- Email: [email protected]
Characteristic patterns of cortical thickness in pathologically-confirmed Alzheimer's disease and frontotemporal lobar degeneration
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Oral O4-06: Other Dementias
overt neuronal loss was observed; GRN-/- mice had microgliosis, astrogliosis and tissue vacuolation. Our oldest GRN-/- mouse (23 months) had focal neuronal loss and very severe gliosis. GRN-/þ were histologically unremarkable and equivalent to wild-type littermates. Conclusions: GRN-/- mice have reduced pre-natal viability consistent with the reported role of progranulin in development. Lipofuscin accumulation, a marker of age-associated cellular stress, suggested that GRN-/- mice may have accelerated neuronal aging. A role of progranulin in successful aging is compatible with its suggested role as a trophic factor required for long-term neuronal survival. Microvacuolation and gliosis at younger ages and focal neuronal loss and very severe gliosis in our oldest GRN-/- mouse suggests that progranulin deficiency leads to neurodegeneration in this model. Exposure of GRN-deficient mice to additional non-lethal stressors (e.g., hypoxic) might produce neurodegeneration in GRN-/þ mice, as well as GRN-/- mice at younger ages. O4-06-02
TDP-43 AND BETA-AMYLOID PRECURSOR PROTEIN PROCESSING PRODUCTS IN CEREBROSPINAL FLUID OF PATIENTS WITH AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL LOBAR DEGENERATION
Markus Otto1, Corinna Hendrich1, Anne Dorte Sperfeld1, Sarah Jesse1, Christine V. Arnim1, Stefan Lehnert1, Alice Pabst1, Ingo Uttner1, Hayrettin Tumani1, Virginia M. Y. Lee2, John Trojanowski2, Hans A. Kretzschmar3, Felix Motthagy4, Albert C. Ludolph1, Manuela Neumann5, Petra Steinacker1, 1University of Ulm, Ulm, Germany; 2 University of Pennsylvania School of Medicine, Philadelphia, MA, USA; 3 Ludwig-Maximilians University, Munich, Germany; 4UZ Leuven, Leuven, Belgium; 5University of Zurich, Zurich, Switzerland. Contact e-mail: [email protected] Background: Recently, TAR DNA-binding protein 43 (TDP-43) was identified to be the major component of ubiquitin-positive tau-negative neuronal and glial inclusions in the most common form of frontotemporal lobar degeneration (FTLD) as well as in amyotrophic lateral sclerosis (ALS). This led to the view of ALS and FTLD representing two manifestations of a clinicopathological spectrum. However for both diseases, changes in metabolism of beta-amyloid precursor protein (APP) are also reported. In this study, we analyzed cerebrospinal fluid from patients of the ALS-FTLD spectrum for APP processing products and TDP-43. Methods: We measured CSF for APP processing products by ELISA and determined relative TDP-43 levels by immunoblot in samples from patients with FTLD, patients with ALS, patients with ALS and FTLD and control patients (CON). Results: ALS and FTLD patients showed higher TDP-43 levels compared to CON, however, with a prominent overlap of values. ALS patients show elevated absolute levels of soluble APP and a shift towards the nonamyloidogenic APP processing pathway in contrast to patients with FTLD or ALS þ FTLD. By the introduction of an Abeta-peptid ratios clearly two different groups in the FTLD cohort could observed. Conclusions: Combined analyis of TDP-43 protein and APP processing products in CSF might aid in subtyping patients across the ALS/FTLD disease spectrum. O4-06-03
EXECUTIVE FUNCTION IN PROGRESSIVE AND NONPROGRESSIVE BEHAVIOURAL VARIANT FRONTOTEMPORAL DEMENTIA
Michael Hornberger1, Olivier Piguet1, Christopher M. Kipps2, John R. Hodges1,3, 1Prince of Wales Medical Research Institute, Sydney, Australia; 2Neurology Department, Southampton General Hospital, Southampton, United Kingdom; 3Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom. Contact e-mail: m. [email protected] Background: Recent studies suggest that behavioural variant frontotemporal dementia (bv-FTD) patients differ in their disease progression with fast and very slow progressing cases (Davies et al., 2006; Kipps et al., 2007). We investigated executive profiles of progressive and non-progressive bvFTD patients to establish diagnostic markers discriminating the two groups
from each other and controls at first presentation. Methods: A range of neuropsychological and behavioural tests were administered. Mean and overlap-based statistical analyses on selected test variables were conducted to investigate profiles of performance in bv-FTD patients and in controls. A logistic regression analysis, based on executive test variables, was performed to classify patients into progressors and non-progressors. Results: Although progressors and non-progressors showed equivalent behavioural profiles they were distinguishable by their performance on executive tasks. While the non-progressors’ performance on all tests was with the normal range, the progressors were consistently impaired on four tests: Digit Span Backward, the Hayling test of inhibitory control, Letter Fluency and Trails B. The logistic regression model showed that 86% of patients could be classified correctly into progressors and non-progressors on the basis of Digit Span Backward and Hayling subscores. Conclusions: Contrary to some prior reports, bv-FTD patients who show progression are typically impaired on frontal executive tasks at first presentation. Previous inconsistencies are probably explicable by the admixture of patients with progressive FTD and non-progressive/phenocopy cases. Importantly, a minority of progressive FTD patients performed normally on a range of executive tasks. O4-06-04
CHARACTERISTIC PATTERNS OF CORTICAL THICKNESS IN PATHOLOGICALLY-CONFIRMED ALZHEIMER’S DISEASE AND FRONTOTEMPORAL LOBAR DEGENERATION
Manja Lehmann1, Matthew J. Clarkson1, Jonathan D. Rohrer1, Rachael I. Scahill1, Marc Modat2, Jason D. Warren1, Sebastien Ourselin2, Martin N. Rossor1, Josephine Barnes1, Nick C. Fox1, 1Dementia Research Centre, Institute of Neurology, London, United Kingdom; 2Centre for Medical Image Computing, University College London, London, United Kingdom. Contact e-mail: [email protected] Background: Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) can be difficult to differentiate clinically due to overlapping symptoms. Subject classification in research studies is often based on clinical rather than pathological criteria which may mean some subjects are misdiagnosed and misclassified. Recently, methods measuring cortical thickness using magnetic resonance imaging (MRI) have been suggested to be effective in differentiating between clinically-defined AD and FTLD. We aimed to assess differences in cortical thickness in pathologically-confirmed cases of AD and FTLD. Methods: MRI scans of 25 pathologically-confirmed AD, 25 pathologically-confirmed FTLD subjects, and 25 age- and gender-matched healthy controls were included. Cortical thicknesses were measured using FreeSurfer and were compared between groups. Results: Compared with control subjects, AD patients showed reduced cortical thickness in broad regions of parietal, temporal and frontal lobes (Figure, Table) with the left hemisphere showing greater differences than the right. Regions with reduced cortical thickness include the posterior parietal lobe (13% lower than control mean thickness in left hemisphere, 10% in the right), entorhinal cortex (27% left, 16% right), fusiform gyrus (14% left, 10% right), posterior cingulate gyrus (19% left, 17% right), and temporal pole (19% left, 12% right). The FTLD group compared with controls had significantly reduced cortical thickness in anterior temporal and frontal regions in both hemispheres. Reduced cortical thickness was more extensive in the left hemisphere than in the right (Figure, Table). Regions with particularly reduced cortical thickness include the entorhinal cortex (32% left, 24% right), fusiform gyrus (17% left, 10% right), superior frontal gyrus (13% left, 12% right), temporal pole (34% left, 20% right), and anterior cingulate gyrus (16% left, 11% right). Direct comparison of differences in cortical thickness between AD and FTLD subjects showed reduced thickness in the posterior parietal region, posterior cingulate and frontal pole in the AD group compared with FTLD, whilst the anterior temporal lobe, anterior cingulate and frontal lobe showed greater cortical thickness in the AD group compared with FTLD. However, these differences did not survive correction for multiple comparisons. Conclusions: These characteristic patterns of cortical thinning in
Oral O4-06: Other Dementias pathologically-confirmed AD and FTLD patients may assist clinical differentiation of these common dementias.
O4-06-05
DIFFUSION TENSOR IMAGING CHARACTERISTICS OF DEMENTIA WITH LEWY BODIES AND ALZHEIMER’S DISEASE
Kejal Kantarci, Ramesh T. Avula, Matthew L. Senjem, Ali R. Samikoglu, Maria M. Shiung, Scott A. Przybelski, Stephen D. Weigand, Heidi A. Ward, Prashanthi Vemuri, Tanis J. Ferman, Bradley F. Boeve, David S. Knopman, Ronald C. Petersen, Clifford R. Jack, Jr., Mayo Clinic, Rochester, MN, USA. Contact e-mail: [email protected] Background: Diffusion tensor MR imaging (DTI) provides information on the integrity of tissue microstructure. The magnitude of diffusivity measured
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with the apparent diffusion coefficient (ADC) increases, and the directionality of diffusivity measured with fractional anisotropy (FA) decreases with neurodegeneration. The two most common neurodegenerative disorders associated with dementia are Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). Little is known about the DTI changes in DLB. Our objective was to determine the regional DTI characteristics of patients with DLB compared to patients with AD and cognitively normal subjects (CN). Methods: We studied clinically diagnosed age, gender and education matched patients with DLB (n ¼ 24), AD (n ¼ 24), and CN (n ¼ 24). DLB and AD subjects were further matched on dementia severity based on Clinical Dementia Rating scores. Parallel imaging was performed at 3 T using an acceleration factor of two. 3DMPRAGE was performed for anatomical segmentation and labeling. In order to avoid partial volume averaging of tissue diffusivity with CSF, we used an EPI-FLAIR-DTI sequence (which nulls CSF) with 21 diffusion sensitive gradient directions (b ¼ 1000 s/mm2). We measured ADC from segmented cortical gray matter in regions derived from the automated anatomic labeling atlas. Color FA maps were used for measuring tract-based FA and ADC. Voxel-based analysis was performed to determine gray matter ADC differences among the clinical groups. Results: In the cortical gray matter, patients with DLB and AD had elevated ADC in the amygdala compared to CN subjects (p ¼ 0.01). In addition, patients with AD had elevated ADC in the hippocampus and other temporal lobe regions, compared to DLB and CN subjects (p < 0.01). The posterior cingulum white matter tract ADC was elevated (p < 0.01) and FA was decreased (p < 0.05) in patients with AD compared to DLB and CN subjects. SPM5 analysis showed additional ADC elevation in the head of caudate nucleus and putamen in patients with DLB. Conclusions: DLB is characterized by elevated ADC in the amygdala, consistent with the neurodegenerative pathological involvement during the limbic-transitional stage of Lewy body disease. DTI findings agree with the expected pattern of neurodegenerative pathological involvement in clinically diagnosed patients with DLB and AD, and may be useful in differential diagnosis and disease characterization.
O4-06-06
THE IMPACT OF VASCULAR AND ALZHEIMER PATHOLOGIES IN LEWY BODY DISEASE
Kurt A. Jellinger1, Johannes Attems2, 1Institute of Clinical Neurobiology, Vienna, Austria; 2Institute of Pathology, Otto Wagner Hospital, Vienna, Austria. Contact e-mail: [email protected] Background: Whereas the prevalence and impact of vascular pathology in Alzheimer disease (AD) are well established, the role of vascular and AD pathologies in Lewy body disease (LBD) is under discussion. Methods: Retrospective clinico-pathologic study of 110 patients with autopsy-proven LBD: 44 cases PD no dementia (PDND), 44 Parkinson-dementia (PDD)
Oral O4-06: Other Dementias
overt neuronal loss was observed; GRN-/- mice had microgliosis, astrogliosis and tissue vacuolation. Our oldest GRN-/- mouse (23 months) had focal neuronal loss and very severe gliosis. GRN-/þ were histologically unremarkable and equivalent to wild-type littermates. Conclusions: GRN-/- mice have reduced pre-natal viability consistent with the reported role of progranulin in development. Lipofuscin accumulation, a marker of age-associated cellular stress, suggested that GRN-/- mice may have accelerated neuronal aging. A role of progranulin in successful aging is compatible with its suggested role as a trophic factor required for long-term neuronal survival. Microvacuolation and gliosis at younger ages and focal neuronal loss and very severe gliosis in our oldest GRN-/- mouse suggests that progranulin deficiency leads to neurodegeneration in this model. Exposure of GRN-deficient mice to additional non-lethal stressors (e.g., hypoxic) might produce neurodegeneration in GRN-/þ mice, as well as GRN-/- mice at younger ages. O4-06-02
TDP-43 AND BETA-AMYLOID PRECURSOR PROTEIN PROCESSING PRODUCTS IN CEREBROSPINAL FLUID OF PATIENTS WITH AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL LOBAR DEGENERATION
Markus Otto1, Corinna Hendrich1, Anne Dorte Sperfeld1, Sarah Jesse1, Christine V. Arnim1, Stefan Lehnert1, Alice Pabst1, Ingo Uttner1, Hayrettin Tumani1, Virginia M. Y. Lee2, John Trojanowski2, Hans A. Kretzschmar3, Felix Motthagy4, Albert C. Ludolph1, Manuela Neumann5, Petra Steinacker1, 1University of Ulm, Ulm, Germany; 2 University of Pennsylvania School of Medicine, Philadelphia, MA, USA; 3 Ludwig-Maximilians University, Munich, Germany; 4UZ Leuven, Leuven, Belgium; 5University of Zurich, Zurich, Switzerland. Contact e-mail: [email protected] Background: Recently, TAR DNA-binding protein 43 (TDP-43) was identified to be the major component of ubiquitin-positive tau-negative neuronal and glial inclusions in the most common form of frontotemporal lobar degeneration (FTLD) as well as in amyotrophic lateral sclerosis (ALS). This led to the view of ALS and FTLD representing two manifestations of a clinicopathological spectrum. However for both diseases, changes in metabolism of beta-amyloid precursor protein (APP) are also reported. In this study, we analyzed cerebrospinal fluid from patients of the ALS-FTLD spectrum for APP processing products and TDP-43. Methods: We measured CSF for APP processing products by ELISA and determined relative TDP-43 levels by immunoblot in samples from patients with FTLD, patients with ALS, patients with ALS and FTLD and control patients (CON). Results: ALS and FTLD patients showed higher TDP-43 levels compared to CON, however, with a prominent overlap of values. ALS patients show elevated absolute levels of soluble APP and a shift towards the nonamyloidogenic APP processing pathway in contrast to patients with FTLD or ALS þ FTLD. By the introduction of an Abeta-peptid ratios clearly two different groups in the FTLD cohort could observed. Conclusions: Combined analyis of TDP-43 protein and APP processing products in CSF might aid in subtyping patients across the ALS/FTLD disease spectrum. O4-06-03
EXECUTIVE FUNCTION IN PROGRESSIVE AND NONPROGRESSIVE BEHAVIOURAL VARIANT FRONTOTEMPORAL DEMENTIA
Michael Hornberger1, Olivier Piguet1, Christopher M. Kipps2, John R. Hodges1,3, 1Prince of Wales Medical Research Institute, Sydney, Australia; 2Neurology Department, Southampton General Hospital, Southampton, United Kingdom; 3Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom. Contact e-mail: m. [email protected] Background: Recent studies suggest that behavioural variant frontotemporal dementia (bv-FTD) patients differ in their disease progression with fast and very slow progressing cases (Davies et al., 2006; Kipps et al., 2007). We investigated executive profiles of progressive and non-progressive bvFTD patients to establish diagnostic markers discriminating the two groups
from each other and controls at first presentation. Methods: A range of neuropsychological and behavioural tests were administered. Mean and overlap-based statistical analyses on selected test variables were conducted to investigate profiles of performance in bv-FTD patients and in controls. A logistic regression analysis, based on executive test variables, was performed to classify patients into progressors and non-progressors. Results: Although progressors and non-progressors showed equivalent behavioural profiles they were distinguishable by their performance on executive tasks. While the non-progressors’ performance on all tests was with the normal range, the progressors were consistently impaired on four tests: Digit Span Backward, the Hayling test of inhibitory control, Letter Fluency and Trails B. The logistic regression model showed that 86% of patients could be classified correctly into progressors and non-progressors on the basis of Digit Span Backward and Hayling subscores. Conclusions: Contrary to some prior reports, bv-FTD patients who show progression are typically impaired on frontal executive tasks at first presentation. Previous inconsistencies are probably explicable by the admixture of patients with progressive FTD and non-progressive/phenocopy cases. Importantly, a minority of progressive FTD patients performed normally on a range of executive tasks. O4-06-04
CHARACTERISTIC PATTERNS OF CORTICAL THICKNESS IN PATHOLOGICALLY-CONFIRMED ALZHEIMER’S DISEASE AND FRONTOTEMPORAL LOBAR DEGENERATION
Manja Lehmann1, Matthew J. Clarkson1, Jonathan D. Rohrer1, Rachael I. Scahill1, Marc Modat2, Jason D. Warren1, Sebastien Ourselin2, Martin N. Rossor1, Josephine Barnes1, Nick C. Fox1, 1Dementia Research Centre, Institute of Neurology, London, United Kingdom; 2Centre for Medical Image Computing, University College London, London, United Kingdom. Contact e-mail: [email protected] Background: Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) can be difficult to differentiate clinically due to overlapping symptoms. Subject classification in research studies is often based on clinical rather than pathological criteria which may mean some subjects are misdiagnosed and misclassified. Recently, methods measuring cortical thickness using magnetic resonance imaging (MRI) have been suggested to be effective in differentiating between clinically-defined AD and FTLD. We aimed to assess differences in cortical thickness in pathologically-confirmed cases of AD and FTLD. Methods: MRI scans of 25 pathologically-confirmed AD, 25 pathologically-confirmed FTLD subjects, and 25 age- and gender-matched healthy controls were included. Cortical thicknesses were measured using FreeSurfer and were compared between groups. Results: Compared with control subjects, AD patients showed reduced cortical thickness in broad regions of parietal, temporal and frontal lobes (Figure, Table) with the left hemisphere showing greater differences than the right. Regions with reduced cortical thickness include the posterior parietal lobe (13% lower than control mean thickness in left hemisphere, 10% in the right), entorhinal cortex (27% left, 16% right), fusiform gyrus (14% left, 10% right), posterior cingulate gyrus (19% left, 17% right), and temporal pole (19% left, 12% right). The FTLD group compared with controls had significantly reduced cortical thickness in anterior temporal and frontal regions in both hemispheres. Reduced cortical thickness was more extensive in the left hemisphere than in the right (Figure, Table). Regions with particularly reduced cortical thickness include the entorhinal cortex (32% left, 24% right), fusiform gyrus (17% left, 10% right), superior frontal gyrus (13% left, 12% right), temporal pole (34% left, 20% right), and anterior cingulate gyrus (16% left, 11% right). Direct comparison of differences in cortical thickness between AD and FTLD subjects showed reduced thickness in the posterior parietal region, posterior cingulate and frontal pole in the AD group compared with FTLD, whilst the anterior temporal lobe, anterior cingulate and frontal lobe showed greater cortical thickness in the AD group compared with FTLD. However, these differences did not survive correction for multiple comparisons. Conclusions: These characteristic patterns of cortical thinning in
Oral O4-06: Other Dementias pathologically-confirmed AD and FTLD patients may assist clinical differentiation of these common dementias.
O4-06-05
DIFFUSION TENSOR IMAGING CHARACTERISTICS OF DEMENTIA WITH LEWY BODIES AND ALZHEIMER’S DISEASE
Kejal Kantarci, Ramesh T. Avula, Matthew L. Senjem, Ali R. Samikoglu, Maria M. Shiung, Scott A. Przybelski, Stephen D. Weigand, Heidi A. Ward, Prashanthi Vemuri, Tanis J. Ferman, Bradley F. Boeve, David S. Knopman, Ronald C. Petersen, Clifford R. Jack, Jr., Mayo Clinic, Rochester, MN, USA. Contact e-mail: [email protected] Background: Diffusion tensor MR imaging (DTI) provides information on the integrity of tissue microstructure. The magnitude of diffusivity measured
P163
with the apparent diffusion coefficient (ADC) increases, and the directionality of diffusivity measured with fractional anisotropy (FA) decreases with neurodegeneration. The two most common neurodegenerative disorders associated with dementia are Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). Little is known about the DTI changes in DLB. Our objective was to determine the regional DTI characteristics of patients with DLB compared to patients with AD and cognitively normal subjects (CN). Methods: We studied clinically diagnosed age, gender and education matched patients with DLB (n ¼ 24), AD (n ¼ 24), and CN (n ¼ 24). DLB and AD subjects were further matched on dementia severity based on Clinical Dementia Rating scores. Parallel imaging was performed at 3 T using an acceleration factor of two. 3DMPRAGE was performed for anatomical segmentation and labeling. In order to avoid partial volume averaging of tissue diffusivity with CSF, we used an EPI-FLAIR-DTI sequence (which nulls CSF) with 21 diffusion sensitive gradient directions (b ¼ 1000 s/mm2). We measured ADC from segmented cortical gray matter in regions derived from the automated anatomic labeling atlas. Color FA maps were used for measuring tract-based FA and ADC. Voxel-based analysis was performed to determine gray matter ADC differences among the clinical groups. Results: In the cortical gray matter, patients with DLB and AD had elevated ADC in the amygdala compared to CN subjects (p ¼ 0.01). In addition, patients with AD had elevated ADC in the hippocampus and other temporal lobe regions, compared to DLB and CN subjects (p < 0.01). The posterior cingulum white matter tract ADC was elevated (p < 0.01) and FA was decreased (p < 0.05) in patients with AD compared to DLB and CN subjects. SPM5 analysis showed additional ADC elevation in the head of caudate nucleus and putamen in patients with DLB. Conclusions: DLB is characterized by elevated ADC in the amygdala, consistent with the neurodegenerative pathological involvement during the limbic-transitional stage of Lewy body disease. DTI findings agree with the expected pattern of neurodegenerative pathological involvement in clinically diagnosed patients with DLB and AD, and may be useful in differential diagnosis and disease characterization.
O4-06-06
THE IMPACT OF VASCULAR AND ALZHEIMER PATHOLOGIES IN LEWY BODY DISEASE
Kurt A. Jellinger1, Johannes Attems2, 1Institute of Clinical Neurobiology, Vienna, Austria; 2Institute of Pathology, Otto Wagner Hospital, Vienna, Austria. Contact e-mail: [email protected] Background: Whereas the prevalence and impact of vascular pathology in Alzheimer disease (AD) are well established, the role of vascular and AD pathologies in Lewy body disease (LBD) is under discussion. Methods: Retrospective clinico-pathologic study of 110 patients with autopsy-proven LBD: 44 cases PD no dementia (PDND), 44 Parkinson-dementia (PDD)