To understand the possible role of the accumulation of mitochondrial DNA mutations in human aging and Alzheimer's disease (AD), it is important to identify the cellular populations that contain these abnormalities. We propose to test the hypothesis that the distinctive pattern of neuronal loss and morphological changes in AD reflects somatic mutations of mitochondrial DNA in cell populations vulnerable to disease and that this process is an acceleration of a ubiquitous phenomenon observed in normal aging. This Pilot will concentrate on the demonstraty by in situ hybridization (ISH) of the well-characterized 4977-base pair """"""""common deletion"""""""" of DNA that has been demonstrated in Kearns-Sayre syndrome (KSS) and also in cardiac myocytes and human brain from aged individuals. In addition, we plan to modify the current strategy of mitochondrial DNA deletion ISH techniques with the development of a deletion-specific ISH method for studying formalin-fixed, paraffin-embedded brains. This technique will be developed through the study of tissue from a patient with a unique single deletion of mitochondrial DNA and KSS in which we have demonstrated a significant accumulation of mutant mitochondrial DNA forms in several organs. The deletion-specific ISH method will then be applied to material collected from patients with AD and age-matched controls, with an emphasis on localization within cells of the neocortex, basal ganglia, hippocampus, thalamus, substantia nigra, and locus coeruleus. These findings will then be correlated with known patterns of neuronal vulnerability in aging and in AD. It is expected that these studies will provide important new information concerning the contributions of mutated mitochondrial DNA and abnormal oxidative phosphorylation in the development of age-related changes in the human brain.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
3P50AG005146-16S1
Application #
6098076
Study Section
Project Start
1998-09-30
Project End
1999-03-31
Budget Start
Budget End
Support Year
16
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Wang, Tingyan; Qiu, Robin G; Yu, Ming (2018) Predictive Modeling of the Progression of Alzheimer's Disease with Recurrent Neural Networks. Sci Rep 8:9161
Ting, Simon Kang Seng; Foo, Heidi; Chia, Pei Shi et al. (2018) Dyslexic Characteristics of Chinese-Speaking Semantic Variant of Primary Progressive Aphasia. J Neuropsychiatry Clin Neurosci 30:31-37
Eavani, Harini; Habes, Mohamad; Satterthwaite, Theodore D et al. (2018) Heterogeneity of structural and functional imaging patterns of advanced brain aging revealed via machine learning methods. Neurobiol Aging 71:41-50
Agogo, George O; Ramsey, Christine M; Gnjidic, Danijela et al. (2018) Longitudinal associations between different dementia diagnoses and medication use jointly accounting for dropout. Int Psychogeriatr 30:1477-1487
Barnes, Josephine; Bartlett, Jonathan W; Wolk, David A et al. (2018) Disease Course Varies According to Age and Symptom Length in Alzheimer's Disease. J Alzheimers Dis 64:631-642
Fredericks, Carolyn A; Sturm, Virginia E; Brown, Jesse A et al. (2018) Early affective changes and increased connectivity in preclinical Alzheimer's disease. Alzheimers Dement (Amst) 10:471-479
Seddighi, Sahba; Varma, Vijay R; An, Yang et al. (2018) SPARCL1 Accelerates Symptom Onset in Alzheimer's Disease and Influences Brain Structure and Function During Aging. J Alzheimers Dis 61:401-414
Alosco, Michael L; Sugarman, Michael A; Besser, Lilah M et al. (2018) A Clinicopathological Investigation of White Matter Hyperintensities and Alzheimer's Disease Neuropathology. J Alzheimers Dis 63:1347-1360
Holingue, Calliope; Wennberg, Alexandra; Berger, Slava et al. (2018) Disturbed sleep and diabetes: A potential nexus of dementia risk. Metabolism 84:85-93
Brent, Robert J (2018) Estimating the monetary benefits of medicare eligibility for reducing the symptoms of dementia. Appl Econ 50:6327-6340

Showing the most recent 10 out of 830 publications