaluations for 2 years. The siblings have exhibited similar cognitive and behavioral features typical of FTD, which have proven challenging to manage despite aggressive pharmacologic and behavioral therapies. The older sibling has undergone neuropsychological testing 4 times over 2 years, and despite normal scores on the MMSE, STMS, and Dementia Rating Scale, she has scored poorly on delayed recall measures and especially on
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FRONTOTEMPORAL DEMENTIA: RELATIONS BETWEEN REGIONAL CEREBRAL GLUCOSE METABOLISM AND C L I N I C A L AND N E U R O P S Y C H O L O G I C A L FINDINGS
Lena Kilander* 1, Maria Lindau 1, Henry Engler 2. 1Uppsala University,
Uppsala, Sweden; 2Uppsala Imanet AB, Uppsala, Sweden. Contact e-mail: lena.kilander @akademiska.se Background: Frontotemporal dementia (FTD) is a clinically heterogenous syndrome, dominated by changes in personality and social behaviour, and language disturbances. Objectives: To study the relation between clinical symptoms and signs, neuropsychological deficits and regional cerebral glucose hypometabolism measured by PET (positron emission tomography). Methods: Five patients who were clinically diagnosed as FTD (mean age 66 years, MMSE 10-28 p, duration 1.5-6 years) were examined with PET scan (18-fluorodeoxy-glucose) and an extensive neuropsychological testing, including an evaluation of self-image. The presence or absence of frontotemporal deficit symptoms during the course of the disease were recorded in a semi-structured interview with the patients and their spouses. Results: PET imaging showed an asymmetrical frontotemporal hypometabolism in all patients; predominantly right-sided in three cases and left-sided in two cases. The neuropsychological test profile was virtually similar in all patients, with impaired performance in tests on verbal fluency, naming and abstract thinking, executive function, and delayed memory. Both patients with predominantly left-sided hypometabolism had language disturbances as first symptoms, such as less fluent speech or difficulties in word finding. Two patients had prosopagnosia as their earliest symptom and later developed signs of frontal involvement, eg. disinhibition. They had similar patterns of hypometabolism, with predominantly right temporal reductions. One patient presenting with florid frontal symptoms had marked, wide-spread metabolic reductions in the right cortex, and hypermetabolism in the left fronto-parietai cortex. Three patients with mild cognitive impairment had hypometabolic areas extending into the parietal cortex. PET was repeated after approximately two years in two patients, confirming a further reduced and more wide-spread cortical hypometabolism, extending also into the posterior cortex, Conclusions: These preliminary descriptive results from a small sample of FTD patients confirm that clinical and neuropsychological signs of frontotemporal engagement is reflected in frontotemporal hypometabolisrn as measured by PET. The study also confirms that there is an overlapping between the three subtypes described earlier: the frontal variant, semantic dementia and progressive nonfluent aphasia. Further research is needed in order to study the relation between the regional distribution of neurodegeneration and how it manifests clinically, along the course of the disease.
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$451
MUTANT TAU E X P R E S S I O N INCREASES ~-CATENIN L E V E L S IN A F F E C T E D CNS R E G I O N S OF TRANSGENIC M I C E
Martina H. Wiedau-Pazos*. UCLA, Los Angeles, CA, USA. Contact e-mail:
mwiedau @mednet, ucla.edu Background: : Mutations of the microtubule-associated protein tan are the only known cause of frontotemporal dementia (FTD). The mechanisms, by which mutant tau causes degeneration of the affected CNS regions remains unknown. Our previous research in a Drosophila model of tan expression has pointed to potential roles of components of the Wnt signaling pathway in tan-induced neuronal loss. Objective(s): To test the hypothesis that mutant tau induces neuronal death in a transgenic mouse model expressing the most common tall mutation P301L via activation of beta-catenin. Methods: Six-month old JNPL3 female mice expressing human P301L tau and wild type control mice were used. Sections for immunohistochemistry of fixed mouse CNS and protein extracts for immunoblotting from fresh mouse CNS were prepared and probed with antibodies against total beta-catenin, total tan, hyperphosphorylated tau and glycogen synthase kinase-3beta (GSK3beta, kinase of tan and beta-catenin). Results: JNPL3 mice that display early changes, such as hyperphosphorylated tau deposits, in CNS regions undergoing degeneration, exhibit increased beta-catenin expression in those CNS regions. This finding was confirmed using Western blotting and immunohistochemical studies. Results are pending of studies investigating the expression of beta-catenin-related transcription factors in the affected CNS regions. Conclusions: Evidence is presented that beta-catenin may be misregulated in YNPL3 mice overexpressing the P301L tan mutation. Further studies are executed to investigate the expression of cell deathrelated transcription factors that are regulated by beta-catenin. Further correlation with GSK-3beta is planned to investigate the hypothesis that abnormal phosphorylation of beta-catenin by GSK-3beta in the presence of mutant tau occurs.
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L O N G I T U D I N A L C H A R A C T E R I Z A T I O N O F TWO SIBLINGS WITH FRONTOTEMPORAL D E M E N T I A ASSOCIATED W I T H THE $305N TAU MUTATION
Bradley F. Boeve* 1, Ivo W. Tremont 2, Andrew J. Waclawik 3, Jill Murrell 4, Brace Hermann 3, Clifford R. Jack 1, Glenn E. Smith I, David S. Knopman 1, Anil R. Nair 1, Noralane Lindor ~, Vinaya Koppikar s, Bernardino Ghetti 4 .
1Mayo Clinic, Rochester, MN, USA; 2Medical University of South Carolina, Charlston, SC, USA; 3University of Wisconsin, Madison, WI, USA; 41ndiana University School of Medicine, Indianapolis, IN, USA; 5Monroe Clinic, Monroe, W1, USA. Contact e-mail: [email protected] Background: Two Japanese kindreds with the $305N tau mutation have been reported. Although the pathologic findings in the autopsied cases were well-characterized, only limited antemortern data was presented. Objective(s): To characterize the longitudinal antemortem features in two Caucasian siblings with the $305N tan mutation. Methods: Longitudinal characterization was carried out in two siblings of European ancestry with frontotemporal dementia (FTD) through comprehensive neurobehavioral examinations and other scales at approximate six month intervals. Scales included the Clinical Dementia Rating scale, Global Deterioration Scale, Record of Independent Living, Mini-Mental State Examination (MMSE), Short Test of Mental Status (STMS), motor subtest of the Unified Parkinson's Disease Rating Scale, detailed neuropsychological testing, Neuropsychiatric Inventory (NPI), and magnetic resonance imaging (MRI) of the brain. Results: The missense mutation in tan, $305N, was detected in the proband who developed features typical of FTD at age 31, and she has undergone serial evaluations for over 3 years. Her older sister, who also has the $305N mutation, developed similar symptoms at age 36 and has undergone serial evaluations for 2 years. The siblings have exhibited similar cognitive and behavioral features typical of FTD, which have proven challenging to manage despite aggressive pharmacologic and behavioral therapies. The older sibling has undergone neuropsychological testing 4 times over 2 years, and despite normal scores on the MMSE, STMS, and Dementia Rating Scale, she has scored poorly on delayed recall measures and especially on