Journal of Alzheimer's Disease - Volume 19, issue 1

Authors: Markesbery, William R.

Article Type: Research Article

Abstract: Mild cognitive impairment (MCI), the earliest clinically detectable phase of the trajectory toward dementia and Alzheimer's disease (AD), led to the need for even earlier detection and prevention of AD. Although it is a clinical diagnosis, its underlying neuropathological findings are just being defined. MCI is best studied in longitudinally followed patients in centers that are experienced in dementing disorders. In this review of the few major clinical-pathological reports of longitudinally followed patients, it appears that most autopsied amnestic MCI (aMCI) patients are on a pathway toward AD. Neurofibrillary pathology in entorhinal cortex, hippocampus, and amygdala – not amyloid plaques …– is the major substrate for aMCI and for memory decline. In addition, many MCI patients have other concomitant pathological alterations, the most common of which are strokes, but also include argyrophilic grains and Lewy bodies. These findings are not surprising because most MCI autopsied cases have been in the older (80 to 90 year) range where these findings are common. In early AD, the phase following MCI, the significant change is an increase in neurofibrillary tangles in the neocortex that correlates with an increase in Braak score and the observed clinical progression. Show more

Keywords: Alzheimer's disease, mild cognitive impairment, neurofibrillary tangles, preclinical Alzheimer's disease

DOI: 10.3233/JAD-2010-1220

Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 221-228, 2010

Authors: Reitz, Christiane | Mayeux, Richard

Article Type: Research Article

Abstract: Cognitive impairment is prevalent in the elderly. The high estimates of conversion to dementia have spurred the interest in identification of genetic risk factors associated with development of cognitive impairment and or its progression. However, despite notable achievements in human genetics over the years, in particular technological advances in gene mapping and in statistical methods that relate genetic variants to disease, to date only a small proportion of the genetic contribution to late-life cognitive impairment can be explained. A likely explanation for the difficulty in gene identification is that it is a multifactorial disorder with both genetic and environmental components, …in which several genes with small effects each are likely to contribute to the quantitative traits associated with the disease. The motivation for identifying the underlying genetic risk factors elderly is clear. Not only could it shed light on disease pathogenesis, but it may also provide potential targets for effective treatment, screening, and prevention. In this article we review the current knowledge on underlying genetic variants and the usefulness of genetic variation as diagnostic tools and biomarkers. In addition, we discuss the potentials and difficulties researchers face in designing appropriate studies for gene discovery. Show more

Keywords: Alzheimer's disease, APOE, cognition, genes, mild cognitive impairment, SORL1

DOI: 10.3233/JAD-2010-1255

Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 229-251, 2010

Authors: Jicha, Gregory A. | Carr, Sarah A.

Article Type: Research Article

Abstract: Over the past several decades, our understanding of Alzheimer's disease (AD) has seen an evolution from the dichotomous concept of normal versus AD in the dementia state to a more accurate and complete appreciation of AD as a progressive disorder with clinical, biological, and pathological features occurring along a continuum from normal to end-stage disease. Integrating our understanding of the relationships and interplay between the clinical, biological, and pathological features of AD may allow the identification of AD at even preclinical, completely asymptomatic stages of the disease. This review attempts to summarize the clinical stages of AD in terms of …epidemiology, historical evolution of disease stage diagnoses, cognitive/neuropsychologic features, psychiatric/behavioral manifestations, and functional decline in the context of our developing understanding of the biological processes responsible for the pathogenesis of AD described in detail in the accompanying articles. Show more

Keywords: Alzheimer's disease, clinical features, mild cognitive impairment, preclinical AD

DOI: 10.3233/JAD-2010-1237

Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 253-272, 2010

Authors: Smith, Charles D.

Article Type: Research Article

Abstract: This review uses an image-indexed framework for the full course of Alzheimer's disease (AD) to provide a perspective on recent neuroimaging findings in the literature. Modalities considered include morphometric, diffusion tensor, and functional magnetic resonance imaging, and resting/functional metabolic and amyloid-label positron emission tomography. The major focus is on the AD pre-states (normal but high AD risk and mild cognitive impairment), and transition from mild cognitive impairment to mild AD. Imaging results relevant to the conduct of future prevention and early intervention trials are emphasized.

Keywords: Alzheimer's disease, computed tomography, diffusion tensor imaging, FDG, functional imaging, human, magnetic resonance imaging, mild cognitive impairment, morphometry, PIB, positron emission tomography, prediction, review

DOI: 10.3233/JAD-2010-1217

Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 273-290, 2010

Authors: Rinne, Juha O. | Någren, Kjell

Article Type: Research Article

Abstract: Mild cognitive impairment (MCI) is considered a transitional state between the cognitive changes of normal aging and the earliest clinical features of Alzheimer's disease (AD). An important goal is to find features that predict which MCI patients will later convert to AD. Identification of such features will be increasingly important when treatments slowing down the progression of AD become available enabling early intervention. Brain imaging might be one possible predictor of conversion to AD. Functional imaging with positron emission tomography (PET) has shown that either normal elderly people carrying apolipoprotein E ε4 allele or people with MCI already show reduced …cerebral glucose metabolism in those brain areas that are typically affected in AD. Investigations of different neurotransmitter systems might increase specificity and help in the differential diagnosis between dementing disorders. Dopamine transporter imaging to aid in the differential diagnosis between AD and dementia with Lewy bodies seems promising. Amyloid imaging is an example of “pathology specific” imaging that has great potential to enhance early detection of AD processes and to help in differential diagnosis. In the future, multi-tracer imaging or development of agents enabling imaging of other protein aggregations in neurodegenerative diseases could further help in the early and differential diagnostics and evaluation of novel treatments. Show more

Keywords: Alzheimer's disease, dementia, imaging, memory, mild cognitive impairment, positron emission tomography

DOI: 10.3233/JAD-2010-1224

Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 291-300, 2010

Authors: Sonnen, Joshua A. | Montine, Kathleen S. | Quinn, Joseph F. | Breitner, John C.S. | Montine, Thomas J.

Article Type: Research Article

Abstract: Given the magnitude of the public health problem of dementia in the elderly, there is a pressing need for research, development, and timely application of biomarkers that will identify latent and prodromal illness as well as dementia. Although identification of risk factors and neuroimaging measures will remain key to these efforts, this review focuses on recent progress in the discovery, validation, and standardization of cerebrospinal fluid (CSF) biomarkers, small molecules and macromolecules whose CSF concentration can aid in diagnosis at different stages of disease as well as in assessment of disease progression and response to therapeutics. A multimodal approach that …brings independent information from risk factor assessment, neuroimaging, and biomarkers may soon guide physicians in the early diagnosis and management of cognitive impairment in the elderly. Show more

Keywords: Alzheimer's disease, biomarkers, cerebrospinal fluid, Lewy body disease, vascular cognitive impairment

DOI: 10.3233/JAD-2010-1236

Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 301-309, 2010

Authors: Murphy, M. Paul | LeVine III, Harry

Article Type: Research Article

Abstract: Alzheimer's disease (AD) pathogenesis is widely believed to be driven by the production and deposition of the amyloid-β peptide (Aβ). For many years, investigators have been puzzled by the weak to nonexistent correlation between the amount of neuritic plaque pathology in the human brain and the degree of clinical dementia. Recent advances in our understanding of the development of amyloid pathology have helped solve this mystery. Substantial evidence now indicates that the solubility of Aβ, and the quantity of Aβ in different pools, may be more closely related to disease state. The composition of these pools of Aβ reflects different …populations of amyloid deposits and has definite correlates with the clinical status of the patient. Imaging technologies, including new amyloid imaging agents based on the chemical structure of histologic dyes, are now making it possible to track amyloid pathology along with disease progression in the living patient. Interestingly, these approaches indicate that the Aβ deposited in AD is different from that found in animal models. In general, deposited Aβ is more easily cleared from the brain in animal models and does not show the same physical and biochemical characteristics as the amyloid found in AD. This raises important issues regarding the development and testing of future therapeutic agents. Show more

Keywords: Amyloid-β, amyloid-β protein precursor, fibril, oligomer

DOI: 10.3233/JAD-2010-1221

Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 311-323, 2010

Authors: Lynn, Bert C. | Wang, Jianquan | Markesbery, William R. | Lovell, Mark A.

Article Type: Research Article

Abstract: The major barrier to treating or preventing Alzheimer's disease (AD) is its unknown etiology and pathogenesis. Although increasing evidence supports a role for mitochondrial dysfunction in the pathogenesis of AD, there have been few studies that simultaneously evaluate changes in multiple mitochondrial proteins. To evaluate changes in sites of potentially interacting mitochondrial proteins, we applied 2-dimensional liquid chromatography coupled with tandem mass spectrometry and the isotope coded affinity tag method to identify and quantify proteins in mitochondrial enriched fractions isolated from short postmortem interval temporal pole specimens from subjects with mild cognitive impairment (4 subjects pooled), early AD (4 subjects …pooled), late-stage AD (8 subjects pooled) and age-matched normal control (7 subjects pooled) subjects. A total of 112 unique, non-redundant proteins were identified and quantified in common to all three stages of disease progression. Overall, patterns of protein change suggest activation of mitochondrial pathways that include proteins responsible for transport and utilization of ATP. These proteins include adenine nucleotide translocase, voltage dependent anion channels, hexokinase, and creatine kinase. Comparison of protein changes throughout the progression of AD suggests the most pronounced changes occur in early AD mitochondria. Show more

Keywords: Disease progression, early Alzheimer's disease (EAD), isotope coded affinity tag (ICAT), LC/MS/MS, late Alzheimer's disease (LAD), mild cognitive impairment (MCI), mitochondria, proteomics, quantitative

DOI: 10.3233/JAD-2010-1254

Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 325-339, 2010

Authors: Sultana, Rukhsana | Butterfield, D. Allan

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized pathologically by the presence of senile plaques, neurofibrillary tangles, and synapse loss. Increasing evidence supports a role of amyloid β-peptide (Aβ)-induced oxidative stress in the progression and pathogenesis of AD. In this review, we summarize evidence for a role of oxidative stress in the progression of AD by comparing the appearance of the same oxidized brain proteins from subjects with mild cognitive impairment (MCI), early AD (EAD), and late-stage AD, and relating these findings to the reported AD pathology. The identification of oxidized brain proteins in common in MCI, …EAD, and AD brain suggest that certain key pathways are triggered and may be involved in the progression of AD. Exploring these pathways in detail may provide clues for better understanding the pathogenesis and progression of AD and also for the development of effective therapies to treat or delay this dementing disorder. Show more

Keywords: Alzheimer's disease, amyloid, early Alzheimer's disease, mild cognitive impairment, oxidative stress, proteomics

DOI: 10.3233/JAD-2010-1222

Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 341-353, 2010

Authors: McGeer, Edith G. | McGeer, Patrick L.

Article Type: Research Article

Abstract: Neuroinflammation is a prominent feature of Alzheimer disease (AD) and other chronic neurodegenerative disorders. It exacerbates the fundamental pathology by generating a plethora of inflammatory mediators and neurotoxic compounds. Inflammatory cytokines, complement components, and toxic free radicals are among the many species that are generated. Microglia attack the pathological entities and may inadvertently injure host neurons. Recent evidence indicates that microglia can be stimulated to assume an antiinflammatory state rather than a proinflammatory state which may have therapeutic potential. Proinflammatory cytokines include IL-1, IL-6 and TNF, while antiinflammatory cytokines include IL-4 and IL-10. Complement activation is a separate process which …causes extensive neuronal damage in AD through assembly of the membrane attack complex. Aggregated amyloid-β is a potent activator of human complement but not of mouse complement. This is an important difference between AD and transgenic mouse models of AD. Many so far unexplored molecules may contribute to neuroinflammation or act to inhibit it. Stable isotope labeling by amino acids in cell culture (SILAC) analysis identified 174 proteins that were upregulated by two-fold or more, and 189 that were downregulated by 2-fold or more following inflammatory stimulation of microglial-like THP-1 cells. Neurotoxicity may result from any combination of these and further exploration is clearly warranted. In addition, many small molecules may play a significant role. One example is hydrogen sulfide which appears to be an endogenous antiinflammatory agent. Show more

Keywords: Amyloid-β, astrocytes, complement, hydrogen sulfide, microglia, neurotoxicity

DOI: 10.3233/JAD-2010-1219

Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 355-361, 2010

Authors: Smith, Mark A. | Zhu, Xiongwei | Tabaton, Massimo | Liu, Gang | McKeel Jr., Daniel W. | Cohen, Mark L. | Wang, Xinglong | Siedlak, Sandra L. | Dwyer, Barney E. | Hayashi, Takaaki | Nakamura, Masao | Nunomura, Akihiko | Perry, George

Article Type: Research Article

Abstract: It is now established that oxidative stress is one of the earliest, if not the earliest, change that occurs in the pathogenesis of Alzheimer's disease (AD). Consistent with this, mild cognitive impairment (MCI), the clinical precursor of AD, is also characterized by elevations in oxidative stress. Since such stress does not operate in vacuo, in this study we sought to determine whether redox-active iron, a potent source of free radicals, was elevated in MCI and preclinical AD as compared to cognitively-intact age-matched control patients. Increased iron was found at the highest levels both in the cortex and cerebellum from the …pre-clinical AD/MCI cases. Interestingly, glial accumulations of redox-active iron in the cerebellum were also evident in preclinical AD patients and tended to increase as patients became progressively cognitively impaired. Our findings suggests that an imbalance in iron homeostasis is a precursor to the neurodegenerative processes leading to AD and that iron imbalance is not necessarily unique to affected regions. In fact, an understanding of iron deposition in other regions of the brain may provide insights into neuroprotective strategies. Iron deposition at the preclinical stage of AD may be useful as a diagnostic tool, using iron imaging methods, as well as a potential therapeutic target, through metal ion chelators. Show more

Keywords: Alzheimer's disease, chelator, diagnostic, free radicals, iron, mild cognitive impairment (MCI), oxidative stress, pre-clinical, redox activity

DOI: 10.3233/JAD-2010-1239

Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 363-372, 2010

Article Type: Announcement

DOI: 10.3233/JAD-2010-1264

Citation: Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 373-374, 2010