Journal of Alzheimer's Disease - Volume 33, issue s1

Authors: Braskie, Meredith N. | Toga, Arthur W. | Thompson, Paul M.

Article Type: Review Article

Abstract: Advances in brain imaging technology in the past five years have contributed greatly to the understanding of Alzheimer's disease (AD). Here, we review recent research related to amyloid imaging, new methods for magnetic resonance imaging analyses, and statistical methods. We also review research that evaluates AD risk factors and brain imaging, in the context of AD prediction and progression. We selected a variety of illustrative studies, describing how they advanced the field and are leading AD research in promising new directions.

Keywords: Alzheimer's disease, amyloid, imaging, magnetic resonance imaging, methods, positron emission tomography, prediction, progression, risk factors

DOI: 10.3233/JAD-2012-129016

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S313-S327, 2013

Authors: Teipel, Stefan J. | Sabri, Osama | Grothe, Michel | Barthel, Henryk | Prvulovic, David | Buerger, Katharina | Bokde, Arun L.W. | Ewers, Michael | Hoffmann, Wolfgang | Hampel, Harald

Article Type: Review Article

Abstract: The diagnosis of Alzheimer's disease (AD) is presently going through a paradigm shift from disease categories to dimensions and toward the implementation of biomarkers to support identification of predementia and even preclinical asymptomatic stages of the disease. We outline the methodological basis of presently available biomarkers and technological methodologies in AD, including exploratory and hypothesis-based plasma and blood candidates, cerebrospinal fluid markers of amyloid load and axonal destruction, and imaging markers of amyloid deposition, synaptic dysfunction, cortical functional and structural disconnection, and regional atrophy. We integrate biomarker findings into a comprehensive model of AD pathogenesis from healthy aging to cognitive …decline, the resilience to cerebral amyloid load (RECAL) matrix. The RECAL framework integrates factors of risk and resilience to cerebral amyloid load for individual risk prediction. We show the clinical consequences when the RECAL matrix is operationalized into a diagnostic algorithm both for individual counseling of subjects and for the identification of at risk samples for primary and secondary preventive trials. We discuss the implication of biomarkers for the identification of prodromal AD for the primary care system that seems presently not even prepared to cope with the increasing number of subjects afflicted with late stage AD dementia, let alone future cohorts of subjects searching counseling or treatment of predementia and asymptomatic stages of AD. The paradigm shift in AD diagnosis and its operationalization into a diagnostic framework will have major implications for our understanding of disease pathogenesis. Now, for the first time, we have access to in vivo markers of key events in AD pathogenesis integrated into a heuristic framework that makes strong predictions on pattern of multimodal biomarkers in different stages of AD. Critical testing of these predictions will help us to modify or even falsify the currently hold assumptions on the pathogenesis of AD based on in vivo evidence in humans. Show more

Keywords: Alzheimer's disease, amyloid, atrophy, biomarker, blood, cerebrospinal fluid, diagnosis, diffusion tensor imaging, hippocampus, mild cognitive impairment, neurodegeneration, neuroimaging, pathophysiology, positron emission tomography, prognosis, resting state functional magnetic resonance imaging, tau, therapy

DOI: 10.3233/JAD-2012-129030

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S329-S347, 2013

Authors: Villemagne, Victor L. | Rowe, Christopher C.

Article Type: Review Article

Abstract: The introduction of radiotracers for the non-invasive in vivo quantification of amyloid-β (Aβ) burden in the brain has revolutionized the approach to the evaluation of Alzheimer's disease (AD). Aβ burden as measured by positron emission tomography (PET) matches histopathological reports of Aβ distribution in aging and dementia. It appears more accurate than FDG for the diagnosis of AD, and is an excellent aid in the differential diagnosis of AD from frontotemporal lobar degeneration. Apolipoprotein E ε4 carriers, independent of diagnosis or disease severity, present with higher Aβ burden than non-ε4 carriers. As new therapies enter clinical trials, the role of …Aβ imaging in vivo is becoming increasingly crucial. Aβ imaging allows the in vivo assessment of brain Aβ pathology and its changes over time, providing highly accurate, reliable, and reproducible quantitative statements of regional or global Aβ burden in the brain, essential for therapeutic trial recruitment and for the evaluation of anti-Aβ treatments. Although Aβ burden as assessed by PET does not strongly correlate with cognitive impairment in AD, it does correlate with memory impairment and a higher risk for cognitive decline in the aging population and mild cognitive impairment (MCI) subjects. This correlation with memory impairment, one of the earliest symptoms of AD, suggests that Aβ deposition is not part of normal aging, supporting the hypothesis that Aβ deposition occurs well before the onset of symptoms and likely represents preclinical AD in asymptomatic individuals and prodromal AD in MCI. Further longitudinal observations, coupled with different disease-specific biomarkers to assess potential downstream effects of Aβ, are required to confirm this hypothesis and further elucidate the role of Aβ deposition in the course of AD. Show more

Keywords: Alzheimer's disease, amyloid-β, brain imaging, dementia, positron emission tomography

DOI: 10.3233/JAD-2012-129034

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S349-S359, 2013

Authors: Zetterberg, Henrik | Blennow, Kaj

Article Type: Review Article

Abstract: The past decades have witnessed an enormous expansion of the literature on cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD). It is now clear that a triplet of CSF biomarkers (total-tau, phospho-tau, and the 42 amino acid fragment of amyloid-β) reflects core neuropathological features of AD and contributes diagnostically relevant information if measured in a proper manner. Here, we discuss what is needed for these biomarkers to become generally implemented in the clinical routine. We also discuss novel CSF biomarkers, the challenge of differential diagnosis-making in diseases with shared pathologies, and if CSF biomarkers will survive in the long run, …given the advancements in molecular neuroimaging and ultra-sensitive blood tests. Show more

Keywords: Alzheimer's disease, amyloid, biomarkers, cerebrospinal fluid, tau

DOI: 10.3233/JAD-2012-129035

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S361-S369, 2013

Authors: Quinn, Joseph F.

Article Type: Review Article

Abstract: The indolent nature of Alzheimer's disease, coupled with burgeoning interest in a “presymptomatic” stage of disease, has motivated efforts to identify, validate, and exploit surrogate disease markers for trials of disease-modifying or preventive strategies. Many of these efforts have been productive, and biomarkers are now routinely applied in selection of study subjects and evaluation of outcomes in clinical trials. On the other hand, biomarkers also have the capacity to lead to bad therapeutic outcomes when they determine “go- no go” decisions in early drug development. This paper reviews several reports of biomarker studies which illustrate the great potential, for both …good and ill, of biomarkers of Alzheimer's disease. Show more

Keywords: Alzheimer's disease, biomarkers, clinical trials

DOI: 10.3233/JAD-2012-129022

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S371-S376, 2013

Authors: Grossman, Murray

Article Type: Review Article

Abstract: Here we provide a brief description of our program to improve diagnostic accuracy in cases with phenotypically similar presentations that are due to distinct histopathologic abnormalities. We propose a staged approach to diagnosis, beginning with a screening assessment of specific, quantitative neuropsychological measures, and followed by assessments of imaging and biofluid biomarkers. Our goal is to determine the specific histopathologic abnormalities contributing to an individual's neurodegenerative condition.

Keywords: Amyotrophic lateral sclerosis, biomarker, corticobasal degeneration, frontotemporal degeneration

DOI: 10.3233/JAD-2012-129002

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S379-S383, 2013

Authors: Brayne, Carol | Barker, Roger A. | Harold, Denise | Ince, Paul G. | Savva, George M. | Williams, Julie | Williams-Gray, Caroline H. | Wharton, Stephen B.

Article Type: Review Article

Abstract: Six papers based on studies with particular epidemiological designs are presented here which have been selected on the basis of their visibility in the literature. The designs are intended to provide robust evidence on risk, natural history, and underpinning neurobiology and outcomes relevant to aging populations. There is a large case control study (the Late Onset Alzheimer's Disease study), a case cohort study of Parkinson's Disease (the CamPaIGN study), and the Medical Research Council Cognitive Function and Ageing Study. Each study has included genetic investigation and risk, and the latter two include investigation of the clinical syndromes and their natural …histories in relation to underlying pathology. Each aimed to provide results which were as generalizable to usual older populations as possible and each has produced findings which have contributed to current understanding of genetic risk, the heterogeneity of the syndrome of Parkinson's disease, and the underlying neuropathology of dementia in older population. They have influenced thinking about future directions, and the cohorts on which the findings are based will continue to provide an important resource for novel areas of research and future health care planning. Show more

Keywords: Alzheimer's disease, dementia, epidemiology, genetics, pathology

DOI: 10.3233/JAD-2012-129006

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S385-S396, 2013

Authors: Bennett, David A. | Wilson, Robert S. | Arvanitakis, Zoe | Boyle, Patricia A. | de Toledo-Morrell, Leyla | Schneider, Julie A.

Article Type: Review Article

Abstract: The Religious Orders Study and the Rush Memory and Aging Project are both cohort studies of aging and dementia that include organ donation at death. Together, more than 2,700 persons have agreed to annual clinical evaluation and brain donation at death. A subset of participants also participated in a substudy that included ante-mortem imaging. We highlight recent findings that have been highly cited over the past five years. The findings fall into three general categories. The first relates to the neuropathology of probable Alzheimer's disease, mild cognitive impairment, and those without dementia or mild cognitive impairment. The second relates to …risk factors for Alzheimer's disease and neuropathology. The third are clinical and imaging studies of mild cognitive impairment. The findings illustrate the range of insights that can be gained into cognitive aging by incorporating neuropathologic indices into well designed, prospective cohort studies. Show more

Keywords: Clinical-pathology, mild cognitive impairment, risk factors

DOI: 10.3233/JAD-2012-129007

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S397-S403, 2013

Authors: Caselli, Richard J. | Reiman, Eric M.

Article Type: Review Article

Abstract: Studies of asymptomatic carriers of genes that are known to predispose to Alzheimer's disease (AD) have facilitated the characterization of preclinical AD. The most prevalent genetic risk factor is the ε4 allele of apolipoprotein E (APOE). Neuropathological studies of young deceased ε4 carriers have shown modest but abnormal amounts of neocortical amyloid and medial temporal neurofibrillary tangles that is also reflected in cerebrospinal fluid (CSF) biomarkers, amyloid-β, and phospho-tau in particular. MRI studies have shown progressive hippocampal and gray matter atrophy with the advent of mild cognitive impairment (MCI), and fluorodeoxyglucose PET scans show reduced cerebral metabolism in posterior cingulate …and related AD regions evident even in 30 year olds. Cerebral amyloidosis disclosed by more recent amyloid ligand PET studies in asymptomatic 60 year olds increases in parallel with ε4 gene dose. Longitudinal neuropsychological studies have revealed accelerated memory decline in ε4 carriers beginning around age 55–60 years whose severity again parallels ε4 gene dose. The clinico-pathological correlation of declining memory and AD-like neuropathological change defines preclinical AD and has set the stage for the accelerated evaluation of presymptomatic AD treatments. In this article, we briefly consider some of the earliest detectable changes associated with the predisposition to AD, and some of the prevention trial strategies that have been proposed to help find treatments to reduce the risk, postpone the onset of, or completely prevent AD symptoms as soon as possible. Show more

Keywords: APOE, normal aging, preclinical, prevention

DOI: 10.3233/JAD-2012-129026

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S405-S416, 2013

Authors: DeCarli, Charles

Article Type: Review Article

Abstract: Cerebrovascular risk factors and stroke are highly prevalent with advancing age, and stroke may be more common than Alzheimer's disease, particularly among older men. While stroke mortality continues to decline, the prevalence of individuals with various vascular risk factors continues to rise and many are undiagnosed or undertreated. Asymptomatic cerebrovascular brain injury that includes asymptomatic brain infarction and white matter hyperintensities as well as accelerated brain atrophy is even more frequent than clinical stroke. Moreover, the impact of cerebrovascular risk factors on brain injury appears to begin in middle life and additively increases the likelihood of later life dementia. This …review focuses on the use of neuroimaging and genetics to understand the impact of asymptomatic vascular risk factors on the trajectories of cognitive aging as well as incident cognitive impairment, stroke, and mortality. Results of this review emphasize the need for early detection and treatment of vascular risk factors to improve the cognitive health of our rapidly aging population. Show more

Keywords: Cerebrovascular disease, magnetic resonance imaging, pathophysiology, white matter hyperintensities

DOI: 10.3233/JAD-2012-129004

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S417-S426, 2013