Journal of Alzheimer's Disease - Volume 26, issue s3

Authors: Shin, Jonghan | Kepe, Vladimir | Barrio, Jorge R. | Small, Gary W.

Article Type: Research Article

Abstract: 2-(1-{6-[(2-[fluorine-18]fluoroethyl)(methyl)amino]-2-naphthyl}-ethylidene)malononitrile (FDDNP) is the first positron emission tomography (PET) molecular imaging probe to visualize Alzheimer's disease (AD) pathology in living humans. The most unique features of FDDNP are that (1) it is the only currently available radiotracer to image neurofibrillary tangles, beside amyloid aggregates, in living humans; and (2) it is also the only radiotracer to visualize AD pathology in the hippocampal region of living humans. In this article, we discuss FDDNP's unique ability to image tau pathology in living humans. Emphasizing tau pathology imaging capability using FDDNP in AD, as well as other tauopathies, is timely and beneficial considering …that (1) post mortem histopathological studies using human specimens have consistently demonstrated that neurofibrillary tangles, compared with amyloid plaques, are better correlated with the disease severity and neuronal death; and (2) recently reported clinical trial failures of disease-modifying drugs in development, based on the amyloid-cascade hypothesis, suggest that some of the basic assumptions of AD causality warrant reassessment and redirection. Show more

DOI: 10.3233/JAD-2011-0008

Citation: Journal of Alzheimer's Disease, vol. 26, no. s3, pp. 135-145, 2011

Authors: Jensen, Jordan R. | Cisek, Katryna | Funk, Kristen E. | Naphade, Swati | Schafer, Kelsey N. | Kuret, Jeff

Article Type: Research Article

Abstract: Tau-bearing neurofibrillary lesions present a promising biomarker for premortem diagnosis and staging of Alzheimer's disease and certain forms of frontotemporal lobar degeneration by whole brain imaging methods. Although brain penetrating compounds capable of binding tau aggregates with high affinity have been disclosed for this purpose, the major barrier to progress remains the need for tau lesion binding selectivity relative to amyloid-beta plaques and other deposits of proteins in cross-beta-sheet conformation. Here we discuss challenges faced in the development of tau lesion-selective imaging agents, and recent preclinical advances in pursuit of this goal.

Keywords: Alzheimer's disease, frontotemporal lobar degeneration, tau, neurofibrillary tangle, paired helical filaments, biomarker

DOI: 10.3233/JAD-2011-0003

Citation: Journal of Alzheimer's Disease, vol. 26, no. s3, pp. 147-157, 2011

Authors: Drago, Valeria | Babiloni, Claudio | Bartrés-Faz, David | Caroli, Anna | Bosch, Beatriz | Hensch, Tilman | Didic, Mira | Klafki, Hans-Wolfgang | Pievani, Michela | Jovicich, Jorge | Venturi, Luca | Spitzer, Philipp | Vecchio, Fabrizio | Schoenknecht, Peter | Wiltfang, Jans | Redolfi, Alberto | Forloni, Gianluigi | Blin, Olivier | Irving, Elaine | Davis, Ceri | Hårdemark, Hans-goran | Frisoni, Giovanni B.

Article Type: Research Article

Abstract: Older persons with Mild Cognitive Impairment (MCI) feature neurobiological Alzheimer's Disease (AD) in 50% to 70% of the cases and develop dementia within the next 5 to 7 years. Current evidence suggests that biochemical, neuroimaging, electrophysiological, and neuropsychological markers can track the disease over time since the MCI stage (also called prodromal AD). The amount of evidence supporting their validity is of variable strength. We have reviewed the current literature and categorized evidence of validity into three classes: Class A, availability of multiple serial studies; Class B a single serial study or multiple cross sectional studies of patients with increasing …disease severity from MCI to probable AD; and class C, multiple cross sectional studies of patients in the dementia stage, not including the MCI stage. Several Class A studies suggest that episodic memory and semantic fluency are the most reliable neuropsychological markers of progression. Hippocampal atrophy, ventricular volume and whole brain atrophy are structural MRI markers with class A evidence. Resting-state fMRI and connectivity, and diffusion MR markers in the medial temporal white matter (parahippocampus and posterior cingulum) and hippocampus are promising but require further validation. Change in amyloid load in MCI patients warrant further investigations, e.g. over longer period of time, to assess its value as marker of disease progression. Several spectral markers of resting state EEG rhythms that might reflect neurodegenerative processes in the prodromal stage of AD (EEG power density, functional coupling, spectral coherence, and synchronization) suffer from lack of appropriately designed studies. Although serial studies on late event-related potentials (ERPs) in healthy elders or MCI patients are inconclusive, others tracking disease progression and effects of cholinesterase inhibiting drugs in AD, and cross-sectional including MCI or predicting development of AD offer preliminary evidence of validity as a marker of disease progression from the MCI stage. CSF Markers, such as Aβ1-42 , t-tau and p-tau are valuable markers which support the clinical diagnosis of Alzheimer's disease. However, these markers are not sensitive to disease progression and cannot be used to monitor the severity of Alzheimer's disease. For Isoprostane F2 some evidence exists that its increase correlates with the progression and the severity of AD. Show more

Keywords: Alzheimer's disease, Mild cognitive impairment, neuropsychology, neuroimaging, diffusion tensor imaging, functional MRI, spectroscopy, positron emission tomography, EEG, cerebrospinal fluid

DOI: 10.3233/JAD-2011-0043

Citation: Journal of Alzheimer's Disease, vol. 26, no. s3, pp. 159-199, 2011

Authors: Babiloni, Claudio | Vecchio, Fabrizio | Lizio, Roberta | Ferri, Raffaele | Rodriguez, Guido | Marzano, Nicola | Frisoni, Giovanni B. | Rossini, Paolo M.

Article Type: Research Article

Abstract: Physiological brain aging is characterized by a combination of synaptic pruning, loss of cortico-cortical connections and neuronal apoptosis that provoke age-dependent decline of cognitive functions. Neural/synaptic redundancy and plastic remodeling of brain networking, also secondary to mental and physical training, promotes maintenance of brain activity in healthy elderly for everyday life and fully productive affective and intellectual capabilities. Unfortunately, in pathological situations, aging triggers neurodegenerative processes that impact on cognition, like Alzheimer's disease (AD). Oscillatory electromagnetic brain activity is a hallmark of neuronal network function in various brain regions. Modern neurophysiological techniques including digital electroencephalography (EEG) allow non-invasive analysis of …cortico-cortical connectivity and neuronal synchronization of firing, and coherence of brain rhythmic oscillations at various frequencies. The present review of field EEG literature suggests that discrimination between physiological and pathological brain aging clearly emerges at the group level, with some promising result on the informative value of EEG markers at the individual level. Integrated approaches utilizing neurophysiological techniques together with biological markers and structural and functional imaging are promising for large-scale, low-cost, widely available on the territory and non-invasive screening of at-risk populations. Show more

Keywords: Consciousness, electroencephalography (EEG), persistent vegetative state, Alzheimer's disease

DOI: 10.3233/JAD-2011-0051

Citation: Journal of Alzheimer's Disease, vol. 26, no. s3, pp. 201-214, 2011

Authors: Olichney, John M. | Yang, Jin-Chen | Taylor, Jason | Kutas, Marta

Article Type: Research Article

Abstract: Cognitive event-related brain potential (ERP) studies of decision-making and attention, language, and memory impairments in Alzheimer's disease (AD) and mild cognitive impairment (MCI) are reviewed. Circumscribed lesions of the medial temporal lobe (MTL), as may be the case in individuals with amnestic MCI, generally produce altered plasticity of the late positive P600 component, with relative sparing of earlier sensory ERP components. However, as the neuropathology of AD extends to neocortical association areas, abnormalities of the P300 and N400 (and perhaps even P50) become more common. Critically, ERP studies of individuals at risk for AD may reveal neurophysiological changes prior to …clinical deficits, which could advance the early detection and diagnosis of “presymptomatic AD”. Show more

Keywords: Alzheimer's disease (AD), mild cognitive impairment (MCI), synaptic dysfunction, preclinical AD, event-related potentials (ERP), P300, N400, P600, Late Positive Component (LPC), EEG

DOI: 10.3233/JAD-2011-0047

Citation: Journal of Alzheimer's Disease, vol. 26, no. s3, pp. 215-228, 2011

Authors: Ashford, J. Wesson | Coburn, Kerry L. | Rose, Terrence L. | Bayley, Peter J.

Article Type: Research Article

Abstract: The amplitude of the event-related potential P300 component is sensitive to aging and Alzheimer's disease (AD). Using a standard 20-electrode configuration, the P300 was measured during an “oddball” task in 14 young normal individuals (YN: 21–41 years), 11 elderly normal individuals (EN: 61–80 years), and 23 probable AD patients (AD: 63–93 years; NINCDS-ADRDA criteria). P300 latencies and amplitudes were measured at PZ. Additionally, algorithmic calculations were made from spline plots across the 11 central electrodes for P300 peak voltage latency and total field energy. The measured versus calculated latencies were in general agreement. Furthermore, the measured P300 voltage amplitude was …closely related to the calculated total field energy. P300 voltage latency was significantly prolonged in the elderly, but not more so in AD patients (average latency [ms ± SD]; YN, 315 ± 21; EN, 364 ± 48 and AD, 361 ± 56). P300 amplitude showed the expected pattern of change from young to elderly to AD (average voltage [uV ± SD]; YN, 13 ± 5.1; EN, 8.3 ± 2.8; and AD, 4.9 ± 3.3). Summing the squares of each wave (an indication of power: P = V2 R) showed the expected change with age more strongly than the P300 amplitude (average ± SD; YN, 44,397 ± 32,386; EN, 9,996 ± 7,018; and AD, 3,347 ± 2,971). Mini-Mental State Exam scores showed no relationship to P300 latency and minimal relationship to amplitude. Results suggest that the P300 is not obliterated in early AD, but is barely discernable in late AD. The approaches to calculating the P300 described here are potentially useful for measuring specific neural systems affected by aging and AD. Show more

Keywords: Aging, Alzheimer's disease, dementia, event-related potentials, P300, P3a, P3b

DOI: 10.3233/JAD-2011-0061

Citation: Journal of Alzheimer's Disease, vol. 26, no. s3, pp. 229-238, 2011

Authors: Verdoorn, Todd A. | McCarten, J. Riley | Arciniegas, David B. | Golden, Richard | Moldauer, Leslie | Georgopoulos, Apostolos | Lewis, Scott | Cassano, Michael | Hemmy, Laura | Orr, William | Rojas, Donald C.

Article Type: Research Article

Abstract: We have conducted multicenter clinical studies in which brain function was evaluated with brief, resting-state magnetoencephalography (MEG) scans. A study cohort of 117 AD patients and 123 elderly cognitively normal volunteers was recruited from community neurology clinics in Denver, Colorado and Minneapolis, Minnesota. Each subject was evaluated through neurological examination, medical history, and a modest battery of standard neuropsychological tests. Brain function was measured by a one-minute, resting-state, eyes-open MEG scan. Cross-sectional analysis of MEG scans revealed global changes in the distribution of relative spectral power (centroid frequency of healthy subjects = 8.24 ± 0.2 Hz and AD patients = …6.78 ± 0.25 Hz) indicative of generalized slowing of brain signaling. Functional connectivity patterns were measured using the synchronous neural interactions (SNI) test, which showed a global increase in the strength of functional connectivity (cO2 value of healthy subjects = 0.059 ± 0.0007 versus AD patients = 0.066 ± 0.001) associated with AD. The largest magnitude disease-associated changes were localized to sensors near posterior and lateral cortical regions. Part of the cohort (31 AD and 46 cognitively normal) was evaluated in an identical fashion approximately 10 months after the first assessments. Follow-up scans revealed multiple MEG scan features that correlated significantly with changes in neuropsychological test scores. Linear combinations of these MEG scan features generated an accurate multivariate model of disease progression over 10 months. Our results demonstrate the utility of brief resting-state tests based on MEG. The non-invasive, rapid and convenient nature of these scans offers a new tool for translational AD research and early phase development of novel treatments for AD. Show more

Keywords: Alzheimer's disease, magnetoencephalography, electrophysiology, biomarkers

DOI: 10.3233/JAD-2011-0056

Citation: Journal of Alzheimer's Disease, vol. 26, no. s3, pp. 239-255, 2011

Authors: Fellgiebel, Andreas | Yakushev, Igor

Article Type: Research Article

Abstract: The hippocampus is among the first brain structures to be affected by Alzheimer's disease (AD) pathology. Microstructural alterations within this region have been quantified in vivo using diffusion tensor imaging (DTI), a relatively novel MRI-based technique for mapping diffusion properties of water. Existing evidence indicates that DTI-derived mean diffusivity (MD) of the anterior hippocampus is more predictive than ordinary volumetric indices of the degree of episodic memory impairment in patients with early AD. Thus, altered MD of the (anterior) hippocampus might be highly indicative of hippocampal dysfunction, thereby potentially qualifying this measure as a candidate marker for monitoring progression of …AD. Longitudinal studies are needed to confirm this concept. DTI-based assessment of hippocampal microstructure might be also of value for early AD diagnosis and for predicting the course of cognitive decline in subjects at risk for Alzheimer's dementia. Mean diffusivity as microstructural and volume as macrostructural index of hippocampal integrity seem to reflect different, albeit overlapping, aspects of the neurodegenerative process. In contrast, fractional anisotropy is less efficient for quantifying microstructural integrity of the diseased hippocampus in the clinical context. Development of automatic algorithms, providing MD measurements of the hippocampus for routine use, is a task for future studies. Show more

Keywords: DTI, mild cognitive impairment, dementia, memory, multi-modal, longitudinal axis, biomarker, atrophy, microstructural, diffusivity

DOI: 10.3233/JAD-2011-0001

Citation: Journal of Alzheimer's Disease, vol. 26, no. s3, pp. 257-262, 2011

Authors: Canu, Elisa | McLaren, Donald G. | Fitzgerald, Michele E. | Bendlin, Barbara B. | Zoccatelli, Giada | Alessandrini, Franco | Pizzini, Francesca B. | Ricciardi, Giuseppe K. | Beltramello, Alberto | Johnson, Sterling C. | Frisoni, Giovanni B.

Article Type: Research Article

Abstract: The macrostructural atrophy of Alzheimer's disease (AD) has been fully described. Current literature reports that also microstructural alterations occur in AD since the early stages. However, whether the microstructural changes offer unique information independent from macrostructural atrophy is unclear. Aim of this study is to define the independent contribution of macrostructural atrophy and microstructural alterations on AD pathology. The study involved 17 moderate to severe AD patients and 13 healthy controls. All participants underwent conventional and non conventional MRI (respectively, T1-weighted and diffusion-weighted MR scanning). We processed the images in order to obtain gray and white matter volumes to assess …macrostructural atrophy, and fractional anisotropy and mean diffusivity to assess the microstructural damage. Analyses of covariance between patients and controls were performed to investigate microstructural tissue damage independent of macrostructural tissue loss, and viceversa, voxel by voxel. We observed microstructural differences, independent of macrostructural atrophy, between patients and controls in temporal and retrosplenial regions, as well as in thalamus, corticopontine tracts, striatum and precentral gyrus. Volumetric differences, independent of microstructural alterations, were observed mainly in the entorhinal cortex, posterior cingulum, and splenium. Measures of microstructural damage provide unique information not obtainable with volumetric mapping in regions known to be pivotal in AD as well as in others thought to be spared. This work expands the understanding of the topography of pathological changes in AD that can be captured with imaging techniques. Show more

Keywords: Diffusion Tensor Imaging (DTI), Alzheimer's disease (AD), Microstructure, Fractional Anisotropy (FA), Mean Diffusivity (MD)

DOI: 10.3233/JAD-2011-0040

Citation: Journal of Alzheimer's Disease, vol. 26, no. s3, pp. 263-274, 2011

Authors: Shu, Ni | Wang, Zhiqun | Qi, Zhigang | Li, Kuncheng | He, Yong

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disease involving the decline of memory and other cognitive functions. Mild cognitive impairment (MCI) represents a transition phase between normal aging and early AD. The degeneration patterns of the white matter across the brain in AD and MCI remain largely unclear. Here we used diffusion tensor imaging and tract-based spatial statistics (TBSS) to investigate white matter changes in multiple diffusion indices (e.g., fractional anisotropy, axial, radial and mean diffusivities) in both AD and MCI patients. Compared with the normal controls, the AD patients had reduced fractional anisotropy and increased axial, radial and mean …diffusivities in widespread white matter structures, including the corpus callosum and the white matter of lateral temporal cortex, the posterior cingulate cortex/precuneus and the fronto-parietal regions. Similar white matter regions with reduced anisotropy were also found in MCI patients but with a much less extent than in AD. Between the AD and MCI groups, there were significant differences in the axial and mean diffusivities of the white matter tracts adjacent to the posterior cingulate cortex/precuneus without anisotropy changes. Taken together, our findings based upon multiple diffusion indices (FA, axial, radial and mean diffusivities) suggest distinct degeneration behaviors of the white matter in AD and MCI. Show more

Keywords: Connectivity, axial diffusivity, radial diffusivity, DTI, TBSS

DOI: 10.3233/JAD-2011-0024

Citation: Journal of Alzheimer's Disease, vol. 26, no. s3, pp. 275-285, 2011