Showing papers by "Donald L. Price published in 2009"
TL;DR: It is concluded that in some individuals, successful cognitive aging results from compensatory mechanisms that occur at the neuronal level (i.e., neuronal hypertrophy and synaptic plasticity) whereas a failure of compensation may culminate in disease.
Abstract: The Baltimore Longitudinal Study of Aging (BLSA) was established in 1958 and is one the oldest prospective studies of aging in the USA and the world. The BLSA is supported by the National Institute of Aging (NIA) and its mission is to learn what happens to people as they get old and how to sort out changes due to aging from those due to disease or other causes. In 1986, an autopsy program combined with comprehensive neurologic and cognitive evaluations was established in collaboration with the Johns Hopkins University Alzheimer's Disease Research Center (ADRC). Since then, 211 subjects have undergone autopsy. Here we review the key clinical neuropathological correlations from this autopsy series. The focus is on the morphological and biochemical changes that occur in normal aging, and the early neuropathological changes of neurodegenerative diseases, especially Alzheimer's disease (AD). We highlight the combined clinical, pathologic, morphometric, and biochemical evidence of asymptomatic AD, a state characterized by normal clinical evaluations in subjects with abundant AD pathology. We conclude that in some individuals, successful cognitive aging results from compensatory mechanisms that occur at the neuronal level (i.e., neuronal hypertrophy and synaptic plasticity) whereas a failure of compensation may culminate in disease.
123 citations
01 Jan 2009
TL;DR: The clinical features, diagnostic studies, the neuropathology, and the biochemistry of the disease are described with a particular focus on the amyloid precursor protein and β- and γ-secretase enzyme activities which generate the Aβ peptide.
Abstract: Alzheimer’s disease (AD) is the most common progressive dementia syndrome of the elderly. Because of prevalence, lack of mechanism-based treatments, care costs, and impact on individuals and families, AD is an extraordinarily challenging disease. It is characterized by dysfunction and death of specific populations of neurons, particularly those in neural systems involved in memory and cognition, and by intracellular and extracellular protein aggregates (tau and Aβ peptides) in neurofibrillary tangles (NFTs) and amyloid plaques, respectively. Genetic evidence indicates that the inheritance of mutations in several genes causes autosomal dominant familial AD (fAD) and the majority of mutations increase the levels of toxic Aβ amyloid peptide species in the brain. In this review, we describe the clinical features, diagnostic studies, the neuropathology, and the biochemistry of the disease with a particular focus on the amyloid precursor protein and β- and γ-secretase enzyme activities which generate the Aβ peptide. Taking advantage of this new information, and the ability to manipulate genes, it is has been possible to produce transgenic models of the disease and to target genes encoding proteins critical in the disease pathways. In turn, this information has been used to develop experimental therapeutics, including strategies to reduce secretase activities and to clear the amyloid peptide from the brain. These discoveries offer genuine hope for the development of mechanism-based therapeutics for this illness.
9 citations
01 Jan 2009
TL;DR: These transport systems are described and how axonal transport functions in regeneration and repair and how malfunctions of transport processes are implicated in both experimental models and in human disorders are discussed.
Abstract: Because neurons possess the most complex geometries of any cell type, intracellular transport systems are essential to deliver critical proteins to specific anatomical and functional sites (e.g., dendrites, axons, and synaptic terminals) where relatively few proteins are synthesized. Although increasing evidence suggests that some proteins are synthesized locally within dendrites and spines and even within axons/terminals, the principal sites of neuronal protein synthesis are the cell bodies; axons and nerve terminals, in particular, depend primarily on this source for a continued supply of certain proteins to perform normal functions. The axonal transport systems, which evolved to deliver essential materials to the most distal parts of nerve cells, participate in the delivery of proteins and prepackaged cargo to specific destinations. These systems were initially distinguished based on velocity (fast, intermediate, or slow) and direction of movement (anterograde and retrograde). The identification of anterograde and retrograde transport motors and delineation of transport vesicles and cargo are critical players in this evolving story of discovery. Because axonal transport is a critical process within nerve cells, it is not surprising that axonal transport is involved in regeneration and that impairments in transport are associated with a variety of disorders of the peripheral and central nervous systems. In this article, we describe these transport systems and discuss how axonal transport functions in regeneration and repair and how malfunctions of transport processes are implicated in both experimental models and in human disorders.
1 citations