Advances in the early detection of Alzheimer s disease

Transcription

1 Advances in the early detection of Alzheimer s disease Peter J Nestor 1,Philip Scheltens 2 & John R Hodges 1,3 The combination of an aging population and the promise, possibly in the near future, of disease-modifying therapies have made the characterization of the early stages of Alzheimer s disease (AD) a topic of major research interest. In this article we review recent progress in our understanding of the evolution of early AD with particular reference to the symptomatic pre-dementia stage designated mild cognitive impairment, emphasizing work on the early cognitive profile and associated neuroimaging studies. 1 University Neurology Unit, Addenbrooke s Hospital, Hills Road, Cambridge, CB2 2QQ, UK. 2 Department of Neurology/Alzheimer Center, VU Medisch Centrum, PO Box 7057, 1007 MB Amsterdam, The Netherlands. 3 MRC Cognition and Brain Sciences Unit, 15 Chaucer Road, Cambridge CB2 2EF, UK. Correspondence should be addressed to J.R.H. (john.hodges@mrc-cbu.cam.ac.uk). Published online 1 July 2004; doi: /nm1433 With increasing life expectancy across the world, the number of elderly people at risk of developing dementia is growing rapidly. The prevalence of dementia rises steeply with age, doubling every 4 5 years from the age of 60, so that more than one-third of individuals over 80 years of age are likely to develop a dementia 1. AD remains the most common cause of dementia in all age groups. In this review, we focus on the early detection of AD, particularly in the context of subjects with memory complaints who do not yet match criteria for AD but who are at high risk of developing a full-blown dementia syndrome in the next few years. This at-risk state is commonly referred to as mild cognitive impairment (MCI). AD is a progressive neurodegenerative disorder that is characterized by the presence of amyloid deposition and neurofibrillary tangles together with the loss of cortical neurons and synapses 2.Postmortem studies suggest that the hippocampus and entorhinal cortex are the first brain areas to be affected at least by neurofibrillary pathology with cortical association areas being increasingly involved as the disease progresses 3 6.The development of neurofibrillary pathology, but not of amyloid deposition, typically follows an orderly progression in topographical terms 4,7.However, it is unclear whether there is a linear progression from one topographical stage to the next in a temporal sense. Recent serial brain imaging and longitudinal neuropsychological studies indicate that diffuse neuronal and synaptic loss might also occur from an early stage. In addition to these cortical changes, subcortical neuronal loss occurs in the NUCLEUS BASALIS OF MEYNERT and in the LOCUS COERULEUS,resulting in a decrease in cortical levels of cholinergic and noradrenergic markers, respectively The most profound and (by extrapolation) earliest cognitive deficits seem to be impairment of episodic memory the ability to recall events that are specific to a time and place 11.As the pathology spreads to involve cortical association areas, this gives rise to a dementia syndrome that is characterized by deficits in attentional and EXECUTIVE FUNCTIONS (goal formulation, planning and the execution of goaldirected plans), semantic memory (word, face and object knowledge), language, praxis, and constructional and visuospatial abilities Current conceptualizations of AD presume that the neurodegenerative changes begin well before the clinical manifestations of the disease become apparent. As neuronal degeneration and the formation of neurofibrillary tangles and neuritic plaques gradually progress, a threshold for the initiation of clinical symptoms of the dementia syndrome is eventually reached. The cognitive deficits that are associated with AD then become evident and gradually worsen. When the cognitive deficits become global and are severe enough to interfere with normal social and occupational functioning, established criteria for a clinical diagnosis of AD are met (for example, those of the American Psychiatric Association s Diagnostic and Statistical Manual of Mental Disorders,edn. 4 (DSM-IV; 1994)). Subjects in this pre-dementia stage of AD are considered to be cognitively impaired but do not meet criteria for dementia because their cognitive deficits are limited to memory alone and/or their everyday abilities are preserved (Fig. 1). A number of labels have been applied to these less clearly defined subjects, including MCI, cognitive impairment no dementia, questionable dementia, isolated memory impairment and minimal AD MCI: definition and prognosis Although the concept of MCI as a high-risk pre-dementia state is straightforward, it has been difficult to develop robust and applicable clinical criteria and there are many unresolved issues 16,20. Some groups have stressed the importance of a clinical history of declining memory with normal performance on a simple cognitive screening instrument (such as the mini-mental state examination or MMSE) 21 and no, or minimal, impairment in everyday life 22.Other groups have applied strict neuropsychological criteria (>1.5 standard deviations below normal) to define memory impairment together with preservation of other cognitive abilities 16,19,23.The two most important questions involve which memory test(s) should be used to define impairment (which will affect sensitivity and specificity) and how strictly we should exclude patients with other cognitive deficits. S34 JULY 2004 NEURODEGENERATION

2 Normal MCI Dementia Cognitive function Pathological load Figure 1 Schematic view of the transition from normal function to dementia in terms of cognitive performance and pathological burden. Time Regarding the latter, attention and lexico-semantics seem to be the most likely non-mnestic domains affected 19,but whether individuals show such deficits might depend mostly on the sensitivity of tests that probe these areas. The use of different inclusion and exclusion criteria probably accounts for the large variability in reported conversion rates from MCI to AD 23. The concept of MCI assumes that it represents a transitional period before the development of AD proper, with some individuals following a more benign course than others.when neuropsychological test performance has been used to define MCI, 12 15% of patients have converted to dementia per annum, which is about ten times higher than the incidence of dementia in the general population 24.Recent evidence suggests that with time most individuals with MCI will develop dementia 23.Others have found, however, that the application of such strict operational criteria, at least to community samples, is poorly predictive over time because of instability of group membership in that, for instance, some cases initially designated as MCI were reclassified as normal with longitudinal follow-up 25. Another important caveat to the concept of MCI in its narrow definition as an amnesic syndrome is that it fails to capture the heterogeneity of clinical AD presentations. For instance, it is known that a minority of AD cases will present with non-mnestic cognitive manifestations such as progressive visuospatial or language deficits 12.The prevalence of such variants relative to that of typical AD is uncertain, so it is difficult to estimate the number of symptomatic early AD cases that are excluded by the narrow definition of amnesic MCI. Furthermore, resolution of this issue is more complex than the simple creation of single cognitive domain analogs such as visuospatial MCI or aphasic MCI because, unlike amnesic MCI, the differential diagnosis of these variants includes a greater likelihood of alternate dementia syndromes such as dementia with Lewy bodies and frontotemporal dementia (FTD), respectively. An ideal early marker of AD For the early detection of AD, an ideal diagnostic tool must be sensitive to the earliest cognitive or biological changes that are found in AD but should be able to differentiate among early AD, normal aging, other organic brain disorders that cause memory loss and, importantly, mimics of early dementia including depression. It should be robust in terms of test retest reliability, be readily applicable and, ideally, be cheap and simple if it is to gain universal application. Here we review whether any of the currently available tools measures up to these exacting standards. It is important to emphasize, however, that at this time direct comparisons of different markers, either alone or as combined algorithms, with respect to issues such as specificity and sensitivity are largely unavailable. We place particular focus on recent neuropsychological and neuroimaging research into the early detection of AD. One further area of research, the study of cerebrospinal fluid (CSF) biomarkers, shares the aim of improving early diagnostic accuracy, with most studies currently focusing on measurement of the proteins tau and Aβ1 42. A crucial problem of both neuroimaging and neuropsychological methods is that the reliability of each is a function of disease severity, and, therefore, as markers attempt to identify individuals at progressively earlier disease stages, there is a risk of increasing overlap with non-ad pathology, psychiatric illness and healthy aging. At a molecular level the pathological process is likely to be well underway at a time when the earliest symptoms manifest, so a marker of these molecular changes, at least in theory, could be useful if it was relatively independent of disease severity. In practical terms, unlike neuroimaging, which has an established place in clinical diagnostic algorithms (not least for its role in excluding alternate pathologies), CSF examination is not part of most clinicians routine diagnostic workup for suspected AD. Therefore, if a CSF biomarker is to be incorporated into routine diagnostic practice, it will need to demonstrate a considerable increase in predictive value over existing algorithms comprising clinical, neuropsychological and imaging modalities. It remains to be established whether a CSF biomarker will fulfill this standard, but considerable research continues and has recently been reviewed elsewhere 26. Neuropsychological markers of early AD Two chief longitudinal approaches have been undertaken to investigate the most useful neuropsychological measures in detecting individuals in the early stages of AD: (i) community-based studies of normal elderly subjects, some of whom develop dementia, and (ii) studies of individuals with MCI who are selected to be at high risk of dementia, or presymptomatic individuals who are at risk of autosomal dominant familial AD. The first, community-based, approach has consistently shown that deficits in episodic memory can be reliably found at least 5 years before the onset of clinical dementia 25,27 32.Deficits in non-memorybased cognitive domains, including mental speed, executive tests, category fluency and auditory attention span, are also indicators of subsequent dementia 28,31,33. Information on familial AD is much more limited, but one group 34 studied over a 6-year period 63 subjects who were at risk of autosomal dominant familial AD; during the study, ten individuals developed clinical deficits. This subgroup of converters had significantly lower NEURODEGENERATION JULY 2004 S35

3 verbal memory scores and performance IQ measures at their baseline assessment, compared with those who did not convert. Given that the cognitive profile of familial AD might differ in subtle, but important, ways from that of sporadic AD, the findings from such studies should be extrapolated with caution. Clinic-based studies have generally contrasted the baseline performance of MCI patient groups (variously defined) who did or did not progress to dementia (converters versus nonconverters). Again, severity of impairment on tests of episodic memory (story recall, word list learning) is generally the most predictive measure, but deficits in semantic memory (category fluency, naming), attentional processing and mental speed (for example, time to complete the Trails B test, the self-ordering test, symbol/digit substitution) also consistently predict conversion to AD Recent work has suggested that semantic knowledge about famous people is lost very early in the course of AD The results of a longitudinal study in Cambridge, UK 42,43 confirmed earlier work from Australia 44,45 suggesting that a test of spatial learning, the paired-associates learning (PAL) test from the CANTAB computed battery, is sensitive to the early stages of AD and might be able to distinguish patients with early AD from depressed subjects (Fig. 2). An analysis of converters and nonconverters showed that an algorithm that takes account of age and performance on PAL and a difficult object-naming test was highly predictive of early AD 43. Complementary work has shown that persons with FTD generally perform within normal limits on PAL, further increasing its clinical usefulness 46. These studies confirm that stringent tests of episodic memory are the best current predictors of conversion to AD. Of these tests, the PAL test shows the highest discriminating ability and is one of the few tests that has been given to patients with other forms of dementia and to depressed subjects. The sensitivity of the PAL test has been attributed to the cross-domain associative learning and spatial components of the task, which might tax hippocampus-dependent episodic memory processes. The early stages of AD also seem to involve subtle deficits in non-mnestic domains such as semantic memory and attentional processes 47,perhaps reflecting early synaptic loss in the temporal neocortex and frontal cortex, respectively. Several computerized Figure 2 The PAL test. (a) Results of a study in AD, MCI, healthy elderly and depressed patients 41 of performance on the six-item PAL task illustrating a bimodal distribution in the MCI group that accurately discriminated those who subsequently converted to AD. (b) The six-item PAL test. The outer boxes are transiently uncovered in a random sequential order, each revealing a different pattern; immediately after presentation of the six patterns, each item reappears in the central box in random order, and the subject has to indicate where each was first seen. Panel a reproduced, with permission, from ref. 42; (2001) Karger Publishers. a Not reaching stage b Errors at 6-pattern stage Study cognitive batteries have been designed that take advantage of these findings, and these show considerable promise 48,49. Structural imaging markers of early AD Numerous structural MRI studies have demonstrated that atrophy of the medial temporal lobe, including the hippocampus and entorhinal cortex, is a sensitive marker of AD Similar measures have been applied to patients with MCI (Fig. 3), and it has been suggested that atrophy of medial temporal lobe structures might predict progression to AD On the basis of the sequence of tangle deposition in the medial temporal lobe in the development of AD pathology 60, it has been argued that decreased entorhinal cortex volume might be a particularly sensitive predictor of AD. For instance, one group 55 used MRI to measure the volumes of the entorhinal cortex and hippocampus in 137 individuals, and found that the volume of the entorhinal cortex distinguished the subjects who were destined to develop dementia with considerable accuracy (84%), whereas the hippocampal measure did not. Other studies have produced less clear-cut results, which might reflect difficulties in delineating the entorhinal cortex on MRI However, it is difficult to carry out volumetric assessment of these structures in routine clinical practice because of the need for digital PAL errors at 6-pattern stage AD MCI Dep Con Test S36 JULY 2004 NEURODEGENERATION

4 Figure 3 Comparable T1-weighted coronal MRI slices perpendicular to the long axis of the hippocampus showing a normal-sized hippocampus in a control person (total hippocampal volume uncorrected for head size 3,480 mm 3 right and 3,164 mm 3 left) and a smaller hippocampus in an MCI patient (total hippocampal volume uncorrected for head size 2,050 mm 3 right and 2,580 mm 3 left). Images courtesy of L. van der Pol, Alzheimer Center and Image Analysis Center, Vrije Universiteit Medical Center, Amsterdam, The Netherlands. three-dimensional MRI data, the time-consuming nature of regionof-interest analysis and the lack of automated volume measurement techniques. By contrast, medial temporal lobe atrophy can be easily assessed using a standardized visual rating scale 63 66,which has surprisingly good predictive accuracy (on the order of 80 90%) that is comparable to that obtained using volumetric methods 57,58,65,66. Despite these encouraging results, no definite conclusions regarding the clinical usefulness of visual ratings can be drawn. Patient samples have tended to be small and highly selected, and not reflective of routine clinical practice. A recent study attempted to address these issues in a large group of subjects and showed that the odds ratio for progression to dementia of a summed visual rating score was 1.8 per point increase in the scale and 5.1 for atrophy based on the dichotomized score (atrophy present versus absent) 67.The sensitivity for detecting persons with dementia at follow-up was 70% and the specificity was 68% (positive and negative predictive values of 68% and 70%, respectively). Overall, these figures indicate that detection of very early AD cases among MCI subjects is feasible. It remains to be established whether either volumetric or visually based rating scales have greater predictive value than routinely used neuropsychological test batteries (discussed earlier), the clinical dementia rating (CDR), or APOE4 genotype, all of which are known predictors of cognitive decline 25,27 33,35 38,43 45,51, The Dementia Research Group in London developed the method of serial registration of MRI scans, in which patients act as their own controls. This technique permits accurate study of changes over time in the early stages of AD 71. A longitudinal study using this method found significantly increased rates of hippocampal atrophy in presymptomatic and mildly affected patients, whereas the inferolateral regions of the temporal lobes showed the most markedly increased rates of atrophy in mildly or moderately affected individuals 72.A study of persons who were at risk for familial AD suggested that medial temporal lobe atrophy commenced 3.5 years (95% confidence interval, years) before disease onset, when these individuals were still asymptomatic 73.Because this study involved persons at risk for familial AD, it is possible that the results might not apply to sporadic AD. In a recent study in which the hippocampus, entorhinal cortex, whole brain and ventricles were measured from serial MRI studies in a large group of sporadic cases, the annualized atrophy rates were greater in normal subjects who converted to MCI or AD than among those who remained stable, greater in MCI subjects who converted to AD than among nonconverters and greater in fast-progressing AD than slow 74.This study did not confirm the preference for medial temporal over neocortical structures in the transition from MCI to AD, however. Another automated method of measuring brain atrophy is voxel-based morphometry (VBM), which, like serial co-registration, objectively maps gray matter loss between populations on a voxel-by-voxel basis analogous to that used in functional imaging. The advantage of VBM over analyses based on region of interest is that VBM produces an unbiased view and considers all available MRI information 75.The first VBM study in MCI patients showed marked gray matter loss predominantly affecting the hippocampal region and cingulate gyri (posterior and subcallosal part of the anterior), extending into the temporal neocortex in MCI 76.Compared with age-matched individuals with mild AD, gray matter density was substantially preserved in MCI in the posterior association cortex. A recent study confirmed and extended these findings by demonstrating significant local reductions in gray matter in the medial temporal lobe, the insula and the thalamus in MCI patients compared with controls. By contrast, when compared with subjects with AD, MCI subjects had better preserved gray matter in parietal association areas and the anterior and posterior cingulate. It therefore seems that gray matter loss in the medial temporal lobe characterizes MCI, whereas more diffuse cortical gray matter loss might be a feature of AD (G. Karas et al.,personal communication) (Fig. 4). Figure 4 Cumulative gray matter loss in patients with MCI (red) and AD (blue) estimated using computational neuroanatomy methods (VBM). Note that damage is initially confined to the medial temporal lobe, and as the disease progresses, it expands to engulf the parietal association areas. Images courtesy of G.B. Karas, Alzheimer Center and Department of Radiology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands. NEURODEGENERATION JULY 2004 S37

5 Figure 5 Imaging from a 59-year-old male (MMSE = 29/30, CDR = 0.5) who met consensus criteria for MCI 23. Left panel, coronal MRI at the level of the hippocampi showing no significant atrophy; right panel, FDG-PET statistical parametric map projected onto his co-registered MRI in sagittal view, indicating posterior cingulate hypometabolism (P uncorr < 0.001). A slightly different view emerges from studies using whole-brain volumetric magnetization transfer imaging, which identifies areas of axonal damage in structures that appear normal. One group of researchers showed that cognitive decline in patients with MCI is associated with widespread structural brain damage, suggesting that pathology in MCI is much more generalized than was expected 77.This finding is in keeping with neuropsychological studies (discussed earlier), which have consistently shown impairment in mental speed and attentional processes in patients with MCI. To conclude, structural MRI gives insight into the presence of typical AD pathology in vivo in MCI and might provide a means to predict, among the heterogeneous group of MCI subjects, those who are likely to become demented in the near future. This has been shown to be true at a group level, and with qualitative analysis might even be feasible in clinical practice, with test characteristics fulfilling the requirements of the ideal marker as described earlier. It has yet to be confirmed in individuals, however, whether this is true for a single MRI marker, or whether an algorithm that combines it with other measures, especially neuropsychological tests, is necessary 78. Functional imaging in MCI and AD Functional brain imaging offers potential insights into all of the main pathological features of AD neuronal loss, tangle deposition, cholinergic depletion and amyloid plaques. As already mentioned, tangle pathology begins in the medial temporal lobe (a region in which focal lesions give rise to amnesia) and episodic memory impairment is the most salient clinical deficit in AD. It is therefore not surprising that considerable attention has focused on changes in structural imaging (see previous section) of this area as a marker of AD and MCI. When one turns from anatomy to physiology, however, a different but complementary picture begins to emerge. This relates in part to the emphasis in structural imaging research on improving diagnostic accuracy, whereas functional studies have to some extent been more concerned with understanding pathophysiological mechanisms. The two most common methods for imaging resting-state cerebral activity are to calculate regional glucose metabolism with POSITRON EMISSION TOMOGRAPHY (PET) or to use regional cerebral blood perfusion as a surrogate of metabolic activity with the less sophisticated but more widely available SINGLE-PHOTON EMISSION COMPUTERIZED TOMOGRAPHY (SPECT). In clinically probable AD, either method shows dysfunction (hypometabolism or hypoperfusion) in temporo-parietooccipital association cortices and later in frontal association cortices. When researchers studied changes in the medial temporal region, however, early studies found that marked abnormalities either were not identified 79,80 or were seen only in cases with established AD Contemporaneous with these studies, the development of voxelbased image analysis techniques proved a major advance in the field. Briefly, these methods (for example, statistical parametric mapping or SPM) involve spatial normalization of individual scans to a standardized brain-volume template and smoothing of data to reduce the effects of interindividual variability in gyral anatomy. Populations can then be compared on a voxel-by-voxel basis to identify regions of abnormality across the whole brain. Using these principles, one group reported that the earliest changes seen in very mild AD (MMSE 25 ± 1) were in the posterior cingulate cortex 84.Subsequent work supported this unexpected finding. For instance, SPECT showed that individuals with MCI who subsequently converted to AD had hypoperfusion in the posterior cingulate cortex 85 87, and a PET study showed that hypometabolism in the posterior cingulate cortex particularly the retrosplenial component was the only cortical abnormality common to all MCI individuals scanned 88 (Fig. 5). Given that epidemiological data suggest that MCI is an antecedent to AD, it is not surprising that subjects who fulfill clinical MCI criteria but in whom functional imaging reveals lateral posterior association cortex abnormalities akin to those found in established AD are at greatest risk of early conversion to dementia The extent to which posterior cingulate changes might offer diagnostic sensitivity and specificity for defining a prodromal AD state remains to be established; in particular, studies in which baseline imaging was related to longitudinal outcome have used an inadequate follow-up duration to be confident of the ultimate diagno- Glossary Single-photon emission computed tomography (SPECT) A method in which images are generated by using radionuclides that emit single photons of a given energy. Images are captured at multiple positions by rotating the sensor around the subject; the threedimensional distribution of radionuclides is then used to reconstruct the images. SPECT can be used to observe biochemical and physiological processes, as well as the size and volume of structures. Unlike positron emission tomography, SPECT requires the physical alignment of the photons for their detection, resulting in the loss of many available photons and the degradation of the image. Positronic emission tomography (PET) Positron emission tomography (PET) A method of functional imaging in which a positron-emitting radionuclide (such as 18F, 11C or 15O) is used to label a molecule of interest (such as water, glucose or dopa) to measure its regional uptake. As the isotope decays, a positron is released; when this encounters an electron in the surrounding matter, the two particles annihilate one another and energy is released in the form of two gamma-ray photons that are emitted at 180 from each other. As the image is created from the detection of coincident dual photons, PET has spatial resolution superior to that of SPECT. Executive function A cluster of high-order capacities, which include selective attention, behavioral planning and response inhibition, and the manipulation of information in problem-solving tasks. Locus coeruleus A nucleus of the brainstem that is the main supplier of noradrenaline to the brain. Nucleus basalis of Meynert A telencephalic structure that provides most of the acetylcholine to the cerebral cortex. S38 JULY 2004 NEURODEGENERATION

6 sis of a sufficiently large cohort. Nevertheless, its repeated appearance in functional imaging studies make this an important area for future clinical research. Returning to the medial temporal lobe, more sensitive methods have since shown that this area is also abnormal in patients with MCI. Using a technique in which regions of interest were traced onto subjects volumetric MRI scans thus improving anatomical localization one group of researchers studied the temporal lobe and found that MCI cases had restricted hypometabolism in the entorhinal and hippocampal areas. In contrast, subjects with AD had additional metabolic reductions beyond these areas in the temporal neocortex 92.In an attempt to reconcile medial temporal lobe pathology with posterior cingulate hypometabolism in early AD/MCI, it was proposed that these two findings might be related in view of anatomical knowledge that the regions are linked through the circuit of Papez (entorhinal cortex hippocampus mamillary body anteromedial thalamus posterior cingulate cortex entorhinal cortex). Also using co-registered volumetric MRI to define anatomical regions of interest, these authors found that groups with clinically probable AD and MCI showed comparable metabolic reductions at each node in this circuit. Furthermore, abnormalities were restricted to this network in the MCI group, whereas in AD additional metabolic reductions were found in the amygdala and lateral association cortices 93. Another question arising from these studies relates to whether changes in this network are a consequence of local pathology at each site or of remote effects of medial temporal damage. In other words, because fluorodeoxyglucose-pet (FDG-PET) is principally a measure of synaptic activity 94,are changes in the diencephalon and posterior cingulate cortex due to medial temporal cell loss? In support of this proposal, epilepsy patients who have undergone medial temporal lobectomy have reductions in cerebral perfusion (H 2 15 O-PET) in the thalamus and posterior cingulate cortex 95.Serial co-registered MRI showed that presymptomatic carriers of autosomal dominant ADrelated mutations have accelerated brain volume loss in both the posterior cingulate cortex and the hippocampus, however, suggesting that local pathology is an important variable 96.This interpretation is further supported by the findings of the VBM studies in MCI discussed in the previous section. These converging lines of evidence suggest that MCI, in which episodic memory impairment is the only significant cognitive deficit, is associated with damage to a restricted neural network. Aside from informing the pathophysiological evolution of early AD, these findings are also relevant to our understanding of normal episodic memory in humans. It is well known that medial temporal and diencephalic lesions can produce amnesia, but, on the basis of anatomical connectivity, it has been speculated that lesions to the posterior cingulate cortex might disrupt a crucial junction between prefrontal and medial temporal networks, thus impairing a neural pathway for retrieval of episodic memory 88.Some support for this hypothesis came from a recent study of encoding and retrieval of episodic memory in subjects with MCI, using a paradigm that varied the load on each process 97. Encoding deficits correlated with atrophy and hypometabolism in the hippocampus, whereas retrieval deficits correlated with hippocampal atrophy and posterior cingulate hypometabolism. These data are consistent with functional imaging literature in healthy subjects that indicates that activation of the posterior cingulate cortex is particularly associated with successful episodic memory retrieval 98. In addition to measurements of cerebral metabolism, functional imaging has offered insights through the development of specific ligands. The cholinergic hypothesis in AD 99 has been prominent for three decades and was the impetus to the development of cholinesterase inhibitor drug therapy. Using PET scanning with the cholinesterase tracer N-[ 11 C]methylpiperidinyl-4-propionate ([ 11 C]PMP), one group showed, in vivo, that cholinesterase activity in moderate AD is reduced. The cortical distribution of changes was homogeneous, however, and did not correlate with FDG-PET findings, suggesting that a cholinergic deficit does not drive the metabolic changes 100.Using a similar piperidyl derivative, N-[ 11 C]methylpiperidinyl-4-acetate ([ 11 C]MP4A), another group of researchers have since reported only modest reduction of cholinesterase activity in the hippocampus of MCI cases, which was not statistically different from that of controls 101.These results are consistent with recent pathological work, which indicates that cholinergic depletion might not be a major feature of very early AD 102,103.These findings are also consistent with clinical experience that the cholinesterase inhibitors do not exert a large benefit on hard cognitive measures such as episodic memory performance. Indeed, one of the studies suggested that cholinergic activity might initially be upregulated in MCI 103.Because cholinergic inputs are thought primarily to modulate attention 104, it is tempting to speculate that this upregulation might be a consequence of greater recruitment of attentional systems in an attempt to compensate for the memory deficit. This proposal has some resonance with the observation that patients with mild AD show greater activation of prefrontal cortex than controls during memory retrieval tasks 105,106,but more evidence is needed before stronger conclusions can be drawn. The latest development in functional imaging relates to the final pathological hallmark of AD amyloid plaques. All of the genetic mutations that have so far been associated with autosomal dominant AD modulate amyloid metabolism. This suggests that amyloid metabolism is an important pathogenic mechanism in AD and, as such, amyloid imaging might be an important surrogate marker for trials of disease-modifying agents. The first in vivo human study of the novel amyloid-marking tracer Pittsburgh Compound-B was recently published and suggested a similar pattern of cerebral uptake to the distribution of amyloid deposition in histopathological studies 107.Further studies evaluating the longitudinal changes in amyloid deposition and its topographical distribution in vivo are awaited with interest. In the meantime, the functional imaging data suggest that the neural basis of the earliest clinical deficits in AD are local, probably glutamatergic, cell loss in medial temporal and interconnected limbic regions such as the posterior cingulate. This pattern approximates, to some degree, the distribution of early tangle pathology. Conclusion Considerable progress has been made in recent years, in both the characterization of the cognitive profile of very early AD and its neural basis. Much work is still required, however, to clarify with greater accuracy and precision the transitional zone between healthy aging and the first manifestations of AD. At present, it is clear that individuals in the prodromal stages of AD can show marked impairments on formal memory tests, although they continue to cope independently in their normal daily routine, and that this state can persist for several years before dementia develops. Reliably distinguishing such individuals from those in whom mild cognitive deficits will remain stable over time is an important challenge for ongoing research. Another question relates to whether a symptomatic pre-mci stage can be accurately identified. For instance, individuals who are diagnosed as having MCI by current consensus criteria 19 are required to have marked memory impairment on neuropsychological testing, but this excludes the population with subjective memory symptoms not confirmed by objective measures. It seems plausible that some of this population will be show- NEURODEGENERATION JULY 2004 S39

7 ing the initial signs of dementia. Ultimately, neuropsychological measures are only semi-objective being confounded by such issues as participant motivation and, therefore, as research probes more closely at the boundary between prodromal dementia and healthy aging, there will probably be a point at which an acceptable signal-to-noise ratio cannot be attained. At this point a purely objective marker would be advantageous. Present evidence suggests that no single marker of MRI atrophy or even PET metabolic change is likely to achieve perfect discriminant value for individual subjects at this prodromal stage on a single scan. Serial co-registration of MRI 71 to identify accelerated volume loss seems to be particularly useful for predicting the fate of individual subjects but requires longitudinal imaging, possibly for >2 years, to achieve diagnostic certainty. Future work focused on novel, disease-specific, MRI sequences or PET-SPECT radioligands might offer greater predictive value. COMPETING INTERESTS STATEMENT Please cite this article as supplement to volume 5 of Nature Reviews Neuroscience, pages S34 S41. Received 6 April; accepted 21 May 2004 Published online at 1. Ritchie, K. & Lovestone, S. The dementias. Lancet 360, (2002). 2. Terry, R.D. et al. Physical basis of cognitive alterations in Alzheimer s disease: synapse loss is the major correlate of cognitive impairment. Ann. Neurol. 30, (1991). 3. Hyman, B.T., Van Hoesen, G.W., Damasio, A.R. & Barnes, C.L. Alzheimer s disease: cell-specific pathology isolates the hippocampal formation. Science 225, (1984). 4. Braak, H. & Braak, E. Neuropathological staging of Alzheimer-related changes. Acta Neuropathol. 82, (1991). 5. Arriagada, P.V., Growdon, J.H., Hedley-Whyte, E.T. & Hyman, B.T. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer s disease. Neurology 42, (1992). 6. De Lacoste, M.C. & White, C.L. The role of cortical connectivity in Alzheimer s disease pathogenesis: a review and model system. Neurobiol. Aging 14, 1 16 (1993). 7. Delacourte, A. et al. The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer s disease. Neurology 52, (1999). 8. Bondareff, W., Mountjoy, C.Q. & Roth, M. Loss of neurons of origin of the adrenergic projection to cerebral cortex (nucleus locus ceruleus) in senile dementia. Neurology 32, (1982). 9. Mann, D.M.A., Yates, P.O. & Marcyniuk, B. A comparison of changes in the nucleus basalis and locus caeruleus in Alzheimer s disease. J. Neurol. Neurosurg. Psychiatry 47, (1984). 10. Whitehouse, P.J. et al. Alzheimer s disease and senile dementia: loss of neurons in the basal forebrain. Science 215, (1982). 11. Welsh, K.A., Butters, N., Hughes, J.P., Mohs, R.C. & Heyman, A. Detection and staging of dementia in Alzheimer s disease: use of the neuropsychological measures developed for the Consortium to Establish a Registry for Alzheimer s Disease. Arch. Neurol. 49, (1992). 12. Galton, C.J., Patterson, K., Xuereb, J.H. & Hodges, J.R. Atypical and typical presentations of Alzheimer s disease: a clinical, neuropsychological, neuroimaging and pathological study of 13 cases. Brain 123, (2000). 13. Perry, R.J. & Hodges, J.R. Attention and executive deficits in Alzheimer s disease: a critical review. Brain 122, (1999). 14. Perry, R.J., Watson, P. & Hodges, J.R. The nature and staging of attention dysfunction in early (minimal and mild) Alzheimer s disease: relationship to episodic and semantic memory impairment. Neuropsychologia 38, (2000). 15. Lambon-Ralph, M.A., Patterson, K., Graham, N., Dawson, K. & Hodges, J.R. Homogeneity and heterogeneity in mild cognitive impairment and Alzheimer s disease: a cross-sectional and longitudinal study of 55 cases. Brain 126, (2003). 16. Petersen, R.C. Mild Cognitive Impairment (Oxford University Press, New York, 2003). 17. Ritchie, K. & Touchon, J. Mild cognitive impairment: conceptual basis and current nosological status. Lancet 355, (2000). 18. DeCarli, C. Mild cognitive impairment: prevalence, prognosis, aetiology, and treatment. Lancet Neurology 2, (2003). 19. Grundman, M. et al. Mild cognitive impairment can be distinguished from Alzheimer disease and normal aging for clinical trials. Arch. Neurol. 61, (2004). 20. Chertkow, H. Mild cognitive impairment. Curr. Opin. Neurol. 15, (2002). 21. Folstein, M.F., Folstein, S.E. & McHugh, P.R. Mini-mental state. A practical method for grading the cognitive state of patients for the clinician. J. Psychiatr. Res. 12, (1975). 22. Morris, J.C. et al. Mild cognitive impairment represents early-stage Alzheimer disease. Arch. Neurol. 58, (2001). 23. Petersen, R.C. et al. Practice parameter: early detection of dementia: mild cognitive impairment (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 56, (2001). 24. Celsis, P. Age-related cognitive decline, mild cognitive impairment or preclinical Alzheimer s disease? Ann. Med. 32, 6 14 (2000). 25. Ritchie, K., Artero, S. & Touchon, J. Classification criteria for mild cognitive impairment a population-based validation study. Neurology 56, (2001). 26. Blennow, K. & Hampel, H. CSF markers for incipient Alzheimer s disease. Lancet Neurology 2, (2003). 27. Fuld, P.A., Masur, D.M., Blau, A.D., Crystal, H. & Aronson, M.K. Object-memory evaluation for prospective detection of dementia in normal functioning elderly: predictive and normative data. J. Clin. Exp. Neuropsychol. 12, (1990). 28. Linn, R.T. et al. The preclinical phase of probable Alzheimer s disease: a 13- year prospective study of the Framingham cohort. Arch. Neurol. 52, (1995). 29. Masur, D.M., Sliwinski, M., Lipton, R.B., Blau, A.D. & Crystal, H.A. Neuropsychological prediction of dementia and the absence of dementia in healthy elderly persons. Neurology 44, (1994). 30. Rubin, E.H. et al. A prospective study of cognitive function and onset of dementia in cognitively healthy elders. Arch. Neurol. 55, (1998). 31. Chen, P. et al. Cognitive tests that best discriminate between presymptomatic AD and those who remain nondemented. Neurology 55, (2000). 32. Orgogozo, J.M., Fabrigoule, C., Rouch, I., Amieva, H. & Dartigues, J.F. Prediction and early diagnosis of Alzheimer s disease with simple neuropsychological tests. Int. J. Geriatr. Psychopharmacol. 2, (2000). 33. Fabrigoule, C. et al. Cognitive process in preclinical phase of dementia. Brain 121, (1998). 34. Fox, N.C., Warrington, E.K., Seiffer, A.L., Agnew, S.K. & Rossor, M.N. Presymptomatic cognitive deficits in individuals at risk of familial Alzhiemer s disease: a longitudinal prospective study. Brain 121, (1998). 35. Tierney, M.C. et al. Prediction of probable Alzheimer s disease in memoryimpaired patients a prospective longitudinal study. Neurology 46, (1996). 36. Albert, M.S., Moss, M.B., Tanzi, R. & Jones, K. Preclinical prediction of AD using neuropsychological tests. J. Int. Neuropsychol. Soc. 7, (2001). 37. Devanand, D.P., Folz, M., Gorlyn, M., Moeller, J.R. & Stern, Y. Questionable dementia: clinical course and predictors of outcome. J. Am. Geriatr. Soc. 45, (1997). 38. Flicker, C., Feris, S. & Reisberg, B. Mild cognitive impairment in the elderly: predictors of dementia. Neurology 41, (1991). 39. Thompson, S.A., Graham, K.S., Patterson, K., Sahakian, B.J. & Hodges, J.R. Is knowledge of famous people disproportionately impaired in patients with early Alzheimer s disease? Neuropsychology 16, (2002). 40. Delazer, M., Semenza, C., Reiner, M., Hofer, R. & Benke, T. Anomia for people names in DAT evidence for semantic and post semantic impairments. Neuropsychologia 41, (2003). 41. Estevez-Gonzalez, A. et al. Semantic knowledge of famous people in mild cognitive impairment and progression to Alzheimer s disease. Dement. Geriatr. Cogn. Disord. 17, (2004). 42. Swainson, R. et al. Early detection and differential diagnosis of Alzheimer s disease and depression with neuropsychological tasks. Dement. Geriatr. Cogn. Disord. 12, (2001). 43. Blackwell, A.D. et al. Detecting dementia: novel neuropsychological markers of pre-clinical Alzheimer s disease. Dement. Geriatr. Cogn. Disord. 17, (2004). 44. Fowler, K.S., Saling, M.M., Conway, E.L., Semple, J.M. & Louis, W.J. Computerized delayed matching to sample and paired associate performance in the early detection of dementia. Appl. Neuropsychol. 2, (1995). 45. Fowler, K.S., Saling, M.M., Conway, E.L., Semple, J.M. & Louis, W.J. Computerized neuropsychological tests in the early detection of dementia: prospective findings. J. Int. Neuropsychol. Soc. 3, (1997). 46. Lee, A.C.H., Rahman, S., Hodges, J.R., Sahakian, B. & Graham, K.S. Associative and recognition memory for novel objects in dementia: implications for diagnosis. Eur. J. Neurosci. 18, (2003). 47. Perry, R.J. & Hodges, J. Attentional control and the time course of attention in mild cognitive impairment measurement of attentional dwell time. Eur. J. Neurosci. 18, (2003). 48. Darby, D., Maruff, P., Collie, A. & McStephen, M. Mild cognitive impairment can be detected by multiple assessments in a single day. Neurology 59, (2002). 49. Dwolatzky, T. et al. Validity of a novel computerized cognitive battery for mild cognitive impairment. BMC Geriatr. 3, 4 (2003). 50. Du, A. et al. Magnetic resonance imaging of the entorhinal cortex and hippocampus in mild cognitive impairment and Alzheimer s disease. J. Neurol. Neurosurg. Psychiatry 71, (2001). 51. Jack, C.R.J. et al. Antemortem MRI findings correlate with hippocampal neuropathology in typical aging and dementia. Neurology 58, (2002). 52. Jack, C.R.J. et al. Medial temporal atrophy on MRI in normal ageing and very mild Alzheimer s disease. Neurology 49, (1997). 53. Killiany, R.J. et al. Use of structural magnetic resonance imaging to predict who will get Alzheimer s disease. Ann. Neurol. 47, (2000). S40 JULY 2004 NEURODEGENERATION

8 54. Scheltens, P., Fox, N., Barkhof, F. & De Carli, C. Structural magnetic resonance imaging in the practical assessment of dementia: beyond exclusion. Lancet Neurol. 1, (2002). 55. Killiany, R.J. et al. MRI measures of entorhinal cortex vs hippocampus in preclinical AD. Neurology 58, (2002). 56. Jack, C.R., Jr. et al. Prediction of AD with MRI-based hippocampal volume in mild cognitive impairment. Neurology 52, (1999). 57. Visser, P.J. et al. Medial temporal lobe atrophy and memory dysfunction as predictors for dementia in subjects with mild cognitive impairment. J. Neurol. 246, (1999). 58. Visser, P.J., Verhey, F.R., Hofman, P.A., Scheltens, P. & Jolles, J. Medial temporal lobe atrophy predicts Alzheimer s disease in patients with minor cognitive impairment. J. Neurol. Neurosurg. Psychiatry 72, (2002). 59. Dickerson, B.C. et al. MRI-derived entorhinal and hippocampal atrophy in incipient and very mild Alzheimer s disease. Neurobiol. Aging 22, (2001). 60. Braak, H. & Braak, E. Evolution of the neuropathology of Alzheimer s disease. Acta Neurolog. Scand. 165, 3 12 (1996). 61. Xu, Y. et al. Usefulness of MRI measures of entorhinal cortex versus hippocampus in AD. Neurology 54, (2000). 62. Goncharova, I.I., Dickerson, B.C., Stoub, T.R. & detoledo-morrell, L. MRI of human entorhinal cortex: a reliable protocol for volumetric measurement. Neurobiol. Aging 22, (2001). 63. Scheltens, P. et al. Atrophy of medial temporal lobes on MRI in probable Alzheimer s disease and normal ageing: diagnostic value and neuropsychological correlates. J. Neurol. Neurosurg. Psychiatry 55, (1992). 64. Galton, C.J. et al. The temporal lobe rating scale: application to Alzheimer s disease and frontotemporal dementia. J. Neurol. Neurosurg. Psychiatry 70, (2001). 65. De Leon, M.J. et al. Measurement of medial temporal lobe atrophy in diagnosis of Alzheimer s disease. Lancet 341, (1993). 66. De Leon, M.J. et al. The radiologic prediction of Alzheimer disease: the atrophic hippocampal formation. Am. J. Neuroradiol. 14, (1993). 67. Korf, E.S.C., Wahlund, L.O., Visser, P.J. & Scheltens, P. Medial temporal lobe atrophy on MRI predicts dementia in subjects with mild cognitive impairment. Neurology (2004), in the press. 68. Graham, J.E. et al. Prevalence and severity of cognitive impairment with and without dementia in an elderly population. Lancet 349, (1997). 69. Di Carlo, A. et al. Cognitive impairment without dementia in older people: prevalence, vascular risk factors, impact on disability. The Italian Longitudinal Study on Ageing. J. Am. Geriatr. Soc. 48, (2000). 70. Petersen, R.C. et al. Apolipoprotein E status as a predictor of the development of Alzheimer s disease in memory-impaired individuals. JAMA 273, (1995). 71. Fox, N.C., Freeborough, P.A. & Rossor, M.N. Visualisation and quantification of rates of atrophy in Alzheimer s disease. Lancet 348, (1996). 72. Scahill, R.I. et al. A longitudinal study of brain volume changes in normal aging using serial registered magnetic resonance imaging. Arch. Neurol. 60, (2003). 73. Schott, J.M. et al. Assessing the onset of structural change in familial Alzheimer s disease. Ann. Neurol. 53, (2003). 74. Jack, C.R.J. et al. Comparison of different MRI brain atrophy rate measures with clinical disease progression in AD. Neurology 62, (2004). 75. Rombouts, S.A., Barkhof, F., Witter, M.P. & Scheltens, P. Unbiased whole-brain analysis of gray matter loss in Alzheimer s disease. Neurosci. Lett. 285, (2000). 76. Chetelat, G. et al. Mapping gray matter loss with voxel-based morphometry in mild cognitive impairment. Neuroreport 13, (2002). 77. Van der Flier, W.M. et al. Cognitive decline in AD and mild cognitive impairment is associated with global brain damage. Neurology 59, (2002). 78. Wolf, H. et al. A critical discussion of the role of neuroimaging in mild cognitive impairment. Acta Neurolog. Scand. Suppl.179, (2003). 79. Fukuyama, H. et al. Coronal reconstruction images of glucose metabolism in Alzheimer s disease. J. Neurol. Sci. 106, (1991). 80. Ishii, K. et al. Relatively preserved hippocampal glucose metabolism in mild Alzheimer s disease. Dement. Geriatr. Cogn. Disord. 9, (1998). 81. Ishii, K., Kitagaki, H., Kono, M. & Mori, E. Decreased medial temporal oxygen metabolism in Alzheimer s diseasse shown by PET. J. Nucl. Med. 37, (1996). 82. Jagust, W.J. et al. The cortical topography of temporal lobe hypometabolism in early Alzheimer s disease. Brain Res. 629, (1993). 83. Ouchi, Y. et al. Altered glucose metabolism in the hippocampal head in memory impairment. Neurology (1998). 84. Minoshima, S. et al. Metabolic reduction in the posterior cingulate cortex in very early Alzheimer s disease. Ann. Neurol. 42, (1997). 85. Kogure, D. et al. Longitudinal evaluation of early Alzheimer s disease using brain perfusion SPECT. J. Nucl. Med. 41, (2000). 86. Johnson, K.A. et al. Preclinical prediction of Alzheimer s disease using SPECT. Neurology 50, (1998). 87. Huang, C., Wahlund, L.O., Svensson, L., Winblad, B. & Julin, P. Cingulate cortex hypoperfusion predicts Alzheimer s disease in mild cognitive impairment. BMC Neurol. 2, 9 (2002). 88. Nestor, P.J., Fryer, T.D., Ikeda, M. & Hodges, J.R. Retrosplenial cortex ( BA29/30) hypometabolism in mild cognitive impairment (prodromal Alzheimer s disease). Eur. J. Neurosci. 18, (2003). 89. Chetelat, G. et al. Mild cognitive impairment. Can FDG-PET predict who is to rapidly convert to Alzheimer s disease? Neurology 60, (2003). 90. Drzezga, A. et al. Cerebral metabolic changes accompanying conversion of mild cognitive impairment into Alzheimer s disease: a PET follow-up study. Eur. J. Nucl. Med. Mol. Imaging 30, (2003). 91. Arnaiz, E. et al. Impaired cerebral glucose metabolism and cognitive functioning predict deterioration in mild cognitive impairment. Neuroreport 12, (2001). 92. De Santi, S. et al. Hippocampal formation glucose metabolism and volume losses in MCI and AD. Neurobiol. Aging 22, (2001). 93. Nestor, P.J., Fryer, T.D., Smielewski, P. & Hodges, J.R. Limbic hypometabolism in Alzheimer s disease and mild cognitive impairment. Ann. Neurol. 54, (2003). 94. Kadekaro, M., Crane, A.M. & Sokoloff, L. Differential effects of electrical stimulation of sciatic nerve on metabolic activity in spinal cord and dorsal root ganglion in the rat. Proc. Natl. Acad. Sci. USA 82, (1985). 95. Minoshima, S., Cross, D.J., Foster, N.L., Henry, T.R. & Kuhl, D.E. Discordance between traditional pathologic and energy metabolic changes in very early Alzheimer s disease. Pathophysiological implications. Ann. NY Acad. Sci. 893, (1999). 96. Scahill, R.I., Schott, J.M., Stevens, J.M., Rossor, M.N. & Fox, N.C. Mapping the evolution of regional atrophy in Alzheimer s disease: unbiased analysis of fluidregistered serial MRI. Proc. Natl. Acad. Sci. USA 99, (2002). 97. Chetelat, G. et al. Dissociating atrophy and hypometabolism impact on episodic memory in mild cognitive impairment. Brain 126, (2003). 98. Cabeza, R. & Nyberg, L. Imaging cognition II: an empirical review of 275 PET and fmri studies. J. Cogn. Neurosci. 12, 1 47 (2000). 99. Francis, P.T., Palmer, A.M., Snape, M. & Wilcock, G.K. The cholinergic hypothesis of Alzheimer s disease: a review of progress. J. Neurol. Neurosurg. Psychiatry 66, (1999) Kuhl, D.E. et al. In vivo mapping of cerebral acetylcholinesterase activity in aging and Alzheimer s disease. Neurology 52, (1999) Rinne, J.O. et al. Brain acetylcholinesterase activity in mild cognitive impairment and early Alzheimer s disease. J. Neurol. Neurosurg. Psychiatry 74, (2003) Tiraboschi, P. et al. The decline in synapses and cholinergic activity is asynchronous in Alzheimer s disease. Neurology 55, (2000) DeKosky, S.T. et al. Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment. Ann. Neurol. 51, (2002) Sarter, M., Bruno, J.P. & Givens, B. Attentional functions of cortical cholinergic inputs: what does it mean for learning and memory? Neurobiol. Learn. Mem. 80, (2003) Backman, L. et al. Brain regions associated with episodic retrieval in normal aging and Alzheimer s disease. Neurology 52, (1999) Becker, J.T. et al. Compensatory reallocation of brain resources supporting verbal episodic memory in Alzheimer s disease. Neurology 46, (1996) Klunk, W.E. et al. Imaging brain amyloid in Alzheimer s disease with Pittsburgh Compound-B. Ann. Neurol. 55, (2004). NEURODEGENERATION JULY 2004 S41