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2. TDP-43 in the Ubiquitin Pathology of Frontotemporal Dementia With VCP Gene Mutations

Author

Neumann, Manuela, Mackenzie, Ian R, Cairns, Nigel J, Boyer, Philip J, Markesbery, William R, Smith, Charles D, Taylor, J Paul, Kretzschmar, Hans A, Kimonis, Virginia E, and Forman, Mark S

Subjects
Dementia, Genetics, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Rare Diseases, Brain Disorders, Acquired Cognitive Impairment, Aging, Frontotemporal Dementia (FTD), Neurosciences, Neurodegenerative, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adenosine Triphosphatases, Aged, Cell Cycle Proteins, Cerebral Cortex, DNA-Binding Proteins, Female, Humans, Inclusion Bodies, Male, Middle Aged, Mutation, Myositis, Inclusion Body, Neurons, Osteitis Deformans, Ubiquitin, Valosin Containing Protein, frontotemporal dementia, neurodegeneration, TDP-43, ubiquitin, valosin-containing protein, Clinical Sciences, Neurology & Neurosurgery
Abstract

Frontotemporal dementia with inclusion body myopathy and Paget disease of bone is a rare, autosomal-dominant disorder caused by mutations in the gene valosin-containing protein (VCP). The CNS pathology is characterized by a novel pattern of ubiquitin pathology distinct from sporadic and familial frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) without VCP mutations. TAR DNA binding protein 43 (TDP-43) was recently identified as a major disease protein in the ubiquitin-positive inclusions of sporadic and familial FTLD-U. To determine whether the ubiquitin pathology associated with mutations in VCP is characterized by the accumulation of TDP-43, we analyzed TDP-43 in the CNS pathology of five patients with VCP gene mutations. Accumulations of TDP-43 colocalized with ubiquitin pathology in inclusion body myopathy and Paget disease of bone, including both intranuclear inclusions and dystrophic neurites. Similar to FTLD-U, phosphorylated TDP-43 was detected only in insoluble brain extracts from affected brain regions. Identification of TDP-43, but not VCP, within ubiquitin-positive inclusions supports the hypothesis that VCP gene mutations lead to a dominant negative loss or alteration of VCP function culminating in impaired degradation of TDP-43. TDP-43 is a common pathologic substrate linking a variety of distinct patterns of FTLD-U pathology caused by different genetic alterations.

Published
2007

5. Novel Ubiquitin Neuropathology in Frontotemporal Dementia With Valosin-Containing Protein Gene Mutations

Author

Forman, Mark S, Mackenzie, Ian R, Cairns, Nigel J, Swanson, Eric, Boyer, Philip J, Drachman, David A, Jhaveri, Bharati S, Karlawish, Jason H, Pestronk, Alan, Smith, Thomas W, Tu, Pang-Hsien, Watts, Giles DJ, Markesbery, William R, Smith, Charles D, and Kimonis, Virginia E

Subjects
Dementia, Rare Diseases, Acquired Cognitive Impairment, Alzheimer's Disease, Frontotemporal Dementia (FTD), Neurosciences, Biotechnology, Genetics, Neurodegenerative, Brain Disorders, Aging, Alzheimer's Disease Related Dementias (ADRD), Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aetiology, 2.1 Biological and endogenous factors, Neurological, Adenosine Triphosphatases, Blotting, Western, Cell Cycle Proteins, Female, Humans, Immunohistochemistry, Male, Mutation, Myositis, Inclusion Body, Osteitis Deformans, Ubiquitin, Valosin Containing Protein, frontotemporal dementia, neurodegenerative disease, ubiquitin, valosin-containing protein, inclusion body myopathy, Paget disease of bone, Clinical Sciences, Neurology & Neurosurgery
Abstract

Frontotemporal dementia (FTD) with inclusion body myopathy and Paget disease of bone (IBMPFD) is a rare, autosomal-dominant disorder caused by mutations in the valosin-containing protein (VCP) gene, a member of the AAA-ATPase gene superfamily. The neuropathology associated with sporadic FTD is heterogeneous and includes tauopathies and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). However, there is limited information on the neuropathology in IBMPFD. We performed a detailed, systematic analysis of the neuropathologic changes in 8 patients with VCP mutations. A novel pattern of ubiquitin pathology was identified in IBMPFD that was distinct from sporadic and familial FTLD-U without VCP gene mutations. This was characterized by ubiquitin-positive neuronal intranuclear inclusions and dystrophic neurites. In contrast to FTLD-U, only rare intracytoplasmic inclusions were identified. The ubiquitin pathology was abundant in the neocortex, less robust in limbic and subcortical nuclei, and absent in the dentate gyrus. Only rare inclusions were detected with antibodies to VCP and there was no biochemical alteration in the VCP protein. VCP is associated with a variety of cellular activities, including regulation of the ubiquitin-proteasome system. Our findings are consistent with the hypothesis that the pathology associated with VCP gene mutations is the result of impairment of ubiquitin-based degradation pathways.

Published
2006

13. Neuropathology of nondemented aging: Presumptive evidence for preclinical Alzheimer disease

Author

Price, Joseph L., McKeel, Daniel W., Jr., Buckles, Virginia D., Roe, Catherine M., Xiong, Chengjie, Grundman, Michael, Hansen, Lawrence A., Petersen, Ronald C., Parisi, Joseph E., Dickson, Dennis W., Smith, Charles D., Davis, Daron G., Schmitt, Frederick A., Markesbery, William R., Kaye, Jeffrey, Kurlan, Roger, Hulette, Christine, Kurland, Brenda F., Higdon, Roger, Kukull, Walter, and Morris, John C.

Published
2009
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29. Recent clinical-pathologic research on the causes of dementia in late life: update from the Honolulu-Asia aging study

Author

White, Lon, Small, Brent J., Petrovitch, Helen, Ross, G. Webster, Masaki, Kamal, Abbott, Robert D., Hardman, John, Davis, Daron, Nelson, James, and Markesbery, William

Subjects
Alzheimer's Disease and Related Disorders Association, Aging -- Case studies, Alzheimer's disease -- Diagnosis -- Case studies, Psychology and mental health, Seniors, Diagnosis, Case studies
Abstract

ABSTRACT In this study, we compare neuropathological findings at autopsy with clinical dementia diagnoses, such as Alzheimer's disease and vascular dementia. Participants consisted of 363 aged Japanese-American men from the [...]

Published
2005

44. Brain donation in normal aging: procedures, motivations, and donor characteristics from the biologically resilient adults in neurological studies (BRAiNS) project. (The Forum)

Author

Schmitt, Frederick A., Wetherby, Mary M.C., Wekstein, David R., Dearth, Chantel M.S., and Markesbery, William R.

Subjects
Aged -- Psychological aspects, Alzheimer's disease -- Research, Organ donors -- Demographic aspects, Death -- Causes of, Health, Seniors
Abstract

Medical autopsy rates have been declining for the past several decades, yet, for more than a decade, the University of Kentucky Alzheimer's Disease Research Center has been recruiting healthy older adults into a program involving annual assessments of mental status, biannual medical and neurological exams, and prearranged postmortem brain examination. The present article focuses on the characteristics of these donors to explore potential factors that contribute to the decision to donate. The motivations of this unique group of individuals could serve to inform physicians who request autopsies for medical and research purposes. Over 500 volunteers who have enrolled in this program are well-educated community-dwelling adults over the age of 60. They are generally motivated by personal experiences with Alzheimer's disease, referral by someone already enrolled, and a desire to promote scientific knowledge. These volunteers' reasons suggest that rates of tissue donation or autopsy for basic research and investigations of causes of death might be increased by providing individuals and families with information concerning the medical and scientific value of the procedure. Within research settings, encouraging participant recruitment of friends or family members would likely increase tissue acquisition rates. Key Words: Alzheimer's disease, Autopsy, Organ donation, Senile plaques, Neurofibrillary tangles, Cognition

Published
2001

45. Vulnerability of synaptosomes from ApoE knock-out mice to structural and oxidative modifications induced by Abeta(1-40): implications for Alzheimer's disease

Author

Lauderback, Christopher M., Hackett, Janna M., Keller, Jeffrey N., Varadarajan, Sridhar, Szweda, Luke, Kindy, Mark, Markesbery, William R., and Butterfield, D. Allan

Subjects
Alzheimer's disease -- Research, Apolipoproteins -- Research, Biological sciences, Chemistry
Abstract

Amyloid beta-peptide oxidizes proteins and lipids in synaptosomes taken from mice who lack the apolipoprotein E gene. The epsilon4 apoE gene has been linked to an increased risk of Alzheimer's disease.

Published
2001

50. Alzheimer's disease, dental amalgam and mercury

Author

Saxe, Stanley R., Wekstein, Merle W., Kryscio, Richard J., Henry, Robert G., Cornett, Charles R., Snowdon, David A., Grant, Ford T., Schmitt, Frederick A., Donegan, Sara Jean, Wekstein, David R., Ehmann, William D., and Markesbery, William R.

Subjects
Alzheimer's disease -- Risk factors, Mercury in the body -- Health aspects, Dental amalgams -- Health aspects, Fillings (Dentistry) -- Health aspects, Health
Abstract

Mercury in dental fillings does not appear to be a risk factor for Alzheimer's disease (AD). Researchers analyzed the dental fillings of 68 people with AD and 33 people with no history of AD and measured the level of mercury in the brains of those who had died. People with dental fillings were no more likely to develop AD than those without. In addition, people with no history of AD were just as likely to have mercury in their brain and those with AD were just as likely to have low levels of mercury in their brain as those without.

Published
1999

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