British Medical Bulletin 65:159-168 (2003)
© 2003 Oxford University Press
Dementia and ageing
Imaging in clinical neuroscience
Catriona D Good
Wellcome Department of Cognitive Neurology, Institute of Neurology, University College London, London, UK
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Abstract
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Sophisticated imaging techniques are required to characterise
the complex dynamic neuro-anatomical changes that occur over
time in health and disease. With the advent of potential therapies
for the treatment of degenerative dementias, imaging strategies
need to enable early diagnosis and facilitate monitoring of
disease progression in treatment trials. This chapter highlights
some of the innovative structural and functional imaging techniques
that have impacted on the clinical management of Alzheimer's
disease.
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Introduction
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Alzheimer's disease is one of the most common terminal illnesses
amongst ageing populations, and its prevalence continues to
increase along with increased human life expectancy. This disease
compromises memory, personality and independence of a substantial
sector of the ageing community and impacts severely on families
and national health budgets. Early diagnosis is a key problem
with this disease. A definitive diagnosis relies on
post mortem assessment, and a presumptive clinical diagnosis is usually
delayed owing to the incipient presentation of Alzheimer's disease
in later life that may be particularly difficult to distinguish
from normal ageing. The two chief pathological hallmarks of
Alzheimer's disease – neurofibrillary tangles and neuritic
amyloid plaques – occur frequently in non-demented ageing
brains, and their number increases with age. Furthermore, their
distribution in elderly brains, matches the hierarchical vulnerability
exhibited in Alzheimer's disease. Such observations have fuelled
controversy about whether ageing and Alzheimer's disease lie
at two ends of a continuous spectrum or whether they are truly
separate entities.
Despite the prevalence of Alzheimer's disease, the current treatment options remain limited for sufferers, so there is a great demand to enable timely detection and monitoring of the disease in its earliest phases, particularly in presymptomatic, genetically at-risk individuals, so that new putative treatment strategies to be tested. In vivo brain structural imaging has an established role in the evaluation and monitoring of neuro-anatomical changes in Alzheimer's disease, acting as a surrogate marker for the underlying histopathological changes and, by inference, disease progression. But identification of individual patients in the earliest phases of the disease remains a challenge due to the overlap between the dynamic imaging appearances of normal ageing and early pathology. This is because complex interindividual variations in cerebral anatomy make it difficult to quantify individual patterns of atrophy against a normative population. With the development of a number of sophisticated imaging strategies, a clearer picture of the patterns of atrophy in physiological ageing and dementia is now possible. This chapter will highlight some of the most important imaging techniques that have allowed advances in clinical diagnosis and management of Alzheimer's disease, but such advances will obviously apply to the broader group of dementias.
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Methodological considerations
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Most imaging studies of the neuro-anatomical changes in ageing
and dementia have been cross-sectional in design,
i.e. studying
a group of subjects of different ages at one time point. Cross-sectional
studies are practical to implement and can accommodate wide
age spectra and large study groups, but have inherent drawbacks.
Firstly, dynamic effects are not actually measured, but are
inferred from measured differences between age cohorts. Secondly,
systematic differences between age cohorts such as differences
in body size (and corresponding brain size) can potentially
reflect spuriously as age-related effects. For example, body
size has increased over the past century, so younger cohorts
will have spuriously larger brains for age than elderly cohorts).
In order to model dynamic change properly, a longitudinal study
is required, where a group of individuals are followed over
time. For practical reasons such studies are generally limited
to very short time windows
1
and small study groups
2.
Structural scanning techniques have advanced considerably over the past decade, and high resolution volumetric magnetic resonance imaging (MRI) sequences are now the required norm for brain morphometry. Measurement techniques vary considerably making comparisons between laboratories difficult. Broadly speaking, there are two main approaches to the measurement of local brain structures: Region of interest (ROI) approaches are based upon the a priori definition of specific brain regions by skilled anatomists. Whole brain approaches involve sophisticated warping algorithms to map brains into a common anatomical framework followed by voxel-wise analysis of anatomical maps. The latter approach allows appraisal of all brain structures and does not require a priori assumptions. ROI-based approaches are the current gold standard, but are extremely laborious and are subject to inter-and intrarater variability. Whole brain approaches, of which there are many hybrids, have been introduced more recently and offer a number of advantages not least because they are semi or fully automated, and thus reproducible and applicable to large groups for cross-sectional and longitudinal studies. The simplest methods apply rigid body registration within a single subject over time to provide information about global change2. Less constrained non-linear registrations can also be used within subject over time to characterise local deformations3,4.
To make meaningful regional comparisons between brains from groups of subjects, confounding factors such as extrinsic differences (e.g. head position and orientation) and intrinsic differences (e.g. brain size and shape and gyral variability) need to be catered for. To achieve this, more sophisticated brain mapping models are required. These involve complex linear or non-linear registrations to map multiple images into a common stereotaxic space enabling region-by-region comparisons in cross-sectional or longitudinal studies followed by robust statistical analyses. At one end of the spectrum, methods that aim to match global brain shapes are relatively quick and easy to perform. At the other end of the spectrum, methods that aim to align gyri and sulci precisely employ very high dimensional warping algorithms that are computer intensive and relatively time consuming. An example of the former method is voxel-based morphometry (VBM)5,6. This is a fully automated technique that maps brain images to a template in stereotaxic space followed by voxel-wise statistical analysis of the spatial distributions of grey matter, white matter and CSF. An example of the latter method is precise cortical mapping and generation of probabilistic brain cortical atlases7–9.
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Neuro-anatomical changes in ageing
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There is convincing evidence from cross-sectional and longitudinal
structural MR imaging studies that the brain shrinks with age.
There is also general consensus that there is age-related shrinkage
of the grey matter compartment with concomitant increase of
the cerebrospinal fluid (CSF) space. It is less clear whether
the white matter compartment declines globally with age, although
recent work suggests that cerebral white matter volume appears
to remain relatively stable until age 70 years, after which
the decline is rapid
10. Several researchers have shown an interaction
of sex with ageing, with accelerated decline in global grey
matter in males compared with females
11. Reports of regionally
specific effects of ageing are generally limited and more conflicting,
predominantly because of the wide variety of imaging and measurement
techniques used. Two recent morphometry reports of age-related
hippocampal changes highlight this problem. One group using
a semi-automated brain segmentation technique followed by ROI
measurements shows accelerated hippocampal volume loss relative
to grey matter losses elsewhere in the brain
10 whereas another
group using a fully automated whole brain technique (VBM) showed
relative preservation of hippocampal, amygdala and entorhinal
cortex volume with ageing, and accelerated ageing bilaterally
in pre- and post-central gyri (
Plate VII see p.xii), superior
parietal gyri, insula, central and cingulate sulci
12. Clearly,
such discordance about physiological, age-related changes in
the normal hippocampus impacts on the appreciation of pathological
changes in this structure which is consistently implicated in
Alzheimer's disease. Reports of regionally specific white matter
changes with ageing are scanty, but there is recent evidence
for accelerated volume loss (over and above global white matter
loss) bilaterally in frontal white matter, optic radiations,
and posterior limbs of the internal capsule and relative preservation
bilaterally in the posterior frontal lobes, right temporal lobe
and cerebellum
11. The implications of these regional white matter
effects are not yet understood, but it is likely that more specialised
imaging techniques such as diffusion tensor imaging (DTI) will
characterise more precisely white matter tracts in ageing and
disease. There is general consensus from ROI-based studies that
the ventricles and sulci enlarge with age, but VBM now also
reveals accelerated age-related enlargement of the chiasmatic
and supracerebellar cisterns, cisterna magna, third ventricle
and the Sylvian and interhemispheric fissures (
Plate. VIII see
p.xii) with relatively little enlargement of the pontine cistern,
including its caudal extent around the medulla. Innovative work
by Thompson and colleagues
7,12 now allows further understanding
of the complex neuro-anatomy of normal elderly brains with three
dimensional probabilistic maps of the major sulci. These cortical
maps encode the parameters of normal anatomical variation revealing
its regional heterogeneity and asymmetries, thus providing a
canonical framework against which diseased populations can be
compared.
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Plate VII Regionally specific effects of ageing detected with VBM. Accelerated grey matter loss (over and above global grey matter loss) with age (depicted in green) is seen in the pre- and post-central gyri. Relative preservation of grey matter with age (depicted in red) is seen in the mesial temporal lobes and thalami.
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Plate VIII Regionally specific effects of ageing on the CSF compartment detected with VBM. Accelerated expansion of the CSF space (over and above global CSF expansion) with age is seen in Sylvian and interhemispheric fissures, chiasmatic and supracerebellar cisterns, cisterna magna and third ventricle.
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Neuro-anatomical changes in dementia
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There is a large body of structural imaging literature on the
anatomical changes observed in Alzheimer's disease. Most reports
have been based on cross-sectional studies using CT or MRI and
ROI-based measurements of mesial temporal structures. The majority
of these studies report volume loss in the hippocampi and entorhinal
cortex in Alzheimer's disease relative to controls. Such studies
have some inherent drawbacks. Firstly, measurements are based
upon a limited number of regions according to
a priori assumptions
of their involvement in Alzheimer's disease, whilst precluding
assessment of other brain structures. This explains the focused
attention to the measurement of mesial temporal structures in
Alzheimer's disease with the exclusion of posterior structures
such as parietal and posterior cingulate cortex (which are consistently
implicated in functional studies of resting glucose metabolism,
even in presymptomatic individuals at genetic risk for Alzheimer's
disease). Secondly, because of the wide physiological variation
in interindividual neuro-anatomy, subtle pathological changes
can be easily missed. Certain brain regions (such as the left
peri-Sylvian language cortex) exhibit great spatial variability.
In order to reveal early pathological change within such regions
as well as distinguishing pathological asymmetries from physiological
asymmetries, specialised registration approaches are needed.
It is now possible to create accurate three dimensional hippocampal
maps using high dimensional non-linear warping methods. These
maps encode the physiological variability in normal subjects
and can discriminate mild Alzheimer's disease from age-matched
controls
13,14. A few groups have applied whole brain morphometric
techniques to characterise the patterns of atrophy in groups
of Alzheimer's disease patient more accurately. Voxel-based
morphometry (VBM) confirms mesial temporal atrophy in patients
with mild Alzheimer's disease
15, but also shows symmetric posterior
cingulate and precuneus atrophy as well as asymmetric (left
more than right) atrophy in the angular gyrus, peri-Sylvian
and frontal cortices
16. A recent VBM study of moderately affected
Alzheimer's disease patients shows predominant posterior cingulate
and precuneus atrophy. Within the temporal lobes, the inferior
and lateral temporal structures appeared more affected than
mesial structures
17. Using accurate cortical mapping techniques,
Thompson and co-workers have created detailed, population-based
maps of cortical grey matter loss in Alzheimer's disease
12.
Their method allows the mathematical separation of variations
in gyral patterns from early pathological changes, revealing
greatest grey matter reductions in the temporoparietal cortices.
In addition, they show exaggerated Sylvian fissure asymmetry
in Alzheimer's disease patients compared to controls.
Longitudinal studies of Alzheimer's disease offer some distinct advantages over cross-sectional studies, not only because dynamic changes can be monitored, but also because subjects can be used as their own controls. In this way, subtle pathological changes within individuals are not masked by wide physiological variability. A number of important studies by Fox and co-workers have shown a clear distinction between the rates of atrophy in patients with Alzheimer's disease compared to controls3,18–24. Importantly, they have shown quantifiable rates of atrophy in presymptomatic patients at risk for Alzheimer's disease. Their earlier studies used sub-voxel linear co-registration and digital subtraction of serial MRI scans. This rigid body co-registration technique allows the quantification of whole brain atrophy (Plate IX see p xiii) and they show global volume loss of 5–20 ml/year in patients versus 2 ml/year in controls. However, local pathological deformations in small complex structures such as the hippocampus cannot be accurately mapped with linear registration. Less constrained, non-linear warping techniques are required. More recently, they have used non-linear registration methods based on a compressible viscous fluid model to characterise local pathological shape deformations in Alzheimer's disease (Plate IXB see p.xiii). Importantly, they have documented the evolution of pathological changes from presymptomatic, at-risk individuals to mild and moderately affected Alzheimer's disease patients (Plate X see p.xiv). They demonstrate significantly increased rates of precuneus and posterior cingulate atrophy in all stages of Alzheimer's disease, with increased rates of atrophy with increasing disease severity. The pattern of temporal lobe atrophy varies with the stage of disease. In presymptomatic individuals and mildly affected patients, significant rates of volume loss are seen in the hippocampi. However, in mild and moderately severe Alzheimer's disease, the distribution of temporal atrophy shifts from mesial structures to inferolateral structures24. It thus appears that precuneus and posterior cingulate atrophy may be useful surrogate markers of disease progression throughout the course of Alzheimer's disease, with hippocampal atrophy being a useful index for the early stages.
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Plate IX Rigid body registration (A) and fluid registration (B) of serial brain MRIs of a 48-year-old male familial Alzheimer's disease subject after an interval of 2 years. In (A), red represents tissue loss and green tissue gain. In (B), red and yellow represent expansion, green and blue represent contraction. There is evidence of diffuse tissue loss throughout the brain. Reproduced with kind permission from the Dementia Unit, Institute of Neurology, University College London, UK.
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Structural imaging can thus characterise the macroscopic neuro-anatomical
sequelae of the underlying pathological process in some detail;
however, different strategies are needed to gain insight into
the pathological changes at a neuronal level. A variety of specialised
imaging techniques can now inform about brain functional parameters
such as regional cerebral perfusion and diffusion properties,
neurochemical receptor distributions, regional glucose metabolism,
local tissue biochemistry and the response of brain regions
to specific tasks. By using a multimodal imaging approach, functional
information can be refined with accurate structural localisation
to understand more about the underlying pathophysiology of dementia.
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Functional imaging
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In Alzheimer's disease, cerebral perfusion studies with single
photon emission computed tomography (SPECT) and MRI consistently
show reduced cerebral blood flow first in the posterior cingulate
and precuneus, even in presymptomatic subjects with the apolipoprotein
E (APOE) genotype
25–27. As the disease progresses, flow
reductions are seen in the temporoparietal association cortices
and medial temporal structures. This pattern is mirrored with
PET studies of glucose metabolism
28,29. Magnetisation transfer
imaging (MTI) is a specialised MR sequence that informs about
the integrity of cell membranes. This technique appears to be
more sensitive to distributed tissue damage than routine MRI
sequences in a number of neurological diseases such as multiple
sclerosis, systemic lupus erythematosus and schizophrenia
30–32.
In Alzheimer's disease patients, magnetisation transfer ratio
measurements from grey matter are reduced relative to controls,
correlating with cognitive impairment
33,34. Diffusion tensor
imaging informs about diffusion properties of brain tissue and,
in particular, the integrity of white matter tracts. Patients
with probable Alzheimer's disease show a significant reduction
in the integrity of the association white matter fibre tracts,
such as the splenium of the corpus callosum, superior longitudinal
fasciculus, and cingulum, but preservation of the pyramidal
tracts. This finding is consistent with the clinical presentation
of Alzheimer's disease, in which global cognitive decline is
a more prominent feature than motor disturbance
35. The mean
diffusivity of grey matter is also altered in Alzheimer's disease
patients
34.
Another strategy for investigating the pathophysiology of Alzheimer's disease is to image the brain after specific cells or chemicals have been labelled with radioligands. For example, amyloid ligands (such as [125I]-TZDM, 2-(4'-dimethylaminophenyl)-6-iodobenzothiazole, a thioflavin derivative or [125I]-IBOX, 3,2-(4'-dimethylaminophenyl)-6-iodobenzoxazole) can inform about the overproduction and accumulation of ß-amyloid plaques in the brains of Alzheimer's disease patients36. Activated microglia have a key role in the brain's immune response to neuronal degeneration. Quantitative in vivo measurements of glial activation can be obtained with PET and a specific ligand for the peripheral benzodiazepine binding site ([11C]-(R)-PK11195). Alzheimer's disease patients show increased regional binding in the entorhinal, temporoparietal, and cingulate cortex, suggesting that microglial activation is an early event in the pathogenesis of the disease37.
Magnetic resonance spectroscopy (MRS) allows the assessment of the biochemical composition of brain tissue in vivo and provides information about the neurochemistry of Alzheimer's disease. Proton MRS consistently shows decreased NAA (marker of neuronal density) and increased myo-inositol (sugar alcohol similar in structure to glucose which may act as a marker of glial cell numbers) in the occipital, temporal, parietal and frontal regions in patients with Alzheimer's disease, even at the early stages of the disease. The NAA/MI ratio in patients with Alzheimer's disease has been shown to correlate significantly with Mini Mental State Examination (MMSE) scores. Phosphorus MRS allows the assessment of high-energy chemicals involved in oxidative metabolism in the brain. Initial studies of post mortem Alzheimer's disease brain tissue showed increases in cell membrane phosphomonoesters and phosphodiesters (indicators of ATP levels) compared with normals. The few in vivo clinical studies have so far produced mixed reports; however, there are suggestions that in early and possibly presymptomatic Alzheimer's disease phosphocreatine levels decline and phosphomonoester levels rise, and these phosphorus metabolite levels normalise with disease progression38.
Activation studies in demented patients provide technical challenges, but PET and fMRI have been feasible and indicate differences in neural metabolism and activity between carriers of the APOE 
4 allele and those who are not at risk for Alzheimer's disease. Persons without dementia carrying the 4 allele showed greater magnitude and extent of brain activation than non-carriers in regions required for memory, suggesting they performed additional cognitive work to accomplish the same task39.
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Conclusions
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At present, no imaging modality is considered the standard diagnostic
test for Alzheimer's disease, particularly for the individual
case. With the considerable advances in medical imaging techniques
and computational power over the last few years, accurate brain
mapping is now possible. By using a multimodal imaging approach,
functional information can now be mapped with anatomical precision,
providing a greater understanding of the dynamic pathological
processes in dementia. With the concomitant advances in gene
mapping, asymptomatic but genetically at risk individuals can
now be identified. This group offers the greatest hope for potential
disease modifying agents, and neuroimaging will continue to
play a major role as a surrogate marker for disease progression
in treatment trials.
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Key points for clinical practice
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- An understanding of the complex dynamic neuro-anatomical changes in physiological ageing is fundamental to the appreciation of pathological changes
- High-resolution, three dimensional MRI is the required norm for brain morphometry
- Whilst brain imaging may be useful for clinical diagnosis in the dementias, subtle pathological structural changes are easy to miss because of the wide overlap with normality
- Brain imaging plays an important role as a surrogate marker for disease progression in treatment trials
- Sophisticated brain mapping techniques are required to compare groups of diseased brains with controls
- Longitudinal studies are the optimal method to characterise the dynamic neuro-anatomical correlates of disease, but such studies are often limited to short time-windows because of practical issues
- Multimodal structural and functional imaging mapped to the same anatomical framework allows the most comprehensive characterisation of pathological processes in the brain
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Footnotes
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Correspondence to: Dr Catriona Good, Wellcome Department of
Cognitive Neurology, 12 Queen Square, London WC1N 3BG, UK
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Abstract
Introduction
