| Volume 26, Supplement 3, October 2011 - "Imaging the Alzheimer Brain" (Guest Editors: J.W. Ashford, A. Rosen, M. Adamson, P. Bayley,
O. Sabri, A. Furst, S.E. Black and M. Weiner)
Pages 1-27
J. Wesson Ashford, Ahmad Salehi, Ansgar Furst, Peter Bayley, Giovanni B. Frisoni, Clifford R. Jack Jr, Osama Sabri, Maheen M. Adamson, Kerry L. Coburn, John Olichney, Norbert Schuff, Daniel Spielman, Steven D. Edland, Sandra Black, Allyson Rosen, David Kennedy, Michael Weiner and George Perry
Introduction: Imaging the Alzheimer Brain
Pages 29-47
Martha Millan Sanchez, Sarah Moghadam, Priyanka Naik, Kara J. Martin, Ahmad Salehi
Hippocampal Network Alterations in Alzheimer’s Disease and Down Syndrome: From Structure to Therapy
Abstract: Hippocampal structural and functional alterations in Alzheimer’s disease (AD), detected by advanced imaging methods, have been linked to significant abnormalities in multiple internal and external networks in this critical brain region. Uncovering the temporal and anatomical pattern of these network alterations would provide important clues into understanding the pathophysiology of AD and suggest new therapeutic strategies for this multisystem and prevalent disorder. Over the last decade, we have focused on studying brain structures that provide major projections to the hippocampus (HC) and the pattern of deafferentation of this area in mouse models of AD and a related neurodegenerative disorder, i.e. Down syndrome (DS). Our studies have revealed that major inputs into the hippocampal structure undergo significant age-dependent alterations. Studying locus coeruleus (LC), the sole source of noradrenergic terminals for the HC, it has been shown that these neurons show significant age-dependent degeneration in both mouse models of DS and AD. Furthermore, increasing noradrenergic signaling was able to restore cognitive function by improving synaptic plasticity, and possibly promoting microglia recruitment, and amyloid β (Aβ) clearance in transgenic (tg) mouse models of AD. Here we re-examine the effects of alterations in major inputs to the hippocampal region and their structural and functional consequences in mouse models of neurodegenerative disorders. We will conclude that improving the function of major hippocampal inputs could lead to a significant improvement in cognitive function in both AD and DS.
Pages 49-60
Christine Fennema-Notestine, Matthew S. Panizzon, Wesley R. Thompson, Chi-Hua Chen, Lisa T. Eyler, Bruce Fischl, Carol E. Franz, Michael D. Grant, Amy J. Jak, Terry L. Jernigan, Michael J. Lyons, Michael C. Neale, Larry J. Seidman, Ming T. Tsuang, Hong Xian, Anders M. Dale, William S. Kremen
Presence of ApoE e4 Allele Associated with Thinner Frontal Cortex in Middle Age
Abstract: The presence of an ApoE e4 allele (e4+) increases the risk of developing Alzheimer’s disease (AD). Previous studies support an adverse relationship between e4+ status and brain structure and function in mild cognitive impairment and AD; in contrast, the presence of an e2 allele may be protective. Whether these findings reflect disease-related effects or pre-existing endophenotypes, however, remains unclear. The present study examined the influence of ApoE allele status on brain structure solely during middle-age in a large, national sample. Participants were 482 men, ages 51-59, from the Vietnam Era Twin Study of Aging (VETSA). T1-weighted images were used in volumetric segmentation and cortical surface reconstruction methods to measure regional volume and thickness. Primary linear mixed effects models predicted structural measures with ApoE status (e3/3, e2/3, e3/4) and control variables for effects of site, non-independence of twin data, age, and average cranial vault or cortical thickness. Relative to the e3/3 group, the e3/4 group demonstrated significantly thinner cortex in superior frontal and left rostral and right caudal midfrontal regions; there were no significant effects of e4 status on any temporal lobe measures. The e2/3 group demonstrated significantly thicker right parahippocampal cortex relative to the e3/3 group. The ApoE e4 allele may influence cortical thickness in frontal areas, which are later developing regions thought to be more susceptible to the natural aging process. Previous conflicting findings for mesial temporal regions may be driven by the inclusion of older individuals, who may evidence preclinical manifestations of disease, and by unexamined moderators of e4-related effects. The presence of the e2 allele was related to thicker cortex, supporting a protective role. Ongoing follow-up of the VETSA sample may shed light on the potential for age- and disease-related mediation of the influence of ApoE allele status.
Pages 61-75
Marina Boccardi, Rossana Ganzola, Martina Bocchetta, Michela Pievani, Alberto Redolfi, George Bartzokis, Richard Camicioli, John G. Csernansky, Mony J. de Leon, Leyla deToledo-Morrell, Ronald J. Killiany, Stéphane Lehéricy, Johannes Pantel, Jens C. Pruessner, H. Soininen, Craig Watson, Simon Duchesne, Clifford R. Jack Jr, Giovanni B. Frisoni
Survey of Protocols for the Manual Segmentation of the Hippocampus: Preparatory Steps Towards a Joint EADC-ADNI Harmonized Protocol
Abstract: Manual segmentation from magnetic resonance imaging (MR) is the gold standard for evaluating hippocampal atrophy in Alzheimer’s disease (AD). Nonetheless, different segmentation protocols provide up to 2.5-fold volume differences. Here we surveyed the most frequently used segmentation protocols in the AD literature as a preliminary step for international harmonization. The anatomical landmarks (anteriormost and posteriormost slices, superior, inferior, medial, and lateral borders) were identified from 12 published protocols for hippocampal manual segmentation ([Abbreviation] first author, publication year: [B] Bartzokis, 1998; [C] Convit, 1997; [dTM] deToledo-Morrell, 2004; [H] Haller, 1997; [J] Jack, 1994; [K] Killiany, 1993; [L] Lehericy, 1994; [M] Malykhin, 2007; [Pa] Pantel, 2000; [Pr] Pruessner, 2000; [S] Soininen, 1994; [W] Watson, 1992). The hippocampi of one healthy control and one AD patient taken from the 1.5T MR ADNI database were segmented by a single rater according to each protocol. The accuracy of the protocols’ interpretation and translation into practice was checked with lead authors of protocols through individual interactive web conferences. Semantically harmonized landmarks and differences were then extracted, regarding: (a) the posteriormost slice, protocol [B] being the most restrictive, and [H,M,Pa,Pr,S] the most inclusive; (b) inclusion [C,dTM,J,L,M,Pr,W] or exclusion [B,H,K,Pa,S] of alveus/fimbria; (c) separation from the parahippocampal gyrus, [C] being the most restrictive, [B,dTM,H,J,Pa,S] the most inclusive. There were no substantial differences in the definition of the anteriormost slice. This survey will allow us to operationalize differences among protocols into tracing units, measure their impact on the repeatability and diagnostic accuracy of manual hippocampal segmentation, and finally develop a harmonized protocol.
Pages 77-90
Duygu Tosun, Norbert Schuff, Leslie M. Shaw, John Q. Trojanowski, Michael W. Weiner, and the Alzheimer’s Disease NeuroImaging Initiative
Relationship Between CSF Biomarkers Of Alzheimer's Disease And Rates of Regional Cortical Thinning In ADNI Data
Abstract: Previously it was reported that Alzheimer’s disease (AD) patients have reduced amyloid (Ab1-42) and elevated total tau (t-tau) and phosphorylated tau (p-tau181p) in the cerebro-spinal fluid (CSF), suggesting that these same measures could be used to detect early AD pathology in healthy elderly (CN) and mild cognitive impairment (MCI). In this study, we tested the hypothesis that there would be an association among rates of regional brain atrophy, the CSF biomarkers Ab1-42, t-tau, and p-tau181p and ApoE ε4 status, and that the pattern of this association would be diagnosis specific. Our findings primarily showed that lower CSF Ab1-42 and higher tau concentrations were associated with increased rates of regional brain tissue loss and the patterns varied across the clinical groups. Taken together, these findings demonstrate that CSF biomarker concentrations are associated with the characteristic patterns of structural brain changes in CN and MCI that resemble to a large extent the pathology seen in AD. Therefore, the finding of faster progression of brain atrophy in the presence of lower Ab1-42 levels and higher p-tau levels supports the hypothesis that CSF Ab1-42 and tau are measures of early AD pathology. Moreover, the relationship among CSF biomarkers, ApoE ε4 status, and brain atrophy rates are regionally varying, supporting the view that the genetic predisposition of the brain to amyloid and tau mediated pathology is regional and disease stage specific.
Pages 91-95
Geoffrey A. Kerchner
Ultra-High Field 7T MRI: A New Tool for Studying Alzheimer’s Disease
Abstract: Ultra-high field 7T MRI offers superior signal-to-noise and spatial resolution relative to any other noninvasive imaging technique. By revealing fine anatomical details of the living brain, 7T MRI allows neuroimaging researchers the opportunity to observe in patients disease-related structural changes previously apparent only on postmortem tissue analysis. Alzheimer’s disease (AD) is a natural subject for this technology, and I review here two AD-related applications of 7T MRI: direct visualization of cortical plaques, and high resolution hippocampal imaging. I also discuss limitations of this technology as well as expected advances that are likely to establish 7T MRI as an increasingly important tool for the diagnosis and tracking of AD.
Pages 97-103
Markus Weih, Ümüt Degirmenci, Sebastian Kreil, Gerald Suttner, Daniela Schmidt, Johannes Kornhuber, Piotr Lewczuk, Torsten Kuwert
Nuclear Medicine Diagnostic Techniques in the Era of Pathophysiology-based CSF Biomarkers for Alzheimer’s disease
Abstract: Nuclear medicine techniques were the first functional imaging techniques used to support the clinical diagnosis of Alzheimer’s Disease (AD). Perfusion-SPECT allows registration of regional cerebral blood flow (rCBF) which is altered in a characteristic temporal-parietal pattern in AD. Numerous studies have shown the diagnostic value of reduced CBF and metabolic changes using perfusion-SPECT and FDG-PET in AD diagnosis as well as in differential diagnosis against frontotemporal dementia (FTD), dementia with Lewy-Bodies (DLB), and vascular cognitive disorders. This renders perfusion-SPECT an important piece of the puzzle (together with other diagnostic tests) by the clinician is often faced when making a final etiologic dementia diagnosis especially between AD and FTD. A similar diagnostic value can be expected when arterial spin labeling (ASL) MRI sequence is used, but the diagnostic value has yet to be confirmed in lager studies. Recently, more pathophysiology-based biomarkers in CSF and Amyloid-PET tracers have been developed that probably have a higher diagnostic accuracy than the more indirect rCBF changes seen in perfusion-SPECT. In the current review, we describe recent advances in AD biomarkers as well as improvements in the SPECT technique.
Pages 105-116
Ansgar J. Furst, Rayhan A. Lal
Amyloid-β and glucose metabolism in Alzheimer’s disease
Abstract: This study used PET with the amyloid-β (Aβ) imaging agent 11C Pittsburgh Compound-B (PIB) and the glucose metabolic tracer 18F-fluorodeoxyglucose (FDG) to map the relationship of Aβ deposition to regional glucose metabolism in Alzheimer’s disease (AD). Comparison of 13 AD patients’ FDG scans with 11 healthy controls confirmed a typical temporo-parietal hypometabolic pattern in AD. In contrast, PIB distribution-volume-ratios showed a distinct pattern of specific tracer retention in fronto-temporo-parietal regions and striatum in AD with peaks in left frontal cortex, precuneus, temporal cortex, striatum and right posterior cingulate. There were no region-to-region or within region correlations between FDG and PIB uptake in PIB positive AD patients but when the impact of Aβ load on glucose metabolism was assessed via probabilistic maps, increased amyloid burden was coupled with decreased metabolism in temporo-parietal regions and the posterior cingulate. However, importantly, severe Aβ burden was not associated with comparable metabolic decreases in large parts of the frontal lobes, the striatum and the thalamus.
Pages 117-121
Henryk Barthel, Osama Sabri
Florbetaben to trace amyloid-β in the Alzheimer brain by means of PET
Abstract: PET imaging of amyloid-β has recently emerged as a valuable biomarker to support the in vivo diagnosis of Alzheimer’s disease (AD). So far, however, no tracer is available suitable for general clinical routine application. Florbetaben is a promising 18F-labeled amyloid-β-targeted PET tracer currently in Phase2/3 clinical development. This review provides an overview on the current knowledge and future research activities on florbetaben. Recently, the first worldwide multi-center trial to test the diagnostic performance of amyloid-β PET in AD was conducted with this tracer. From this trial, a sensitivity and specificity of 80 and 91% in the discrimination between patients with probable AD and age-matched healthy controls was reported. Ongoing florbetaben PET trials deal with correlating the in vivo PET signal to post mortem histopathology evaluation, and with investigating the value of the tracer to predict progression to AD at the stage of mild cognitive impairment. The preclinical and clinical data currently available verify florbetaben as a safe and efficacious PET tracer suitable for detection of amyloid-β deposition in the brain. The results of the ongoing trials will contribute to current knowledge on the characteristics of florbetaben, and will help to determine the future potential of florbetaben PET imaging as a visual adjunct to supplement the routine clinical “AD diagnostic toolbox”.
Pages 123-133
Benjamin P. Austin, Veena A. Nair, Timothy. B. Meier, Guofan Xu, Howard A. Rowley, Cynthia M. Carlsson, Sterling C. Johnson, Vivek Prabhakaran
Effects of Hypoperfusion in Alzheimer’s Disease
Abstract: The role of hypoperfusion in Alzheimer’s disease (AD) is a vital component to understanding the pathogenesis of this disease. Disrupted perfusion is not only evident throughout disease manifestation, it is also demonstrated during the pre-clinical phase of AD (i.e., mild cognitive impairment) as well as in cognitively healthy persons at high-risk for developing AD due to family history or genetic factors. Studies have used a variety of imaging modalities (e.g., SPECT, MRI, PET) to investigate AD, but with its recent technological advancements and non-invasive use of blood water as an endogenous tracer, arterial spin labeling (ASL) MRI has become an imaging technique of growing popularity. Through numerous ASL studies, it is now known that AD is associated with both global and regional cerebral hypoperfusion and that there is considerable overlap between the regions implicated in the disease state (consistently reported in precuneus/posterior cingulate and lateral parietal cortex) and those implicated in disease risk. Debate exists as to whether decreased blood flow in AD is a cause or consequence of the disease. Nonetheless, hypoperfusion in AD is associated with both structural and functional changes in the brain and offers a promising putative biomarker that could potentially identify AD in its pre-clinical state and be used to explore treatments to prevent, or at least slow, the progression of the disease. Finally, given that perfusion is a vascular phenomenon, we provide insights from a vascular lesion model (i.e., stroke) and illustrate the influence of disrupted perfusion on brain structure and function and, ultimately, cognition in AD.
Pages 135-145
Jonghan Shin, Vladimir Kepe, Jorge R. Barrio, Gary W. Small
The Merits of FDDNP-PET Imaging in Alzheimer’s Disease
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.
Pages 147-157
Jordan R. Jensen, Katryna Cisek, Kristen E. Funk, Swati Naphade, Kelsey N. Schafer, Jeff Kuret
Research towards tau imaging
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.
Pages 159-199
Valeria Drago, Claudio Babiloni, David Bartrés-Faz, Anna Caroli, Beatriz Bosch, Tilman Hensch, Mira Didic, Hans-Wolfgang Klafki, Michela Pievani, Jorge Jovicich, Luca Venturi, Philipp Spitzer, Fabrizio Vecchio, Peter Schoenknecht, Jans Wiltfang, Alberto Redolfi, Gianluigi Forloni, Olivier Blin, Elaine Irving, Ceri Davis, Hans-goran Hårdemark, Giovanni B. Frisoni
Disease Tracking Markers for Alzheimer’s Disease at the Prodromal (MCI) Stage
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.
Pages 201-214
Claudio Babiloni, Fabrizio Vecchio, Roberta Lizio, Raffaele Ferri, Guido Rodriguez, Nicola Marzano, Giovanni B. Frisoni, Paolo M. Rossini
Resting State Cortical Rhythms in Mild Cognitive Impairment and Alzheimer’s Disease: Electroencephalographic Evidence
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.
Pages 215-228
John M. Olichney, Jin-Chen Yang, Jason Taylor, Marta Kutas
Cognitive event-related potentials: biomarkers of synaptic dysfunction across the stages of Alzheimer’s Disease
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”.
Pages 229-238
J. Wesson Ashford, Kerry L. Coburn, Terrence L. Rose, Peter J. Bayley
P300 Energy Loss in Aging and Alzheimer’s Disease
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]; 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]; 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 = V2R) showed the expected change with age more strongly than the P300 amplitude (average; 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.
Pages 293-255
Todd A. Verdoorn, J. Riley McCarten, David Arcienegas, Richard Golden, Leslie Moldauer, Apostolos Georgopoulos, Scott Lewis, Michael Cassano, Laura Hemmy, William Orr, Donald Rojas
Evaluation and tracking of Alzheimer’s disease severity using resting-state magnetoencephalograpy
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 (c02 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.
Pages 257-262
Andreas Fellgiebel, Igor Yakushev
Diffusion tensor imaging of the hippocampus in MCI and early Alzheimer’s disease
Abstract: The hippocampus is among the first brain structures to be affected by Alzheimer’s disease (AD) pathology. Microstructural alterations within this region can 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. 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.
Pages 263-274
Elisa Canu, Donald G McLaren, Michele E Fitzgerald, Barbara B Bendlin, Giada Zoccatelli, Franco Alessandrini, Francesca B Pizzini, Giuseppe K Ricciardi, Alberto Beltramello, Sterling C Johnson, Giovanni B Frisoni
Mapping the structural brain changes in Alzheimer’s disease: The independent contribution of two imaging modalities.
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, diffusion-weighted and T1-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.
Pages 275-285
Ni Shu, Zhiqun Wang, Zhigang Qi, Kuncheng Li, Yong He
Multiple diffusion indices reveals white matter degeneration in Alzheimer’s disease and mild cognitive impairment: a tract-based spatial statistics study
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.Tetween 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.
Pages 287-296
Kenichi Oishi, Michelle M. Mielke, Marilyn Albert, Constantine G. Lyketsos, Susumu Mori
DTI analyses and clinical applications in Alzheimer’s Disease
Abstract: DTI is one of the most effective MR tools for the investigation of the brain anatomy. In addition to the gray matter, histopathological studies indicate that white matter is also a good target for both the early diagnosis of AD and for monitoring disease progression, which motivates us to use DTI to study AD patients in vivo. There are already a large amount of studies reporting significant differences between AD patients and controls, as well as to predict progression of disease in symptomatic non-demented individuals. Application of these findings in clinical practice remains to be demonstrated.
Pages 297-305
Michael A. Yassa
Searching for novel biomarkers using high resolution diffusion tensor imaging
Abstract: Diffusion tensor imaging is capable of resolving large fiber bundles (e.g. the corpus callosum) and has been quite informative in understanding the overall structural connectivity of the brain. Recent data, however, has shown that traditional resolution limitations can be exceeded in humans in vivo to submillimeter resolution. This chapter discusses these new techniques, and specific applications to small pathways such as the perforant path in the medial temporal lobe. High-resolution diffusion tensor imaging is a promising new tool that can be used to discover novel biomarkers for Alzheimer’s disease and other disorders. It allows for a much more detailed investigation of brain white matter than previously possible, perhaps offering clues into the first signs of synaptic deterioration that may precede frank neuronl loss. Although these methods are still in their infancy and many challenges have to be overcome before they can be used in a clinical fashion, results so far have been promising. Challenges and future directions are discussed in detail.
Pages 307-319
Eric Westman, Lars-Olof Wahlund, Catherine Foy, Michaela Poppe, Allison Cooper, Declan Murphy, Christian Spenger, Simon Lovestone, Andrew Simmons
Magnetic Resonance Imaging and Magnetic Resonance Spectroscopy for detection of Early Alzheimer’s Disease
Abstract: Alzheimer’s disease is the most common form of neurodegenerative disorder and early detection is of great importance if new therapies are to be effectively administered. We have investigated whether the discrimination between early Alzheimer’s disease (AD) and elderly healthy control subjects can be improved by adding magnetic resonance spectroscopy (MRS) measures to magnetic resonance imaging (MRI) measures. In this study 30 AD patients and 36 control subjects were included. High resolution T1-weighted axial magnetic resonance images were obtained from each subject. Automated regional volume segmentation and cortical thickness measures were determined for the images. 1H MRS was acquired from the hippocampus and LCModel was used for metabolic quantification. Altogether, this yielded 58 different volumetric, cortical thickness and metabolite ratio variables which were used for multivariate analysis to distinguish between subjects with AD and Healthy controls. Combining MRI and MRS measures resulted in a sensitivity of 97% and a specificity of 94% compared to using MRI or MRS measures alone (sensitivity: 87%, 76%, specificity: 86%, 83% respectively). Adding the MRS measures to the MRI measures more than doubled the positive likelihood ratio from 6 to 17. Adding MRS measures to a multivariate analysis of MRI measures resulted in significantly better classification than using MRI measures alone. The method shows strong potential for discriminating between Alzheimer’s disease and controls.
Pages 321-329
Eric M. Reiman, Jessica B.S. Langbaum, Adam S. Fleisher, Richard J. Caselli, Kewei Chen, Napatkamon Ayutyanont, Yakeel T. Quiroz, Kenneth S. Kosik, Francisco Lopera, Pierre N. Tariot
Alzheimer’s Prevention Initiative: A Plan to Accelerate the Evaluation of Presymptomatic Treatments
Abstract: There is an urgent need to find effective presymptomatic Alzheimer’s disease (AD) treatments that reduce the risk of AD symptoms or prevent them completely. It currently takes too many healthy people, too much money and too many years to evaluate the range of promising presymptomatic treatments using clinical endpoints. We have used brain imaging and other measurements to track some of the earliest changes associated with the predisposition to AD. We have proposed the Alzheimer’s Prevention Initiative (API) to evaluate investigational amyloid-modifying treatments in healthy people who, based on their age and genetic background, are at the highest imminent risk of developing symptomatic AD using brain imaging, cerebrospinal fluid (CSF), and cognitive endpoints. In one trial, we propose to study AD-causing presenilin 1 [PS1] mutation carriers from the world’s largest early-onset AD kindred in Antioquia, Colombia, close to their estimated average age at clinical onset. In another trial, we propose to study apolipoprotein E (APOE)e4 homozygotes (and possibly heterozygotes) close to their estimated average age at clinical onset. The API has several goals: 1) to evaluate investigational AD-modifying treatments sooner than otherwise possible; 2) to determine the extent to which the treatment’s brain imaging and other biomarker effects predict a clinical benefit—information needed to help qualify biomarker endpoints for use in pivotal prevention trials; 3) to provide a better test of the amyloid hypothesis than clinical trials in symptomatic patients, when these treatments may be too little too late to exert their most profound effect; 4) to establish AD prevention registries needed to support these and other presymptomatic AD trials; and 5) to give those individuals at highest imminent risk of AD symptoms access to the most promising investigational treatments in clinical trials.
Pages 331-336
J. Wesson Ashford, Maheen M. Adamson, Tamara Beale, Dawn La, Beatriz Hernandez, Art Noda, Allyson Rosen, Ruth O’Hara, Jennifer Kaci Fairchild, Daniel Spielman, Jerome A. Yesavage
MR Spectroscopy for Assessment of Memantine Treatment in Mild to Moderate Alzheimer Dementia
Abstract: Magnetic Resonance Spectroscopy (MRS) provides a precise and reliable assessment of the extent and severity of neural tissue loss caused by various diseases. In particular, the N-Acetyl Aspartate (NAA) over Creatine (Cr) ratio has been found to be an indicator of the degree of neuronal loss in Alzheimer’s disease (AD). Memantine is thought to benefit the AD brain by stabilizing the NMDA receptors on neurons in turn reducing excitotoxicity. Despite its effectiveness in treating moderate to severe AD, memantine has not had similar success in the treatment of mildly demented AD patients. The objective of this study was to test whether memantine would slow or prevent the loss of neurons in mild to moderate AD patients. A double-blind placebo-controlled study was designed to measure the effect of a year-long course of memantine in patients with a probable AD diagnosis with mild to moderate dementia. The primary outcome measure was stipulated to be change in MRS NAA/Cr (ratio) in inferior parietal cortex in memantine relative to the placebo treatment condition. The secondary outcome measures were changes in cognitive and function scale scores.This pilot study failed to demonstrate a benefit of memantine on the primary outcome measure, the inferior parietal NAA/ Cr ratio, or the secondary outcome measures. More studies are needed to determine the effect of memantine on regions of the brain significantly affected by AD pathology.
Pages 337-348
Stefan Förster, Verena C. Buschert, Stefan J. Teipel, Uwe Friese, Hans-Georg Buchholz, Alexander Drzezga, Harald Hampel, Peter Bartenstein, Katharina Buerger
Effects of a 6-month cognitive intervention on brain metabolism in patients with amnestic MCI and mild Alzheimer´s disease
Abstract: The effect of cognitive intervention on brain metabolism in AD is largely unexplored. Therefore, we aimed to investigate cognitive parameters and 18FDG PET to test for effects of a cognitive intervention in patients with aMCI or mild AD. Patients with aMCI (N=24) or mild AD (N=15) were randomly assigned either to cognitive intervention groups (IGs), receiving weekly sessions of group-based multicomponent cognitive intervention, or active control groups (CGs), receiving pencil-paper exercises for self-study. We obtained resting-state FDG-PET scans and neuropsychological testing at baseline and after six-months. Normalized FDG-PET images were analyzed using voxel-based SPM5 approaches to determine longitudinal changes, group-by-time interactions and correlations with neuropsychological outcome parameters. Primary global cognitive outcome was determined by analyses of covariance with MMSE and ADAS-cog scores as dependent measures. Both, aMCI and AD subgroups of CGs showed widespread bilateral cortical declines in FDG uptake, while the AD subgroup of IGs showed discrete decline or rather no decline in case of the aMCI subgroup. Group by time analyses revealed strongest attenuation of metabolic decline in the aMCI subgroup of the IGs, involving left anterior temporal pole and anterior cingulate gyrus. However, correlation analyses revealed only weak non-significant associations between increased FDG uptake and improvement in primary or secondary outcome parameters. Concurrently, there was significant improvement in global cognitive status in the aMCI subgroup of the IGs. A six-month cognitive intervention imparted cognitive benefits in patients with aMCI, which were concurrent with an attenuated decline of glucose metabolism in cortical regions affected by neurodegenerative AD.
Pages 349-357
Allyson C. Rosen, Lisa Sugiura, Joel H. Kramer, Susan Whitfield-Gabrieli, John D. Gabrieli
Cognitive training changes hippocampal function in mild cognitive impairment: A pilot study
Abstract: A randomized pilot experiment examined the neural substrates of response to cognitive training in participants with mild cognitive impairment (MCI). Participants performed exercises previously demonstrated to improve verbal memory and an active control group performed other computer activities. An auditory-verbal fMRI task was conducted before and after the two-month training program. Verbal memory scores improved significantly and left hippocampal activation increased significantly in the experimental group (gains in 5 of 6 participants) relative to the control group (reductions in all 6 participants). Results suggest that the hippocampus in MCI may retain sufficient neuroplasticity to benefit from cognitive training.
Pages 359-367
Ningnannan Zhang, Xiaowei Song, Yunting Zhang, Wei Chen, Ryan CN D’Arcy, Sultan Darvesh, John D Fisk, Kenneth Rockwood
An MRI brain atrophy and lesion index to assess the progression of structural changes in Alzheimer’s disease, mild cognitive impairment, and normal aging: A follow-up study
Abstract: Background: A brain atrophy and lesion index (BALI) based on high-field magnetic resonance imaging (MRI) has recently been validated to evaluate structural changes in the aging brain. The present study investigated the two-year progression of brain structural deficits in people with Alzheimer’s disease (AD) and mild cognitive impairment (MCI), and in healthy control older adults (HC) using the BALI rating. Methods: T1-weighted high-resolution anatomical imaging data using 3 Tesla MRI at baseline (AD=39, MCI=82, HC=58) and at 24-months were obtained from the Alzheimer’s disease Neuroimaging Initiative database. Lesions in various brain structures, including the infratentorial and basal ganglia areas, and the periventricular and deep white matter and global atrophy, were evaluated and combined into the BALI scale. Results: Mean progression of brain deficits over two years was evident in all diagnostic groups (p<0.001) and was statistically greater in MCI-AD converters than in the non-converters (p=0.044). An increase in the BALI score was significantly associated with cognitive test scores (p=0.008 for the Mini-Mental State Examination MMSE and p=0.013 for the Alzheimer’s Disease Assessment Scale-Cognitive Subscale ADAS-cog) in a model that adjusted for age, sex, and education. Conclusion: The BALI rating quantified the progression of brain deficits over two years, which is associated with cognitive decline. BALI ratings may be used to help summarize AD-associated structural variations.
Pages 369-377
Michael C. Ard, Steven D. Edland
Power Calculations for Clinical Trials in Alzheimer's Disease
Abstract: The Alzheimer research community is actively pursuing novel biomarker and other biologic measures to characterize disease progression or to use as outcome measures in clinical trials. One product of these efforts has been a large literature reporting power calculations and estimates of sample size for planning future clinical trials and cohort studies with longitudinal rate of change outcome measures. Sample size estimates reported in this literature vary greatly depending on a variety of factors, including the statistical methods and model assumptions used in their calculation. We review this literature and suggest standards for reporting power calculation results. Regardless of the statistical methods used, studies consistently find that volumetric neuroimaging measures of regions of interest, such as hippocampal volume, outperform global cognitive scales traditionally used in clinical treatment trials in terms of the number of subjects required to detect a fixed percentage slowing of the rate of change observed in demented and cognitively impaired populations. However, statistical methods, model assumptions, and parameter estimates used in power calculations are often not reported in sufficient detail to be of maximum utility. We review the factors that influence sample size estimates, and discuss outstanding issues relevant to planning longitudinal studies of Alzheimer’s disease.
Pages 379-388
Fu-qiang Gao, Richard H. Swartz, Philip Scheltens, Farrell S. Leibovitch, Alex Kiss, Kie Honjo, Sandra E. Black
Complexity of MRI white matter hyperintensity assessments in relation to cognition in aging and dementia from the Sunnybrook Dementia Study
Abstract: Purpose: Quantification methods for white matter hyperintensities (WMH) on Magnetic Resonance Imaging are heterogeneous, deterring their application. This study compared three WMH rating scales, varying in complexity, and a volumetric method, to evaluate trade-offs between complexity and clinical utility in differentiating dementia subgroups and in correlating with cognition. Methods: WMH were rated using the Fazekas, Age-Related White Matter Changes (ARWMC) and Scheltens scales, and segmented by computational volumetry in 108 patients with Alzheimer's Disease (AD), 23 with Mild Cognitive Impairment (MCI) and 34 normal controls (NC). Global and hippocampal atrophy, age and education, were accounted for in correlations of WMH with cognitive domains. Results: Intra- and inter-rater reliability were high (intraclass correlation coefficients =0.88-0.97) across rating scales. WMH scores of all scales were highly correlated with volumes (Spearman r=0.78-0.90, Ps<0.001), as well as with each other (Spearman r=0.86-0.91, Ps<0.001). The Fazekas scale showed significant separation between AD, MCI and NC using non-parametric analysis, while the ARWMC and Scheltens' scales, and WMH volumes demonstrated significant correlations (standardized β=−0.19 to −0.24, Ps<0.05) with cognitive domain scores using multivariate regression analysis, controlling for age, education, global and hippocampal atrophy in patients with AD. Conclusions: This study suggests that the degree of complexity of WMH rating scales did not affect validation against WMH volumes, but did vary in validation against cognition. The simplest scale performed best in separating cognitive subgroups, but the more complex scales and quantification correlated better with cognitive measures, especially executive function. Hence the best choice of scale depends on the particular application.
Pages 389-394
Sven Haller, Karl O Lovblad, Panteleimon Giannakopoulos
Principles of classification analyses in mild cognitive impairment (MCI) and Alzheimer Disease
Abstract: The majority of advanced neuroimaging studies implement group level analyses contrasting a group of patients versus a group of controls, or two groups of patients. Such analyses may identify for example changes in grey matter in specific regions associated with a given disease. Although such group investigations provided key contributions to the understanding of the pathological process surrounding a wide range of diseases, they are of limited utility at an individual level. Recently, there is a trend towards individual classification analyses, representing a fundamental shift of the research paradigm. In contrast to group comparisons, these latter studies do not provide insights on vulnerable brain areas but may allow for an early (and ideally preclinical) identification of at risk individuals in routine clinical setting. One currently very popular method in this domain are support vector machines (SVM), yet this method is only one of many available methods in the field of individual classification analyses. The current manuscript reviews the fundamental properties and features of such individual level classification analyses in neurodegenerative diseases.
Pages 395-405
Simon J. Furney, Deborah Kronenberg, Andrew Simmons, Andreas Güntert, Richard J. Dobson, Petroula Proitsi, Lars-Olof Wahlund, Iwona Kloszewska, Patrizia Mecocci, Hilkka Soininen, Magda Tsolaki, Bruno Vellas, Christian Spenger, Simon Lovestone
Combinatorial markers of Mild Cognitive Impairment conversion to Alzheimer’s disease - cytokines and MRI measures together predict disease progression
Abstract: Progression of people presenting with Mild Cognitive Impairment (MCI) to dementia is not certain and it is not possible for clinicians to predict which people are most likely to convert. The inability of clinicians to predict progression limits the use of MCI as a syndrome for treatment in prevention trials and, as more people present with this syndrome in memory clinics, and as earlier diagnosis is a major goal of health services, this presents an important clinical problem. Some data suggest that CSF biomarkers and functional imaging using PET might act as markers to facilitate prediction of conversion. However, both techniques are costly and not universally available. The objective of our study was to investigate the potential added benefit of combining biomarkers that are more easily obtained in routine clinical practice to predict conversion from MCI to Alzheimer’s disease. To explore this we combined automated regional analysis of structural MRI with analysis of plasma cytokines and chemokines and compared these to measures of APOE genotype and clinical assessment to assess which best predict progression. In a total of 205 people with MCI, 77 of whom subsequently converted to Alzheimer’s disease, we find biochemical markers of inflammation to be better predictors of conversion than APOE genotype or clinical measures (Area under the curve (AUC) 0.65, 0.62, 0.59 respectively). In a subset of subjects who also had MRI scans the combination of serum markers of inflammation and MRI automated imaging analysis provided the best predictor of conversion (AUC 0.78). These results show that the combination of imaging and cytokine biomarkers provides an improvement in prediction of MCI to AD conversion compared to either datatype alone, APOE genotype or clinical data and an accuracy of prediction that would have clinical utility.
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