Ebook: Handbook of Imaging the Alzheimer Brain

Alois Alzheimer first described the syndrome associated with his name in a conference in 1906 and then published a paper that accurately described this condition, both the clinical presentation and the pathology, in 1907. The patient who he described was 51 years of age when she first presented to him with dementia and psychosis, at an age close to the average life-expectancy of that region of Germany at that time. He also described her presentation as a rare, presenile form of dementia, and pathologically she had severe atherosclerosis as well as a form of changes in the brain that he saw for the first time due to the newly available silver stains, senile plaques and neurofibrillary changes, which are now the pathological hallmarks of this disease. Two factors have brought Alzheimer's disease from a rare condition to what is now the leading factor associated with death in the developed world: 1) the presence of the senile plaques and neurofibrillary changes in the most common form of dementia in the elderly, and 2) the progressive increase in life-expectancy (about 25 years since Alzheimer's time) leading to a huge growth in the elderly population in the age range which is most susceptible to this condtion.

The great developments that have led to this handbook are the advances in the technology for imaging the brain of the living person. In the last 50 years, a wide variety of techniques have emerged, including measurement of electromagnetic signals, anatomy, functional activity, chemical composition, and neuropathological changes. These techniques are not yet able to image individually the senile plaques and neurofibrillary changes that are seen by the pathologists at autopsy, but they are reflecting Alzheimer pathological changes more and more closely. Now, these techniques allow imaging of brain regions that estimates the presence of senile plaques that are seen by the pathologists at autopsy, and ligands for neurofibrillary changes are under active development, so new techniques are able to report more and more accurate estimations of pathological changes of Alzheimer's disease. Other techniques reviewed in this handbook are able to convey critical information about the function and connectivity of the brain that is disrupted by Alzheimer pathology.

This handbook was developed to provide an overview of the state of the art of brain-imaging approaches that have recently emerged to reveal the critical characteristics of brains of patients with Alzheimer's disease. The book was initially conceived as an opportunity to present the major findings produced from the Alzheimer's Disease Neuroimaging Initiative (ADNI), which has been led by Michael Weiner, and has led to the publication over 200 hundred papers on imaging the brains of individuals along the transition from elderly normal to mild cognitive impairment to mild dementia. This book provides numerous chapters that examine this critical phase of Alzheimer's disease, but chapters also discuss diagnosis, early biomarkers, late changes, the role of vascular disease, and treatment. The book drew from presentations at the International Conference on Alzheimer's Disease (ICAD), which met in Hawaii in July, 2010, and the associated Alzheimer's Imaging Consortium, chaired by Sandra Black and Giovanni Frisoni.

This book is organized in 10 sections. Each section addresses a particular neuroimaging modality that has been found to be useful in understanding or diagnosing Alzheimer's disease. Each section has an introduction to the particular technique and how it has the potential for informing clinical care or evaluating novel therapies for Alzheimer's patients. The chapters provide clinicians with specific information as to how the particular neuroimaging technique is or can be useful in a clinical setting, including the gamut from Radiology to Primary Care and address specific advances in the various types of neuroimaging. The book includes brief overviews of imaging of Alzheimer's disease and reviews fundamental principles for neuroimaging pathological changes that it causes, with an emphasis on practical and future applications.

The basic concept of this compendium is that each section provides an overview of the use of brain imaging in the specific area of Alzheimer's disease neuroimaging. The chapters in this book provide the field with perspectives on the value of the various imaging techniques for screening for Alzheimer's disease, determining the early markers of the disease, making the diagnosis, following the progression of the disease, determining the variability of the manifestation of Alzheimer's disease, and estimating the utility of these metrics of disease severity for examining the effects of treatments. However, this work has not addressed all of the numerous complexities of Alzheimer's disease, including co-occurrence, Parkinson's disease, fronto-temporal dementia, etc., and only briefly touches on vascular risk factors and subcortical ischemic vasculopathy.

The target audience for this book is the clinical community, including medical students, residents-in-training with an interest in neuroimaging, as well as clinicians and faculty in fields where neuroimaging of Alzheimer's disease is and will become even more critical as automatic quatnification methods start coming on-line and available for practicing clinicians taking care of the affected patients (Family Practitioners, Geriatric Medicine, Neurologists, Radiologist, Psychiatrists). The overview is relatively brief but highly accessible for students, clinicians, and other researchers studying Alzheimer's disease, since a need to understand the clinical aspects of the disease are critical for guiding basic investigations.

Alzheimer's disease is a common problem which is becoming progressively more prevalent and burdensome to the World. Through better recognition of this disease and more precise diagnosis, led by brain imaging in the appropriate clinical context, it is our sincere hope that mankind can conquer this terrible disease.

Alzheimer's disease (AD), first described by Alois Alzheimer in 1906, is a combination of neuropathological processes, which is devastating the world socially and economically. The distinct neuropathological observations are the senile plaques, composed predominantly of the amyloid-beta protein, and the neurofibrillary changes (threads and tangles), made of hyperphosphorlyated micro-tubule associate protein tau. Autosomal-dominant genetic factors can cause AD under 60 years of age, and Apo-lipo-protein E factors are strongly related to risk after age 60. AD affects basic neuronal plasticity mechanisms leading to relentless loss of memory function that causes insidious and progressive dementia. Recent conceptualizations have emphasized the progression of AD from the earliest abnormal preclinical changes, through appearances of memory and other cognitive impairments, leading to losses of function associated with dementia. This brief summary introduces a compendium of articles on AD which examines the advances in the science, engineering, and technology of imaging the brain to better understand and diagnose AD and develop treatments and cures. This introduction emphasizes the primary importance of understanding pathology, pathophysiology, and causation, genetic and environmental. The approaches described in this compendium are arranged according to widely used practices, including structural and functional imaging techniques as well as electro-magneto-encephalography and magnetic resonance spectroscopy, with additional chapters focusing on vascular factors, techniques for assessing longitudinal change, and multi-modal integration for the future. Advances in brain imaging hold the promise to contribute understanding of AD for development of therapies to prevent the disease at its earliest stages, halt its progression, and reverse its dementia.

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 de-afferentation 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.

Ventricular enlargement is a common finding among patients with Alzheimer's disease (AD), and has recently been shown to occur from an early disease stage. A possible pathophysiological link between ventricular enlargement and AD has been suggested, with faulty cerebrospinal fluid (CSF) clearance implicated as one possible mechanism. We examined whether ventricular enlargement is associated with CSF amyloid beta (Aβ) early in the disease, even before cognitive symptoms are present, as one would expect to observe this relationship if CSF clearance is impaired. Baseline CSF biomarker data (Aβ, tau, and phosphorylated tau) and MRI brain volumetric measures were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Data from 288 participants classified as cognitively asymptomatic (n = 87), mild cognitive impairment (MCI; n = 136), or mild AD (n = 65) were analyzed by multiple linear regression with brain volumes and age as independent variables, and each biomarker as dependent variables. Ventricular volume was negatively associated with CSF Aβ in APOE ε4-positive cognitively asymptomatic participants. In contrast, ventricular volume was not associated with Aβ among ε4-positive MCI or AD patients. Tau concentrations were negatively associated with ventricular volume among ε4-positive AD patients. These findings indicate that increased ventricular volume is associated with decreased CSF Aβ among cognitively asymptomatic people who are at risk for AD based on ε4 genotype. The effects of APOE ε4 genotype on these relationships are currently not well understood, but may involve impaired CSF clearance and possibly CSF-blood-brain barrier dysfunction.

The aim of the present study was to examine the relationship between cerebral morphological changes and cognitive deficits as determined by the CERAD neuropsychological test battery in a large group of patients with MCI and with AD and otherwise healthy elderly controls. Patients were recruited among typical memory clinic referrals and carefully matched for age, gender and educational level. Optimized voxel based morphometry was used to reveal gray matter differences between groups and to investigate the association of neuropsychological deficits with brain structural alterations. When compared to controls, AD patients and, to a lesser extent, patients with MCI showed significant atrophy predominantly in the medial temporal lobe. Deficits in verbal fluency and word finding were significantly correlated with left fronto-temporal and left temporal (including the hippocampus) changes, respectively. Decreased scores in immediate and delayed recall and in delayed recognition were associated with several cortical and subcortical areas including the parahippocampal and posterior cingulate gyrus, the right thalamus, and the right hippocampus, whereas deficits in constructional praxis and constructional praxis recall referred to regions in the left thalamus and cerebellum, and the temporal cortices, respectively. These findings lend further support to medial temporal lobe degeneration in MCI and AD and suggest that cognitive deficits reflect morphological alterations in widespread cortico-subcortical networks.

Alzheimer's disease (AD) can be difficult to differentiate clinically from other forms of dementia, such as frontotemporal lobar degeneration (FTLD), due to overlapping symptoms. Research studies often base their diagnostic inclusion criteria on clinical rather than pathological data which may mean some subjects are misdiagnosed and misclassified. Recently, methods measuring cortical thickness using magnetic resonance imaging (MRI) have been suggested to be effective in differentiating between clinically-defined AD and frontotemporal dementia (FTD) in addition to showing disease-related patterns of atrophy. In this study, cortical thickness was measured in 28 pathologically-confirmed AD patients, of which 11 had a typical amnestic presentation and 17 an atypical presentation during life, 23 pathologically-confirmed FTLD subjects, and 25 healthy controls. Patients with AD pathology, irrespective of clinical diagnosis, showed reduced cortical thickness bilaterally in the medial temporal lobe, posterior cingulate gyrus, precuneus, posterior parietal lobe, and frontal pole compared with controls. Lower cortical thickness in the posterior cingulate gyrus, parietal lobe and frontal pole was shown to be suggestive of AD pathology in patients with behavioural or language deficits. In contrast, lower cortical thickness in the anterior temporal lobe and frontal lobe is indicative of the presence of FTLD pathology in patients with a clinical presentation of FTD. Reduced cortical thickness in the posterior cingulate gyrus is characteristic of AD pathology in patients with typical and atypical clinical presentations of AD, and may assist a clinical distinction of AD pathology from FTLD pathology.

Neuropathological research consistently revealed that the olfactory bulb and tract (OBT) is subjected to degenerative processes in Alzheimer's disease (AD). In the present study, we assessed OBT volumes in individuals with mild cognitive impairment (MCI), in patients with probable AD, and in healthy comparison subjects using high-resolution magnetic resonance imaging. In both MCI and AD patients OBT volumes were significantly lower compared to controls with atrophy being most prominent in the AD group. In the patient group, lower mean OBT volumes were associated with a decreased gray matter density in the MTL bilaterally. Further, OBT volumes in patients were significantly correlated with cognitive performance. Our findings suggest the OBT volume as a potentially useful marker of AD and MCI related neurodegeneration.

The presence of an ApoE ε4 allele (ε4+) increases the risk of developing Alzheimer's disease (AD). Previous studies support an adverse relationship between ε4+ status and brain structure and function in mild cognitive impairment and AD; in contrast, the presence of an ε2 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 (ε3/3, ε2/3, ε3/4) and control variables for effects of site, non-independence of twin data, age, and average cranial vault or cortical thickness. Relative to the ε3/3 group, the ε3/4 group demonstrated significantly thinner cortex in superior frontal and left rostral and right caudal midfrontal regions; there were no significant effects of ε4 status on any temporal lobe measures. The ε2/3 group demonstrated significantly thicker right parahippocampal cortex relative to the ε3/3 group. The ApoE ε4 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 ε4-related effects. The presence of the ε2 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.

The medial temporal lobe is affected early on in Alzheimer's disease (AD), and the presence of medial temporal atrophy can be used in the differential diagnosis of AD. However, the hippocampus has a complex structure, and subregions of the hippocampus are differentially affected in different dementia types. We used high resolution (0.3 mm in-plane) coronal 3T MR imaging of the medial temporal lobe in 16 subjects with Alzheimer's disease (AD), 16 with dementia with Lewy bodies (DLB) and 16 similarly aged healthy subjects to investigate differences in the hippocampus subregions. On the anterior section of the hippocampus body, regions of interest were manually drawn blind to diagnosis on the CA1, CA2 & CA3/4 subregions, and the width of the subiculum and entorhinal cortex was measured. Controlling for intracranial volume, age and years of education, we found the subiculum thickness was significantly reduced in AD (2.03 ± 0.29 mm) compared to both control (2.37 ± 0.28 mm, p = 0.008) and DLB (2.35 ± 0.24 mm, p = 0.001) subjects. The area of CA1 was likewise reduced in AD compared to controls and DLB. In the hippocampus images, a hypointense line is visible between CA1 and CA3/4. This line was significantly less distinct in AD, suggesting disease related changes to this region. Future studies should investigate whether subiculum thickness or the hypointense line could be a diagnostic feature to help discriminate AD from DLB.

We examine morphological changes in cortical thickness of patients with Alzheimer's disease (AD) using image analysis algorithms for brain structure segmentation in order to automatic detect AD patients using cortical and volumetric data. Cortical thickness of 14 AD patients was measured using FreeSurfer software package in T1 weighted MRI images and compared with 20 healthy subjects. An automated classifier based on Support Vector Machine (SVM) was applied over the volumetric measurements of subcortical and cortical structures to separate AD patients from controls. Besides the volumetric classification we noticed that the cortical thickness group analysis showed cortical thickness reduction in the superior temporal lobe, parahippocampal gyrus, and enthorhinal cortex in both hemispheres. We also found cortical thinning in the isthmus of cingulate gyrus and middle temporal gyrus at the right hemisphere, as well as a reduction of the cortical mantle in areas previously shown to be associated with AD. Automatic classification algorithms using SVM can be helpful to distinguish AD patients from healthy controls. Moreover, the same areas implicated in the pathogenesis of AD were the main parameters driving the classification algorithm. While the patient sample used in this study was relatively small, we expect that using a database of regional volumes derived from MRI scans of a large number of subjects will increase the SVM power of AD patient identification.

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.

Previously it was reported that Alzheimer's disease (AD) patients have reduced amyloid (Aβ_1-42) and elevated total tau (t-tau) and phosphorylated tau (p-tau_181p) 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 Aβ_1-42, t-tau, and p-tau_181p and ApoE ε4 status, and that the pattern of this association would be diagnosis specific. Our findings primarily showed that lower CSF Aβ_1-42 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 Aβ_1-42 levels and higher p-tau levels supports the hypothesis that CSF Aβ_1-42 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.

Combined utility of biomarkers in prediction of neurodegenerative diseases gains popularity, and is expected to become a future standard for early diagnosis, screening and monitoring of disease progression. This study investigated combined use of MRI and CSF biomarkers for prediction of pre-clinical Alzheimer's disease (AD). Forty-five subjects (21 controls (NL-NL), 16 stable mild cognitive impairment patients (MCI-MCI) and 8 MCI patients who declined to AD (MCI-AD)) received MRI and lumbar puncture at baseline and again after 2-years. CSF biomarkers included total and phosphorylated tau (T-tau, P-tau₂₃₁), amyloid beta Aβ₄₂/Aβ₄₀ and isoprostane (IP). Structural MRI images were used to identify brain regions with differences of gray matter concentration (GMC) best distinguishing study groups and to calculate individual GMC values. Additionally, rate of medial temporal lobe (MTL) atrophy was examined using regional boundary shift (rBS) method. At baseline, for MRI, MCI-AD showed reduced GMC in MTL, and for CSF higher CSF T-tau, P-tau₂₃₁, IP and lower Aβ₄₂/Aβ₄₀ as compared with MCI-MCI or NL-NL. Longitudinally, rBS-MTL atrophy was higher in MCI-AD than in either MCI-MCI or NL-NL, particularly in the left hemisphere. CSF data showed longitudinally greater increases of CSF IP in MCI-AD as compared with healthy controls. Combining baseline CSF-P-tau₂₃₁ and GMC-MTL significantly increased overall prediction accuracy of preclinical AD from 74 to 84% (p_step < 0.05). These results justify use of multiple modalities of biomarkers in the identification of memory clinic patients at increased risk for dementia.

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.

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.

Unawareness of the disease or anosognosia is a common symptom among many neuropsychiatric patients and may affect the quality of life and treatment compliance in patients suffering from AD and make them to behave unsafely. Although generalized cognitive impairment may be a prerequisite for anosognosia in dementia, not all patients with cognitive impairment, present anosognosia. Deficit in regional cerebral blood flow (rCBF) can be seen in different brain regions in dementia with a typical posterior temporoparietal defect in patients with Alzheimer's disease. Although functional brain imaging methods such as single photon emission computed tomography (SPECT) have relatively limited spatial resolution, they offer the potential advantage of being able to assess functional connectivity patterns, associated with neural networks involved in awareness. We try to determine the brain regions that contributed to unawareness in patients with Alzheimer's disease, using SPECT. This study will focus on awareness deficits in cognitive and behavioral domains, rather than personality.

Visuoperceptual processing is impaired early in the clinical course of Alzheimer's disease (AD). The 15-Objects test (15-OT), a visual discrimination task based on the Poppelreuter test consisting on 15 overlapping objects, detects such subtle performance deficits in Mild Cognitive Impairment (MCI) and mild AD. Single Photon Emission Tomography (SPECT) studies have reported reduced brain perfusion in temporal, parietal and prefrontal regions in early AD and MCI. The aim of the present study was to confirm the role of the 15-OT in the diagnosis of MCI and AD, and to investigate the brain perfusion correlates of visuoperceptual dysfunction in subjects with MCI, AD and normal aging. For this purpose, 42 AD, 42 MCI and 42 control subjects underwent a brain SPECT and separately completed the 15-OT. Results showed that the 15-OT performace was impaired in MCI and AD patients. In terms of SPECT scans, AD patients showed reduced perfusion in temporal-parietal regions, while MCI subjects had decreased perfusion in the middle and posterior cingulate. When MCI and AD groups were compared, a greater brain perfusion reduction was found in temporo-parietal regions in AD than MCI. In the whole sample, 15-OT performance was significantly correlated with clinical dementia rating scores, and with perfusion in the bilateral posterior cingulate and the right temporal pole, with no significant correlation in each separate group. Our findings suggest that the 15-OT performance provides a useful gradation of impairment from normal aging to AD, and it seems to be related to perfusion in the bilateral posterior cingulate and the right temporal pole.

Alzheimer's disease (AD) is characterized by a progressive loss of controlled cognitive processes (processes requiring mental effort and attentional resources), and functional neuroimaging at early stages of AD provides an opportunity to tease out the neural correlates of controlled processes. Controlled and automatic memory performance was assessed with the Process Dissociation Procedure in 50 patients diagnosed with questionable Alzheimer's disease (QAD). The patients' brain glucose metabolism was measured using FDG-PET. After a follow-up period of 36 months, 27 patients had converted to AD, while 23 remained stable. Both groups showed a similar decrease in controlled memory processes but preserved automatic processes at entry into the study, suggesting that impairment of controlled memory would not be specific for AD. Patients who subsequently converted to Alzheimer type dementia showed significantly decreased brain metabolism at baseline compared to stable QAD in associative cortices known to be involved in AD (the left precuneus, the right inferior parietal lobule and bilateral middle temporal cortex).Voxel-based cognitive and metabolic correlations showed that a decrease in controlled memory processes was preferentially correlated with lower activity in the dorsomedial prefrontal and posterior cingulate cortices in very early AD patients. The dorsomedial prefrontal cortex would play a role in controlled memory processes as they relate to reflective and monitoring processes, while the posterior cingulate cortex is involved in the controlled access to previously encoded episodes. In stable QAD patients, reduced controlled performance in verbal memory correlated with impaired activity in the left anterior hippocampal structure, which would alter the reactivation of associations created at encoding.

Despite brain perfusion SPECT with technetium radiopharmaceuticals has not been formally included among the biomarkers for the early diagnosis of Alzheimer's disease (AD), its worldwide availability and the large literature evidence in AD and related disorders still make of it a valid alternative to FDG-PET, wherever the latter is unavailable. In this article, baseline brain SPECT has been evaluated in 80 subjects presenting with a cognitive complaint who have been followed for a mean of about two years, when twelve patients developed AD-dementia (AD-D), nineteen showed significant memory decline (D), and forty-three had normal cognition assessment (stable: S), while six patients dropped-out. Volumetric Regions of Interest (VROI) analysis was performed in six associative cortical areas in each hemisphere. ANOVA for repeated measures showed significant effects for both the group (S, D, and AD-D; p < 0.004) and VROI (p < 0.0001) factors, with significant group*region interaction (p < 0.01). At post-hoc comparison, hippocampal VROIs values were lower in AD-D than in D and S, while parietal VROIs values were lower in D and AD-D than in S. These four VROI significantly correlated with verbal delayed recall score at follow-up visit. Receiver operating characteristic (ROC) curves for the mean hippocampal VROI value showed 0.81 sensitivity with 0.86 specificity in separation of S + D from AD-D (p < 0.0001), and 0.69 sensitivity with 0.75 specificity in separation of S from D + AD-D (p < 0.0002). ROC curves for the mean parietal VROI value showed 0.62 sensitivity with 0.70 specificity in separation of S from D + AD-D (p < 0.0002). Baseline SPECT can support outcome prediction in subjects with MCI and assist clinicians in identifying MCI patients with biological signs of neurodegeneration of the AD-type in critical cortical areas.

The development of prevention therapies for Alzheimer's disease (AD) would greatly benefit from biomarkers that are sensitive to subtle brain changes occurring prior to the onset of clinical symptoms, when the potential for preservation of function is at the greatest. In vivo brain imaging is a promising tool for the early detection of AD through visualization of abnormalities in brain structure, function and histopathology. Currently, Positron Emission Tomography (PET) imaging with amyloid-beta (Aβ) tracers and 2-[¹⁸F]fluoro-2-Deoxy-D-glucose (FDG) is largely utilized in the early and differential diagnosis of AD. Aβ PET tracers bind to Aβ plaques in brain, and provide an in vivo estimate of AD pathology. FDG-PET is used to measure glucose metabolism, a marker of brain activity. This paper reviews brain Aβ- and FDG-PET studies in AD patients as well as in non-demented individuals at risk for AD. We then discuss the potential of combining symptoms-sensitive FDG-PET measures with pathology-specific Aβ-PET to improve the early detection of AD.