- Email: [email protected]
P4-154: Neuronal atrophy and neuropil loss, rather than neuronal loss, underlies age-related cortical brain atrophy in elderly subjects without Alzheimer's disease
Poster Presentations P4: formed. Supported by the Internationale Stichting Alzheimer Onderzoek and Zon-MW Innovation Research (Vidi program). P4-152
SEX DIFFERENCES IN PERIVASCULAR TAUOPATHY IN THE MEDIOBASAL TUBERAL HYPOTHALAMUS IN NEURODEGENERATIVE DISEASES IN HUMANS
Brittany N. Dugger1, Hirotake Uchikado2, Zshan Ahmed3, Dennis W. Dickson1, 1Mayo Clinic College of Medicine, Jacksonville, FL, USA; 2Maioka Hospital, Yokohama, Japan; 3King’s College, London, United Kingdom. Contact e-mail: [email protected] Background: The human hypothalamus regulates many metabolic and autonomic functions through the release of hormones into the blood stream. The neurovascular connections between nuclei in this circuitry are critical to neuroendocrine regulation of pituitary gonadotropin secretion. The hypothalamus is known to be pathologically affected in a number of neurodegenerative diseases, including Alzheimer’s disease (AD) (a disease more frequent in women), progressive supranuclear palsy (PSP, no sex difference) and dementia with Lewy bodies (DLB) (a disease more frequent in men). Previous published studies have shown that some AD cases have hypothalamic perivascular neuritic pathology that is argyrophilic and immunopositive for tau protein (“perivascular tauopathy”) and more frequent in men. Hypothalamic perivascular tauopathy has been shown to be independent of AD related neurofibrillary pathology and is characterized by a network of tau-positive, swollen dystrophic neurites adjacent to capillaries of the posterior median eminence and adjacent infundibular nucleus. Methods: In addition to AD (n⫽90; 47 men), we screened other disorders, including DLB (n⫽35; 16 men), PSP (n⫽47; 26 men) and normal elderly controls (n⫽38; 14 men), for hypothalamic perivascular tauopathy using an phospho-tau antibody (CP13). To further characterize perivascular tauopathy select cases with robust perivascular tauopathy were studied with double labeling immunohistochemistry using phospho-tau and glial (GFAP for astrocytes and Iba-1 for microglia) antibodies. Results: Of the 210 cases screened, 16 had perivascular tauopathy (8%), of which 15 were men. It was detected in 12 with AD (13%), 1 with DLB (3%) and 3 with PSP (6%). The only woman with perivascular tauopathy had PSP. None of normal controls had perivascular tauopathy. When considering all cases together, perivascular tauopathy correlated with Braak neurofibrillary tangle stage in addition to sex. We found no colocalization of the phospho-tau with either of the glial markers in the rubust perivascular tauopathy cases. Conclusions: The present results are consistent with the existence of a sex difference in perivascular neuritic tau pathology in the mediobasal tuberal hypothalamus in age-associated neurodegenerative disorders. This study also noted that perivascular tauopathy was neuronal rather than glial in origin. P4-153
FIBRILLAR BETA-AMYLOID IN WHITE MATTER OF ALZHEIMER’S DISEASE BRAIN
Aaron S. Farberg1, Rebecca F. Rosen2, Marla Gearing3, Jeff F. Pare1, Lary C. Walker4, 1Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA; 2Grad. Program Neuroscience, Emory University, Atlanta, GA, USA; 3Dept. Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA; 4Dept. Neurology, Emory University, Atlanta, GA, USA. Contact e-mail: [email protected] Background: Sensitive and specific immunohistochemical methods for visualizing beta-Amyloid have expanded the spectrum of histologically identifiable ABeta deposits in brain. These heterogeneous lesions are differentiated by shape, size, density, and location. While the majority of ABeta accumulates in the grey matter, some ABeta-deposits also occur in the white matter, and their nature and significance remain poorly understood. Methods: We evaluated the presence, distribution, and structure of cerebral ABeta-lesions in the neocortex and adjacent white matter of the superior temporal cortex, occipital cortex, and posterior cingulate cortex of
T715
six Alzheimer’s disease (AD) cases and four nondemented control cases. Results: At the light microscopic level, we identified two distinct types of ABeta-immunoreactive white matter deposits that occurred only in AD: granular material that occasionally coalesced into plaque-like aggregates, and, in two AD cases, bundles of ABeta-immunoreactive threads. Ultrastructural analysis of white matter ABeta threads revealed numerous collections of ABeta-immunoreactive filaments coursing parallel to the myelinated axons. The shape and diameter of the filaments was consistent with amyloid fibrils, and they were extracellular in all observed instances. Immunoelectron microscopic analysis of the granular deposits is in progress. Conclusions: ABeta deposits in the white matter may have pathogenic significance, inasmuch as white matter lesions are frequently seen in older patients, and the degree of age-related myelin disruption is exacerbated in AD. Our findings indicate that ABeta aggregates in the white matter are not simply diffuse accumulations of the peptide, but rather that they can exist as fully developed amyloid fibrils. The potential impact of white matter ABeta deposits on myelin integrity and cognitive function remains to be determined. Supported by NIH RR-00165 and P50AG025688. P4-154
NEURONAL ATROPHY AND NEUROPIL LOSS, RATHER THAN NEURONAL LOSS, UNDERLIES AGE-RELATED CORTICAL BRAIN ATROPHY IN ELDERLY SUBJECTS WITHOUT ALZHEIMER’S DISEASE
Stefanie Freeman1,2, Ruth Kandel3, Luis Cruz4, Anete Rozkalne2, Kathy Newell5, Matthew P. Frosch1,2, E. Tessa Hedley-Whyte1, Lewis Lipsitz3, Bradley T. Hyman1,2, 1Massachusetts General Hospital/ Harvard Medical School, Boston, MA, USA; 2MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA, USA; 3Hebrew Rehabilitation Center/Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA, USA; 4Boston University, Boston, MA, USA; 5University of Kansas Medical Center, Kansas City, KS, USA. Contact e-mail: [email protected] Background: Cerebral volume loss has been associated with normal aging but whether this is due to the aging process or to age-related diseases including incipient Alzheimer disease is uncertain. Methods: In order to understand the aging brain we examined the cerebral cortex of 27 individuals ranging in age from 56 through ⬎90 years. None fulfilled the criteria for the neuropathological diagnosis of Alzheimer disease or other neurodegenerative diseases. Seventeen of the elderly participants had cognitive testing prior to death. Since the volume of the cerebral cortex reflects the sum of input fibers, neuronal cell bodies, dendritic arbors, and output fibers, we used two different quantitative approaches to analyze overall cortical thickness, neuronal number, neuronal size distribution and changes within the neuropil. Results: Both frontal and temporal neocortical regions (BA 8, 9, and 17) had clear evidence of cortical thinning with age. In these same anatomic regions, neuronal density calculated for the entire cortical thickness revealed an increase in both frontal and temporal cortex, while the total neuronal number remained relatively constant over a 50-year age range. Measurements of neuronal size in the frontal, but not temporal cortex demonstrated decreasing perikaryal size with age. Conclusions: The combination of these changes suggests that loss of dendritic structures, rather than loss of neurons, underlies neocortical volume loss with increasing age. P4-155
PRECLINICAL ALZHEIMER’S DISEASE IN A LARGE AUTOPSY SERIES OF LONGITUDINALLY STUDIED, COGNITIVELY NORMAL CONTROL SUBJECTS
Gregory A. Jicha, Erin Abner, Frederick A. Schmitt, Peter T. Nelson, Daron Davis, William R. Markesbery, University of Kentucky, Lexington, KY, USA. Contact e-mail: [email protected]
SEX DIFFERENCES IN PERIVASCULAR TAUOPATHY IN THE MEDIOBASAL TUBERAL HYPOTHALAMUS IN NEURODEGENERATIVE DISEASES IN HUMANS
Brittany N. Dugger1, Hirotake Uchikado2, Zshan Ahmed3, Dennis W. Dickson1, 1Mayo Clinic College of Medicine, Jacksonville, FL, USA; 2Maioka Hospital, Yokohama, Japan; 3King’s College, London, United Kingdom. Contact e-mail: [email protected] Background: The human hypothalamus regulates many metabolic and autonomic functions through the release of hormones into the blood stream. The neurovascular connections between nuclei in this circuitry are critical to neuroendocrine regulation of pituitary gonadotropin secretion. The hypothalamus is known to be pathologically affected in a number of neurodegenerative diseases, including Alzheimer’s disease (AD) (a disease more frequent in women), progressive supranuclear palsy (PSP, no sex difference) and dementia with Lewy bodies (DLB) (a disease more frequent in men). Previous published studies have shown that some AD cases have hypothalamic perivascular neuritic pathology that is argyrophilic and immunopositive for tau protein (“perivascular tauopathy”) and more frequent in men. Hypothalamic perivascular tauopathy has been shown to be independent of AD related neurofibrillary pathology and is characterized by a network of tau-positive, swollen dystrophic neurites adjacent to capillaries of the posterior median eminence and adjacent infundibular nucleus. Methods: In addition to AD (n⫽90; 47 men), we screened other disorders, including DLB (n⫽35; 16 men), PSP (n⫽47; 26 men) and normal elderly controls (n⫽38; 14 men), for hypothalamic perivascular tauopathy using an phospho-tau antibody (CP13). To further characterize perivascular tauopathy select cases with robust perivascular tauopathy were studied with double labeling immunohistochemistry using phospho-tau and glial (GFAP for astrocytes and Iba-1 for microglia) antibodies. Results: Of the 210 cases screened, 16 had perivascular tauopathy (8%), of which 15 were men. It was detected in 12 with AD (13%), 1 with DLB (3%) and 3 with PSP (6%). The only woman with perivascular tauopathy had PSP. None of normal controls had perivascular tauopathy. When considering all cases together, perivascular tauopathy correlated with Braak neurofibrillary tangle stage in addition to sex. We found no colocalization of the phospho-tau with either of the glial markers in the rubust perivascular tauopathy cases. Conclusions: The present results are consistent with the existence of a sex difference in perivascular neuritic tau pathology in the mediobasal tuberal hypothalamus in age-associated neurodegenerative disorders. This study also noted that perivascular tauopathy was neuronal rather than glial in origin. P4-153
FIBRILLAR BETA-AMYLOID IN WHITE MATTER OF ALZHEIMER’S DISEASE BRAIN
Aaron S. Farberg1, Rebecca F. Rosen2, Marla Gearing3, Jeff F. Pare1, Lary C. Walker4, 1Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA; 2Grad. Program Neuroscience, Emory University, Atlanta, GA, USA; 3Dept. Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA; 4Dept. Neurology, Emory University, Atlanta, GA, USA. Contact e-mail: [email protected] Background: Sensitive and specific immunohistochemical methods for visualizing beta-Amyloid have expanded the spectrum of histologically identifiable ABeta deposits in brain. These heterogeneous lesions are differentiated by shape, size, density, and location. While the majority of ABeta accumulates in the grey matter, some ABeta-deposits also occur in the white matter, and their nature and significance remain poorly understood. Methods: We evaluated the presence, distribution, and structure of cerebral ABeta-lesions in the neocortex and adjacent white matter of the superior temporal cortex, occipital cortex, and posterior cingulate cortex of
T715
six Alzheimer’s disease (AD) cases and four nondemented control cases. Results: At the light microscopic level, we identified two distinct types of ABeta-immunoreactive white matter deposits that occurred only in AD: granular material that occasionally coalesced into plaque-like aggregates, and, in two AD cases, bundles of ABeta-immunoreactive threads. Ultrastructural analysis of white matter ABeta threads revealed numerous collections of ABeta-immunoreactive filaments coursing parallel to the myelinated axons. The shape and diameter of the filaments was consistent with amyloid fibrils, and they were extracellular in all observed instances. Immunoelectron microscopic analysis of the granular deposits is in progress. Conclusions: ABeta deposits in the white matter may have pathogenic significance, inasmuch as white matter lesions are frequently seen in older patients, and the degree of age-related myelin disruption is exacerbated in AD. Our findings indicate that ABeta aggregates in the white matter are not simply diffuse accumulations of the peptide, but rather that they can exist as fully developed amyloid fibrils. The potential impact of white matter ABeta deposits on myelin integrity and cognitive function remains to be determined. Supported by NIH RR-00165 and P50AG025688. P4-154
NEURONAL ATROPHY AND NEUROPIL LOSS, RATHER THAN NEURONAL LOSS, UNDERLIES AGE-RELATED CORTICAL BRAIN ATROPHY IN ELDERLY SUBJECTS WITHOUT ALZHEIMER’S DISEASE
Stefanie Freeman1,2, Ruth Kandel3, Luis Cruz4, Anete Rozkalne2, Kathy Newell5, Matthew P. Frosch1,2, E. Tessa Hedley-Whyte1, Lewis Lipsitz3, Bradley T. Hyman1,2, 1Massachusetts General Hospital/ Harvard Medical School, Boston, MA, USA; 2MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA, USA; 3Hebrew Rehabilitation Center/Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA, USA; 4Boston University, Boston, MA, USA; 5University of Kansas Medical Center, Kansas City, KS, USA. Contact e-mail: [email protected] Background: Cerebral volume loss has been associated with normal aging but whether this is due to the aging process or to age-related diseases including incipient Alzheimer disease is uncertain. Methods: In order to understand the aging brain we examined the cerebral cortex of 27 individuals ranging in age from 56 through ⬎90 years. None fulfilled the criteria for the neuropathological diagnosis of Alzheimer disease or other neurodegenerative diseases. Seventeen of the elderly participants had cognitive testing prior to death. Since the volume of the cerebral cortex reflects the sum of input fibers, neuronal cell bodies, dendritic arbors, and output fibers, we used two different quantitative approaches to analyze overall cortical thickness, neuronal number, neuronal size distribution and changes within the neuropil. Results: Both frontal and temporal neocortical regions (BA 8, 9, and 17) had clear evidence of cortical thinning with age. In these same anatomic regions, neuronal density calculated for the entire cortical thickness revealed an increase in both frontal and temporal cortex, while the total neuronal number remained relatively constant over a 50-year age range. Measurements of neuronal size in the frontal, but not temporal cortex demonstrated decreasing perikaryal size with age. Conclusions: The combination of these changes suggests that loss of dendritic structures, rather than loss of neurons, underlies neocortical volume loss with increasing age. P4-155
PRECLINICAL ALZHEIMER’S DISEASE IN A LARGE AUTOPSY SERIES OF LONGITUDINALLY STUDIED, COGNITIVELY NORMAL CONTROL SUBJECTS
Gregory A. Jicha, Erin Abner, Frederick A. Schmitt, Peter T. Nelson, Daron Davis, William R. Markesbery, University of Kentucky, Lexington, KY, USA. Contact e-mail: [email protected]