American Journal of Neuroradiology 26:2488-2491, November-December 2005
© 2005 American Society of Neuroradiology
BRAIN
Multiple Sclerosis and Alzheimer Disease through the Looking Glass of MR Imaging
Giovanni B. Frisonia and
Massimo Filippib
a Laboratory of Epidemiology NeuroImaging and TeleMedicine, IRCCS San Giovanni di Dio FBF, Brescia, and Associazione Fatebenefratelli per la Ricerca, Rome, Italy
b Neuroimaging Research Unit, Department of Neurology, Scientific Institute and University Ospedale San Raffaele, Milan, Italy
Address correspondence to Massimo Filippi, MD, Neuroimaging Research Unit, Department of Neurology, Scientific Institute and University Ospedale San Raffaele, via Olgettina 60, 20132 Milan, Italy
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Introduction
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MR imaging has led to a profound shift of perspective in many
central nervous system conditions. In epilepsy, quantitative
evidence of hippocampal volume loss by MR imaging has been highly
correlated with seizure onset in medial temporal structures
(
1); in stroke, it has enabled detection of the earliest structural
changes and targeting of patients for thrombolysis (
2); and
in brain tumors, it has allowed unprecedented, accurate preoperative
work-up (
3). The field in which MR imaging has contributed most
to shape current knowledge about the mechanisms leading to irreversible
disability and, as a consequence, the identification of effective
treatment, however, is perhaps multiple sclerosis (MS) and allied
white matter diseases.
MR imaging also holds substantial promise to improve our understanding of Alzheimer disease (AD). Unfortunately, although the first attempts to image the typical medial temporal lobe damage of AD date back to 1992 (4, 5), little progress has since been made in other likely relevant aspects of the disease. Although it is believed that, by the time patients meet a diagnosis of AD, tissue damage has already spread from the medial temporal lobe to all neocortical regions (6), only recently in vivo changes of the most affected neocortical areas (ie, the temporoparietal junction and the posterior cingulate cortex) have been quantified by using MR imaging (7, 8). As a consequence, the detection of predementia changes by MR imaging is still a matter of active research (9). Moreover, although one of the 2 pathologic hallmarks of AD (neurofibrillary tangles, the other being senile plaques) is intracytoplasmic and is believed to disrupt axonal transport (10), white matter damage specific to AD has been only marginally investigated by using MR imaging. Finally, the ability of MR imaging to detect brain tissue loss in AD with great precision (7) has been used well below its potential to assess the efficacy of disease-modifying drugs in AD. In the following report, major advances in understanding the pathophysiology of MS through the use of MR imaging are discussed briefly and compared with what is currently being done in AD (Table).
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Understanding Disease Pathophysiology
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There is an increasing body of evidence derived from both postmortem
(
11–
13) and quantitative MR imaging (
14–
16) studies
indicating that (a) MS is not simply the result of inflammatory
demyelination, but that prominent neurodegeneration also occurs
(
13); (b) neurodegeneration starts very early in the course
of the disease (
14); and (c) inflammatory demyelination and
neuroaxonal loss are only partially associated (
14). Both of
these 2 pathologic aspects of the disease contribute to the
development of patients’ symptoms and disability (
17).
Similarly, AD neuropathology features not only neurodegeneration, but also inflammation. Positron-emission tomography (PET) and pathologic studies have shown that microglial activation is an important aspect of AD pathology (18, 19), which might develop as a reaction to amyloid deposition and is associated to the subsequent loss of cerebral tissue (20). Although these observations support the notion that inflammation might be a therapeutic target in AD (21), whether inflammation in AD is harmful or protective by promoting amyloid clearance (20) remains unclear. In light of its sensitivity to inflammatory changes and its noninvasivity, a more extensive use of modern MR imaging technology (eg, cellular MR imaging and perfusion MR imaging) is warranted to achieve a better understanding of the role of inflammation in AD.
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Diffuse Structural Tissue Damage
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MS causes not only focal, T2-visible white matter lesions, which
represent the "tip of the iceberg," but also diffuse white matter
pathology, which is undetected by conventional MR imaging. This
"occult" component of MS pathology has been shown in all MS
phenotypes (
22), including patients presenting with clinically
isolated syndromes (CIS) suggestive of MS (
15,
23). The extent
of these occult abnormalities has been found to correlate better
than the burden of focal lesions to the clinical manifestations
of the disease, such as cognitive impairment (
24). The nature
of these changes is still unclear, but it is likely secondary
to Wallerian degeneration of fibers passing through large white
matter lesions or subtle changes—which can, however, include
axonal loss (
25)—beyond the resolution of commonly available
scanners.
As is the case for MS (26), several MR imaging studies of patients with AD have shown that the correlation between regional gray matter atrophy and global cognitive impairment is relatively weak (27–29), which suggests that other pathologic processes such as microstructural gray and white matter damage might also play a significant role (27, 30). This is likely to be the result of structural and metabolic injury to neurons, which can eventually lead to neuronal death. A study based on the combined quantification of tissue loss of the hippocampus and damage of the remaining tissue has shown a strong correlation between cognitive impairment and MR imaging findings (31). There is, therefore, an urgent need to quantify the extent and define the nature of tissue damage of the AD brain beyond sensitivity of conventional MR imaging. A deeper appreciation of microstructural gray matter damage in AD might indeed provide precious diagnostic information at the earliest stages of the disease (9), account for the wide variability of memory performance in patients with similar degrees of hippocampal atrophy (32), and contribute to the definition of the neurobiologic substrates of clinically disruptive, but yet elusive, symptoms such as insomnia, agitation, and psychosis (33).
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White/Gray Matter Involvement
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MS-related tissue damage is not limited to white matter, but
also significantly involves the gray matter (
22). Thus, MS should
be viewed as a global brain pathology rather than a disease
confined to the white matter. This notion is supported by both
postmortem (
11–
13) and quantitative MR imaging (
14–
16)
studies showing marked and evolving gray matter damage in patients
with various MS phenotypes. Gray matter damage in MS might be
secondary to neuronal loss due to retrograde degeneration or
discrete gray matter lesions (
12).
Similarly, AD pathology is not limited to the gray matter, but involves the white matter as well. Several studies, specifically designed to rule out white matter abnormalities of different origin, have shown that white matter areas linked to associative cortices are sites of tissue damage, which remains occult on conventional MR imaging scans (34–36). These studies also found strong correlations between the extent and severity of white matter damage and AD-related cognitive decline (34, 36). White matter damage in AD can be either the consequence of abnormal axonal transport due to the presence of neurofibrillary tangles involving the cytoskeleton or, but not mutually exclusive, the result of anterograde axonal degeneration. The damage to the white matter specific to AD might add to the aspecific age-associated myelin breakdown occurring in late-myelinating association regions, such as the splenium and genu of the corpus callosum and contribute to the "dysconnection syndrome" of old age (37). This is a hypothetical scenario, however, that needs much deeper investigation. Alternatively, white matter damage might be caused by direct deposition of amyloid in the white matter (38).
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The Earliest Clinical Phase
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The clinical onset of MS is frequently represented by a CIS,
involving the optic nerve, the brain stem or the spinal cord.
Identifying which patients with CIS will go on to develop definite
MS and severe disability is a challenging task with important
treatment implications. MR imaging can be of enormous help in
this context, because it has been shown in a 14-year follow-up
study, which strengthens previous observations based on shorter
follow-up periods (
39), that >80% of patients with CIS and
MR imaging lesions go on to be diagnosed with MS, whereas approximately
20% have self-limited processes (
40). This has led to the development
of new diagnostic criteria that allow a diagnosis of MS to be
made in a patient presenting with a CIS and appropriate MR imaging
findings (
41). The recent application of quantitative MR imaging
technology to patients with CIS has convincingly shown that
tissue loss is already present at this very early clinical stage
of the disease (
15) and that it progresses at a relatively rapid
pace in the subsequent few months (
14), thus indicating the
need for early therapeutic intervention, with the potential
to limit the irreversible consequences of MS-related tissue
injury.
Seminal studies of patients with mild cognitive impairment, a condition progressing to AD in about half of the cases (9), and that can be viewed as having the same relationship that CIS has with MS, have shown that a reduction of the size of the hippocampus is one of the most sensitive indicators of the full clinical development of the disease (42). Hippocampal atrophy alone, however, does not seem sufficient to predict progression with clinically satisfactory accuracy (9, 42). It is conceivable that a combination of this with other biologic markers of AD, such as high levels of tau protein in the CSF (43) and cortical metabolic defects on PET (44) or single-photon emission tomography (SPECT) (45), might be associated with an increased accuracy (9). In this context, the definition of novel MR-based markers with a high degree of prognostic accuracy would facilitate greatly a preclinical diagnosis of AD and would have treatment implications that might be paramount once disease-modifying drugs are available (46).
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Cortical Plasticity
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Significant functional cortical reorganization takes place in
MS, which is likely to have a role in limiting the impact of
irreversible tissue damage on the clinical outcome (
47). This
is central to the development of new treatment strategies aimed
at enhancing the natural capability of the human brain to respond
to disease injury, thus reducing or delaying the development
of "fixed" disability.
Significant functional cortical reorganization also takes place in AD, as suggested by a number of functional MR imaging studies (48–51) showing that, when performing cognitive tasks, patients activate larger cortical areas than cognitively intact elderly persons. Such cortical reorganization is believed to represent an attempt of the brain to compensate for the decreased function of the areas more affected by plaque and tangle pathology through enhanced recruitment of those that are still less affected. Empirical observations have shown that nonpharmacologic interventions alone (52) or in combination with cholinesterase inhibitors (Onder et al, personal communication) have a symptomatic effect in AD. The efficacy of these interventions might be better exploited if their functional neurobiology will be assessed more deeply.
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Monitoring Treatment Efficacy
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During the past several years, 6 treatment options (3 interferon
beta preparations, glatiramer acetate, mitoxantrone, and natalizumab)
have been approved for treating MS. It is likely that this would
not have occurred without the use of MR imaging as a surrogate
outcome measure in the context of double-blind, randomized,
placebo-controlled trials (
53). At present, conventional MR
imaging-derived metrics are used as additional measures of outcome
in virtually all MS trials. Recent work is also showing that
the application of modern quantitative MR technology is contributing
significantly in elucidating whether and how experimental treatment
works in MS (
54).
Drugs presently licensed for use in patients with AD (donepezil, rivastigmine, galantamine, and memantine) have been developed based on clinical trials designed in the 1990s with behavioral outcome measures (eg, cognitive performance, daily function, clinician-based impression of change) (55). Only more recent trials (56) have included MR imaging–measured brain atrophy as an additional outcome measure, and none has yet exploited the potential of quantitative MR techniques, such as proton MR spectroscopy and diffusion-weighted MR imaging. PET- and SPECT-based in vivo imaging with specific beta-amyloid tracers will likely bring a new and most significant tool to assess the efficacy of disease modifying drugs (57).
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Conclusion
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During the past decade, MR imaging has contributed significantly
to elucidate MS pathophysiology and improve clinical management
and treatment monitoring of these patients. Extensive application
of MR imaging technology is likely to be equally rewarding in
the assessment of AD. Other neurodegenerative brain conditions—such
as dementia with Lewy bodies, frontotemporal dementia, and multiple
system atrophy, which share with AD the key pathophysiologic
mechanisms of toxic protein deposition—might also benefit
significantly. This calls for enhanced research activity in
the field and, as a consequence, the need to allocate more resources
to the application of MR imaging to AD and allied conditions.
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Received February 8, 2005;
accepted after revision March 28, 2005.
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Introduction
Understanding Disease...