Phone: (205) 975-5940
Ph.D. 2002 (Neuroscience and Neurology), University of Kuopio
STATUS: Currently has open positions for undergraduates.
Aging, Alzheimer's disease
The role of white matter changes in aging and Alzheimer's disease
A) The role of white matter pathology in age-related cognitive deficits.
Aging is associated with the well-known deterioration of cognitive performance, especially in deficits in memory functioning, but also with substantial changes in the white matter of the brain. For instance the corpus callosum shrinks in size with age, and other fiber tracts in the brain are similarly affected, and these changes correlate with cognitive decline. Whereas, clearly, changes in the white matter are not the sole cause of cognitive deficits in aging, mounting evidence indicates that the increased demyelination that occurs with age contributes to the cognitive deficits. Few studies thus far have specifically addressed the causes of the changes in the white matter of the brain with aging. Our preliminary studies indicate that relatively early in the aging process changes occur in the crosstalk between astrocytes and oligodendrocytes that ultimately lead to malfunctioning of oligodendrocytes and demyelination of axons. This in turn leads to an increase in inflamma tion markers in the white matter, such as activated microglia, likely leading to further damage of the white matter. This white matter dysfunction leads to functional neuronal disconnection and finally, memory loss and decline in cognitive functioning. Our preliminary studies also indicate that cholesterol metabolism is disturbed early in the aging process in the white matter, specifically in astrocytes. Because astrocytes are the main source of cholesterol in the brain, and the main source of cholesterol for oligodendrocytes, this likely leads to changes in membrane composition of these cells. Changing the fluidity of the cell membrane will lead to relocation of rafts, intramembrane peptides and channels, but more importantly affect the myelin sheath.
Our studies are designed to investigate these changes in astrocyte functioning and communication in the white matter, and the development of cognitive impairments. Finally, we will test whether prevention or retardation of this process will ameliorate the cognitive impairments of aging.
B) The role of vascular white matter pathology in Alzheimer’s disease.
Alzheimer’s disease (AD) is associated with the pathological hallmarks of neurofibrillary tangles (NFTs) and accumulation of amyloid beta (Aß) in neuropil plaques and intracellular sites as well as substantial Aß deposition in the cerebral vasculature. Although alterations in the cerebral vasculature are clearly not the sole cause of AD, mounting evidence indicates that the accumulation of microinfarcts does contribute to the cognitive impairments associated with AD. These findings have led to the hypothesis that neuronal dysfunction due to small ischemic episodes contributes to the pathology and cognitive deterioration of AD (Burton et al, 2006), possibly through neuronal disconnection. Two separate processes can act to generate an excess of Aß in the brain following ischemic episodes, Aß overproduction due to neuronal injury and reduced Aß clearance through the damaged vasculature. Together, these factors synergize with the ongoing disease process and increase AÍ deposition in the parenchyma, ultimately, contributing to the dementia of AD. In earlier studies examining the course of amyloidosis in AD model mice, we (Van Groen et al, 2003) and others (e.g., Tanzi et al, 2004) have shown that both overproduction and lack of clearance contribute to Aß deposition. Overabundance of Aß appears to result in cognitive deficits, likely from neuronal injury and synaptic dysfunction. However, despite the growing interest in vascular factors in AD, the relationship between small infarcts and cognitive decline is still not clearly defined.
Our recent preliminary studies in AD model mice have shown that small ischemic infarcts increase parenchymal Aß deposition and worsen cognitive outcome. Further, we have found that infarcts involving the white matter have a significantly worse outcome. Our studies are designed to systematically test the hypothesis that multiple, limited islands of neural/vascular damage, which reproduce age-related small ischemic infarcts, can accelerate Aß deposition and lead to cognitive impairments in a Tg mouse model of AD.
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