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Review Article

Pathological Aging of the Brain

An Overview

Bastos Leite, António J MD*†‡; Scheltens, Philip MD, PhD‡§¶; Barkhof, Frederik MD, PhD*‡¶

Author Information
Topics in Magnetic Resonance Imaging: December 2004 - Volume 15 - Issue 6 - p 369-389
doi: 10.1097/01.rmr.0000168070.90113.dc
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Abstract

THE PROBLEM

The number of elderly people is increasing rapidly, and this tendency will continue in the near future. As a consequence of the aged population, an increase in neurologic illnesses is expected, such as neurodegenerative dementias, cerebrovascular disease (CVD), and movement disorders.1

In this review, we will focus on dementia, the most severe consequence of pathologic brain aging. The definition of dementia recommended by the American Academy of Neurology2 as proposed in the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised (DSM-IIIR)3 states:

▪ the essential feature of dementia is impairment in short and long term memory, associated with impairment in abstract thinking, impaired judgment, other disturbances of higher cortical function, or personality change… severe enough to interfere significantly with work or usual social activities…

Since dementia is a growing health problem4,5 with an enormous impact on society, measures should be taken to restructure the diagnostic algorithms and rehabilitation support.5 From the diagnostic point of view, structural neuroimaging with either a noncontrast computed tomography (CT) or magnetic resonance (MR) imaging is already recommended for the initial evaluation of patients with dementia,2 and is increasingly being used to support the clinical diagnosis beyond the traditional exclusionary approach.6 Additionally, there is an increasing urge for an early and more accurate diagnosis of dementia, given the current availability of therapies, such as cholinesterase inhibitors, that for the most frequent dementias,7-10 improve or stabilize cognition, treat behavioral symptoms, and delay institutionalization.11 Moreover, the recognition of conditions that may precede dementia, such as mild cognitive impairment (MCI) or vascular cognitive impairment (VCI),12-15 which may be more amenable to intervention, also raise the importance of an earlier diagnosis.

In the future, the introduction of new therapies, for example the anti-amyloid drugs16 for Alzheimer disease (AD), will reinforce the need of a more rigorous and early diagnosis, given the expectation that the earlier a specific therapy can be started, the more effective it will be in preventing or slowing disease progression.

Alzheimer disease is the most common cause of dementia, with prevalence rates higher than 40% at the age of 85 and a total annual cost approaching 70 billion dollars in the United States of America.17-19 It is projected that the prevalence will nearly quadruple over the next 50 years, by which time approximately 1 in 45 Americans will be affected with this disease.5

A large proportion of patients with dementia have a combination of degenerative and vascular pathology in the brain,20-28 and there are multiple causes of dementia other than AD. Vascular dementia (VaD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD) are the most common causes after AD. Parkinson's disease (PD) can also be associated with dementia, as well as some rare atypical parkinsonian syndromes.29 Argyrophilic grain disease is probably an underestimated cause of dementia in old patients.30 Huntington's disease is an autosomal dominant inherited condition characterized by chorea, behavioral disturbances, and cognitive deterioration,29 whose genetic defect is already known.31 One of the main features of prionic diseases, like Creutzfeldt-Jacob disease, is rapidly progressive dementia.29 Cases of amyotrophic lateral sclerosis and parkinsonism-dementia complex, the so-called Lytico-Bodig disease, are extremely rare and occur almost exclusively in the Chamorran population of southern Guam.29,32 Other causes of dementia include infections, inflammatory white matter diseases, metabolic disorders, drugs and toxins, heavy metal poisoning, lipophilic substances, renal insufficiency and dialysis, paraneoplastic syndromes, tumors, radiotherapy, cranial trauma, hydrocephalus, and idiopathic calcinosis of Fahr.29

Although there are established clinical criteria for the diagnosis of diseases causing dementia,33-36 the definite diagnosis was always believed to be histopathological. Currently, not even neuropathology can be considered a gold standard anymore. There are considerable discrepancies between different postmortem pathologic criteria and clinical information is still needed for a correct classification.37 For example, Polvikoski et al38 in an autopsy-controlled, prospective, population-based study on the prevalence of AD in very old people (≥85 years) found that 55% of the individuals with neuropathological criteria for AD were either non-demented during life or classified as having VaD. Conversely, they also found that 35% of those with clinical AD did not fulfill the neuropathological criteria.

CHOICE OF IMAGING MODALITY

Computed tomography without contrast is sufficient to rule out almost all surgically manageable causes of dementia,39 but except in cases where MR is contraindicated, not available, or not affordable, there is no reason to prefer CT over MR.40 When CT is the only alternative, axial thin slices parallel to the long axis of the temporal lobe (using a negative scan angle) should be obtained.41

Magnetic resonance without contrast is the preferred imaging modality for dementia, and the protocol should include at least axial T2-weighted images (T2-WI), axial fluid-attenuated inversion recovery (FLAIR) or proton density-weighted images (PD-WI), axial gradient-echo T2*-weighted images (T2*-WI), and coronal high resolution T1-weighted images (T1-WI) perpendicular to the long axis of the temporal lobe. Axial T2-WI, FLAIR, and PD-WI are crucial for the detection of cerebrovascular pathology and white matter changes. Axial T1-WI facilitate the distinction between ischemic lacunae (hypointense on T1-WI) and focal incomplete infarcts (isointense on T1-WI), and are useful for the assessment of global brain atrophy. Coronal high resolution T1-WI are extremely important to evaluate medial temporal lobe atrophy (MTA). Axial gradient-echo T2*-WI are needed to detect microbleeds and calcifications.29

Functional imaging techniques have also been applied to the diagnosis of dementia.40,42-44 Single photon emission computed tomography (SPECT) evaluates brain perfusion, but does not yield absolute quantification of blood flow, and positron emission tomography (PET) is currently used almost exclusively to evaluate brain's glucose metabolism. At present, SPECT and PET are second-line investigations employed when MR is inconclusive (eg, in early AD and FTD cases). In the future, SPECT and PET may become more important, especially due to the development of radioligands for in vivo detection of AD pathology.45,46 Currently, PET imaging is already reimbursed in the United States for dementia patients who have atypical symptoms that preclude a clinical diagnosis.

ALZHEIMER DISEASE

The criteria of the National Institute of Neurologic, Communicative Disorders and Stroke (NINCDS)-AD and Related Disorders Association (ADRDA) for the diagnosis of AD include insidious onset and progressive impairment of memory and other cognitive functions in the absence of motor, sensory, or coordination deficits early in the course of disease. They also state that the diagnosis can not be made with laboratory tests, which should be employed to identify other possible causes of dementia.33 Therefore, the NINCDS-ADRDA criteria recognize the lack of a single “gold standard” for the identification of AD as well as the insufficient knowledge about its cause,47 except for the extremely rare familial autosomal dominant inherited cases with early onset, whose genetic defects were discovered in the early nineties.48

The apolipoprotein E-ε4 (APOE-ε4) allele is genetically associated with the most common late onset familial and sporadic forms of AD.49 Although the specificity and positive predictive value of the APOE-ε4 allele were found to be 100% in some series,50-52 it is now accepted that APOE genotyping does not provide sufficient sensitivity or specificity to be used as a single diagnostic test.53

The neuropathological characteristics of AD include intraneuronal neurofibrillary tangles (NFTs) and neuropil threads (NTs) consisting of paired helical filaments whose main component is abnormally phosphorylated tau protein; extracellular deposits of β-amyloid, some associated with dystrophic neurites, activated microglia, and reactive astrocytes−neuritic plaques (NPs); granulovacuolar degeneration; Hirano bodies; corpora amylacea; increased accumulation of lipofuscin in neurons; loss of neurons and synapses; and amyloid angiopathy.54 NFTs and NPs are the most important pathologic features of this disease. NFTs also occur in other dementias, but their composition varies according to the isoform of abnormal tau protein.55 NPs are more specific for AD than other aggregations of β-amyloid.56

Braak and Braak57 proposed a neuropathological staging of AD based on the distribution, pattern, and density of NFTs and NTs. Neurofibrillary changes develop in only a few types of pyramidal cells, first in the transentorhinal cortex (stages I and II), and then in the entorhinal cortex, hippocampal formation (stages III and IV), and neocortex (stages V and VI), progressing hierarchically in the inverse sequence of cortical myelination, predominantly in neurons with a high density of lipofuscin. They also proposed that the stages of progressive cortical destruction correlate with clinical status of patients with AD. Stages I and II (transentorhinal stages) are considered to represent the presymptomatic phase of AD, stages III and IV (limbic stages) are the counterpart of clinically incipient AD, and stages V and VI (neocortical stages) represent the fully developed cases.58,59 Staging classifications for the progression of amyloid deposition were also proposed,60,61 but the initial neurofibrillary changes, which may occur several decades before dementia, are believed to indicate the beginning of AD.62

Current histologic criteria for the diagnosis of AD63 are based on both the density of NPs and NFTs in the neocortex and limbic areas, combining previous criteria based only on number of NPs in the neocortex64 and the staging criteria of Braak and Braak for neurofibrillary changes.57

Two neural networks are particularly vulnerable to progression of AD pathology early in the course of disease.65 One is the Papez circuit,66 whose disruption starts in the entorhinal cortex and subiculum due to pathology affecting cells that interconnect the hippocampal formation with other brain structures. This results in isolation of the hippocampal formation from most of its connections and accounts for the memory impairment in AD.67 The other affected network is the cortical cholinergic system that originates in neurons within the basal forebrain,65 with selective neuronal loss in the substantia innominata's nucleus basalis of Meynert.68 It forms the anatomic basis of the cholinergic hypothesis proposed in the mid seventies for AD, and explains the decrease of acetylcholine in the brain of patients with AD and other dementias, which is partially responsible for the cognitive and behavioral deficits. Moreover, it serves as the rationale for the use of cholinesterase inhibitors.

Imaging Findings in Alzheimer Disease

Structural neuroimaging in AD is focused on detection of MTA, particularly of the hippocampus, parahippocampal gyrus (including the entorhinal cortex), and amygdala. MR and CT are indeed sensitive to MTA in AD,69-71 correlating with AD pathology at postmortem.72,73 MTA can be assessed using visual rating scales, linear measurements of temporal lobe structures, and volumetry of the hippocampus.41,74-76 Volumetric analyses are time consuming and therefore not well suited for clinical practice.77 Moreover, MR studies comparing volumetric and visual assessment of MTA found there is no advantage of volumetry in differentiating AD patients from controls.77-79 Linear measurements of the temporal horns are reliable, can be used in routine clinical settings, and have the advantage of being applicable both to CT and MR.75,80 The visual rating of MTA74 is based on subjective evaluation of the choroidal fissure width, the temporal horn width, and the hippocampal height (Table 1) using coronal high resolution T1-weighted images perpendicular to the long axis of the temporal lobe (Fig. 1). It is easily applicable in clinical practice, but slightly observer dependent.81 In a recent review6 of studies employing visual rating scales or linear measurements to evaluate MTA, the weighted sensitivity and specificity for detection of patients with AD (versus controls) was 85% and 88%, respectively.

T1-6
TABLE 1:
Visual Rating Scale for Medial Temporal Lobe Atrophy
F1-6
FIGURE 1:
Coronal high resolution T1-weighted images perpendicular to the long axis of the temporal lobe showing the different degrees of medial temporal lobe atrophy (MTA), according to the visual rating scale proposed by Scheltens et al74: (A) absence of atrophy (MTA = 0); (B) minimal atrophy (MTA = 1); (C) mild atrophy in the right side (MTA = 2), severe atrophy on the left (MTA = 4); (D) moderate atrophy (MTA = 3); and (E) severe atrophy (MTA = 4).

Because the initial neuropathological changes in AD occur in the entorhinal cortex, some volumetric MR studies compared the discriminative power of measurements in both the entorhinal cortex and hippocampus to identify patients with early stages of AD. Although they found that both regions are affected, they did not find advantage by assessing the entorhinal cortex as an alternative for the hippocampus.82,83

Besides the existence of MTA, the most important structural imaging feature of AD is progression of such atrophy. Jack et al84 found a yearly decline in hippocampal volume approximately 2.5 times greater in patients with AD than in normal aged subjects, and a relationship exists between memory loss and hippocampal damage across the spectrum from normal aging to dementia.85 However, neuroanatomical changes over time may be too mild, diffuse, or topographically complex to be detected by simple visual inspection or even with manually traced measurements of regions of interest. New serial volumetric imaging techniques developed in the past few years represent an added value to identify subtle structural brain changes (Fig. 2), which have brought extensive neocortical changes to the fore.86,87 In addition, voxel based morphometry (VBM), a voxel-wise, fully automated and unbiased technique that enables comparisons of the local brain tissue concentration between groups of subjects,88 when applied to compare normal elderly controls with AD patients, demonstrates in these patients: MTA, global cortical atrophy (with relative sparing of the sensorimotor cortex, occipital poles, and cerebellum), as well as atrophy of the caudate nuclei and medial thalami.89 Furthermore, VBM shows that patients with early onset AD have greater neocortical atrophy at the temporoparietal junction, but less hippocampal atrophy, than patients with late onset AD.90

F2-6
FIGURE 2:
Coronal high resolution T1-weighted images of a patient with early onset Alzheimer disease: (A) baseline scan; (B) scan repeated after 12 months; (C) voxel compression mapping overlay displaying brain volume loss (during the interval of 12 months) in green, and expansion of the cerebrospinal fluid volume in yellow (courtesy of Jasper Sluimer and Nick Fox).

Magnetic resonance studies employing thin-section coronal T2-WI have suggested it is possible to demonstrate shrinkage of the substantia innominata, a finding more pronounced in AD patients who respond to cholinesterase inhibitors, but that may also occur in other dementias.91-93

SPECT and PET studies may show hypoperfusion and hypometabolism in several brain regions of AD patients.94,95 Studies comparing SPECT with structural MR for the differentiation between AD patients and normal controls almost always found temporoparietal hypoperfusion in AD, but there was no clear advantage of SPECT over MR,96-98 even though the combination of both significantly improved discrimination.98 Moreover, the use of MR alone was found to be the most cost-effective approach.99

Mild Cognitive Impairment

Mild cognitive impairment (MCI) is a clinical condition characterized by a prominent but nearly isolated impairment in memory, while other cognitive functions are consistent with normal aging.13 MCI is considered a transitional stage between normal aging and AD, but there is some degree of overlap with both. It seems to represent a heterogeneous group of patients, some progressing to dementia or AD, and others stabilizing or even reversing to normal.40

Identification of patients with MCI is an area where modern imaging techniques might yield the greatest added value, since clinical criteria may be poorly specific.39 Hippocampal atrophy determined by MR volumetry was found to predict conversion to AD,100 and entorhinal cortex volumetry might even better distinguish MCI from AD.101 Visual rating of MTA is a good alternative to hippocampal volumetry, although not so accurate.102 Finally, VBM shows that MCI patients have less gray matter in the medial temporal lobe, insula, and thalamus than normal elderly controls, but more gray matter in the parietal association areas and cingulate cortex than AD patients.103

Functional neuroimaging studies can also accurately identify converters from MCI to AD, and even from normal aging to MCI.104-107 Combinations of serial volumetric studies and cognitive or functional imaging assessments may prove to be the best option in the near future.108-110 Prospective studies on the effect of white matter lesions in conversion from MCI to dementia are also warranted,111,112 as well as on their impact in transition to disability.113

Alzheimer Disease With Cerebrovascular Disease and Other Pathologies

The most frequent combination of brain pathologies in dementia is that which results from both degenerative and vascular lesions,21-23,25-28 but there are also combinations among different types of degenerative pathologies, namely between AD, PD, and DLB.20,25,27

Changes in the endothelium, disruption of the blood-brain barrier, and amyloid angiopathy occur in AD, but it is not known whether these vascular changes represent a cause, an effect, or even the consequence of a common pathogenesis of AD and CVD.114 Nevertheless, recent studies suggest that CVD and late-onset AD share common risk factors.115

The recognition of additional pathologies in AD is important, since they can lower the threshold for dementia or increase its severity, and may represent an independent target for treatment. For example, the burden of AD pathology is lower in cases of AD mixed with other pathologies than in cases of pure AD,22,24,116,117 and patients with brain infarcts fulfilling neuropathological criteria for AD have poorer cognitive function and higher prevalence of dementia than those without infarcts,22,23 especially when they have lacunae in the basal ganglia, thalamus, or in deep white matter.22 Dementia may also occur in a considerable proportion of post-stroke patients, particularly in those with MTA.118,119 Moreover, when there is neuroimaging evidence of mixed pathology (degenerative and vascular) (Fig. 3), atrophy correlates better with dementia than CVD,120-123 and may even result from both ischemic and degenerative injuries.120

F3-6
FIGURE 3:
Coronal T2-weighted image showing extensive white matter hyperintensity and severe medial temporal lobe atrophy, which is suggestive of combination between degenerative and vascular brain pathology.

Neuroimaging is very important for the diagnosis of CVD, particularly of small vessel disease, which is frequently not suspected clinically,124,125 and more often associated with dementia than large vessel disease.126 MR signal abnormalities of deep white and gray matter127 occurring in AD, VaD, and usual aging can be considered as a surrogate marker for small vessel disease.6,128 Currently, it is unclear whether CVD, as depicted by MR imaging, should be a separate target for treatment in AD patients, but this seems to be quite plausible.

DEMENTIA WITH LEWY BODIES

Formerly considered a variant of AD, dementia with Lewy bodies (DLB) is now recognized a common degenerative dementia.129 It is clinically characterized by an often rapidly progressive clinical syndrome including dementia, fluctuations in cognitive function, and spontaneous parkinsonism. Attention deficits, disproportionate problem solving, and visuospatial difficulties are often prominent and early in the course of disease. Persistent well-formed visual hallucinations are also a feature with diagnostic significance. Neuroleptic medication is contraindicated, but DLB patients are particularly responsive to cholinesterase inhibitors.8,35

Brainstem or cortical Lewy bodies (LB) are the only features considered essential for a pathologic diagnosis of DLB, although Lewy-related neurites, Alzheimer pathology, and spongiform changes may also be seen.35 The precise nosological relationships between DLB, AD, and PD dementia (PDD) are not yet completely clarified. NPs are frequent in both DLB and AD, but neocortical NFTs are rare in DLB. In addition, the main component of LB, which are either present in DLB, PD, and PDD, is α-synuclein rather than abnormal tau protein.35,129

Magnetic resonance studies comparing DLB, AD, VaD, and normal controls found that although MTA was more frequent and severe in all dementia groups than in controls, subjects with DLB had significantly lower MTA scores and larger temporal lobe, hippocampal, and amygdala volumes than those with AD. Therefore, in the differentiation of DLB from AD, the absence of MTA may be considered suggestive of DLB.130,131 Conversely, atrophy of the putamen is a feature of DLB, but not of AD.132

Functional studies found occipital hypoperfusion and hypometabolism in DLB133,134 that do not seem to be associated with occipital atrophy.135

DEMENTIA ASSOCIATED WITH PARKINSON'S DISEASE

Contrary to the initial assumption that cognitive function would be spared, it is now recognized that patients with PD may develop dementia, as their age increases. Clinically, PDD is characterized by an early impairment of executive functions, but there are no formal criteria for the diagnosis yet.136 When fully developed, PDD and DLB overlap both clinically and pathologically. If the previous history is unknown, patients with each of these disorders may be indistinguishable. Currently, an arbitrary rule used for the distinction between these disorders is to consider that in DLB the onset of dementia should occur within 12 months of parkinsonism, and in PDD only after more than 12 months.129,136

The underlying pathology of PDD has been a matter of controversy, both in terms of site and type, and is currently classified into three groups: subcortical pathology, AD-type pathology, and LB-type pathology. The main pathology seems to be LB-type degeneration with cellular and synaptic loss in cortical and limbic structures.136

Whereas PDD was claimed not to be associated with a specific pattern of MR abnormalities,137 Laakso et al138 found severe hippocampal atrophy in these patients, which is surprising considering the aforementioned resemblance between PDD and DLB. Additionally, functional studies found patterns of brain hypoperfusion and hypometabolism in PDD not very different from those described in AD.136 One explanation for these findings may be that PDD patients included in the referred studies had coexistent Alzheimer pathology.

FRONTOTEMPORAL LOBAR DEGENERATION

Frontotemporal lobar degeneration (FTLD) accounts for a substantial proportion of primary degenerative dementia cases occurring before the age of 65 years, and includes a heterogeneous group of patients with behavioral or language disturbances usually preceding or overshadowing memory deficits.36 Recent clinical criteria proposed by Neary et al36 discern three main prototypic syndromes-frontotemporal dementia (FTD), progressive nonfluent aphasia (PNA), and semantic dementia (SD), also known as progressive fluent aphasia or temporal variant of FTLD.

Two main histopathological types are considered as the major substrates of FTLD, but clinical presentation reflects the distribution of pathology rather than the exact histopathological type. The commonest pathology is that of neuronal loss and spongiform change (microvacuolation), without other specific features-frontal lobe degeneration type. The other is characterized by severe astrocytic gliosis with or without ballooned cells and inclusion bodies-Pick type.36,139 Both AD, FTLD, and several other neurodegenerative dementias belong to the group of tauopathies, all displaying aggregations of different isoforms of abnormal tau protein.55 In addition to the sporadic form, there are also familial cases of FTLD, often linked to chromosome 17 abnormalities.

Neuroimaging studies in patients with clinical and pathologic diagnosis of FTLD show a pattern of marked anterior temporal and frontal atrophy resulting in the so-called “knife edge” appearance and in dilatation (ballooning) of the temporal and frontal horns of the lateral ventricles (Fig. 4), in some cases associated with predominantly frontal white matter changes.140,141 Characteristically, FTLD affects more the temporal pole, but relatively spares the posterior part of the hippocampus.142

F4-6
FIGURE 4:
Axial fluid-attenuated inversion recovery image of a patient with frontotemporal dementia revealing severe anterior temporal lobe atrophy with “knife edge” appearance, dilatation of the ventricular temporal horns, and subcortical hyperintensity.

Asymmetric atrophy is also a distinctive feature of FTLD, particularly of SD and PNA. Selective inferolateral and anterior left temporal atrophy is characteristic of SD. In PNA, atrophy appears to be more diffuse and involves the left frontal and perisylvian structures.143-146 One variant of FTLD affecting the right temporal lobe presents with progressive prosopagnosia.146

Studies employing SPECT for the differential diagnosis between FTD and other dementias found hypoperfusion in the same regions where atrophy occurs,147,148 and since hypoperfusion or hypometabolism may precede volume loss, functional studies can be useful in early cases.

DEMENTIA AND ATYPICAL PARKINSONIAN SYNDROMES

The most well-known atypical parkinsonian syndromes are multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). Clinical criteria for the diagnosis of PSP include cognitive impairment,149 and patients with CBD may have dementia as the predominant clinical feature.150 Both PSP and CBD are sporadic tauopathies that may overlap between each other, as well as with FTD and other disorders.151-153 Since dementia is not considered a diagnostic feature of MSA,154,155 this disease will not be discussed.

Characteristic findings on routine MR imaging can contribute to the identification of atypical parkinsonian syndromes.156,157 Asymmetric atrophy involving the posterior frontal and parietal regions (Fig. 5) contralateral to the clinically most affected side occurs in most of CBD patients. Mild signal changes on FLAIR and PD-WI in the atrophic cortex have been described in some of these patients.158 On the other hand, despite the existence of pathologic changes in the basal ganglia, MR imaging abnormalities of these structures were almost never reported.158

F5-6
FIGURE 5:
Coronal high resolution T1-weighted image showing asymmetric atrophy involving predominantly the right parietal lobe of a patient with corticobasal degeneration (courtesy of Luís Maia and António Bastos Lima).

Midbrain atrophy and diffuse hyperintensity on T2-WI in the mesencephalic tegmentum and tectum (Fig. 6A) are characteristic of PSP, and occur due to predominance of tau pathology in these regions.159,160 Midbrain atrophy can be simply and accurately assessed measuring the antero-posterior midbrain diameter on axial T2-WI,157,161 but visual assessment using sagittal T1-WI should also be done, because when there is midbrain atrophy the mesencephalic caudo-cranial dimension is reduced and the third ventricle's floor appears more superiorly concave than normal (Fig. 6B).156,158 Besides the infratentorial abnormalities, VBM and serial volumetric studies also show a distinct pattern of mesio-frontal atrophy in PSP (Fig. 6B).162,163

F6-6
FIGURE 6:
Axial T2-weighted image (A) showing midbrain atrophy and diffuse hyperintensity in the mesencephalic tegmentum and tectum of a patient with progressive supranuclear palsy (PSP). Sagittal T1-weighted image (B) showing midbrain atrophy (especially of the tectum), dilatation of the cerebral aqueduct, pronounced superior concavity of the third ventricle's floor, and the mesio-frontal atrophy characteristic of PSP.

Although asymmetric frontoparietal atrophy in CBD and mesencephalic atrophy in PSP are considered the most useful aids to the clinical diagnosis,164 other neuroimaging abnormalities were also described. Asymmetric involvement of the corpus striatum and thalamus in CBD was disclosed by PET in addition to asymmetric cortical hypometabolism.165 Moreover, patients with PSP and cognitive impairment studied both with MR and PET were found to have predominantly anterior corpus callosum atrophy as well as predominantly frontal cortical hypometabolism.166

VASCULAR DEMENTIA

Vascular dementia (VaD) is the second most common type of dementia, and it is generally assumed that risk factors for VaD are the same as for simple stroke.167 Unlike AD, executive dysfunction is commonly seen in VaD and memory impairment is less severe.168 The most specific diagnostic criteria for VaD are the National Institute of Neurologic Disorders and Stroke (NINDS)-Association Internationale pour la Recherche et l'Enseignement en Neurosciences (AIREN) criteria. These criteria emphasize the heterogeneity of both clinical syndromes and pathologic subtypes of VaD, the need to establish a temporal relationship between stroke and the onset of dementia, as well as the importance of brain imaging to support clinical findings.34

The main clinicopathological subtypes of VaD are large vessel VaD and small vessel VaD. Ischemic-hypoperfusive VaD and hemorrhagic VaD may also be considered as separate groups. Large vessel VaD can be further subdivided into multi-infarct dementia and strategic infarct dementia (caused by vascular lesions located in strategic regions of the brain, such as the hippocampus, paramedian thalamus, and the thalamocortical networks). Small vessel disease may also affect strategic regions. Binswanger's disease, lacunar state (état lacunaire), and cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) are examples of subcortical ischemic small vessel VaD. Cerebral amyloid angiopathies (CAA) are considered as a subtype of cortical-subcortical small vessel disease, but they have associated large vessel pathology as well. Both CADASIL and some forms of CAA have a genetic basis.167,169-171

Most patients with the diagnosis of VaD have small vessel rather than large vessel disease.126,172 Therefore, research criteria were formulated specifically for subcortical ischemic VaD, now recognized as the most broad and homogeneous subtype of VaD.173

The pathology of VaD may be described considering either the type of brain lesion or the underlying type of vessel abnormality. Brain lesions include: large vessel cortical-subcortical infarcts, small vessel cortical microinfarcts, small vessel deep infarcts, enlarged perivascular (Virchow-Robin) spaces, hemorrhages, microbleeds, and diffuse white matter lesions. Vessel abnormalities include: atherosclerosis, arteriolosclerosis, amyloid angiopathy, source of emboli, or no obvious structural abnormality at all.174

Infarcts may either be complete or incomplete. Complete infarcts correspond to areas of tissue destruction, whereas incomplete infarcts may only represent demyelination and edema. Complete infarcts of deep small vessels are defined as lacunar infarcts, and some authors consider this definition also dependent on size (from 2-3 to 15-20 mm in diameter).167,175,176 In addition, one proposed neuropathological classification of lacunae includes both ischemic (type I) and hemorrhagic (type II) lesions, as well as enlarged Virchow-Robin spaces (type III).177

Diffuse white matter lesions include: spongiosis (vacuolization), gliosis, diffuse myelin and axonal loss, breakdown of ependymal lining, edema, as well as enlarged Virchow-Robin spaces.178

Given that patients with coexistent AD and CVD (mixed dementia) represent an important and previously underestimated group,179 the causal relation between vascular lesions alone and dementia is only clear in the following circumstances: when patients are young and it is unlikely they have associated Alzheimer pathology; when cognitive functions are normal before stroke, impaired immediately after, and do not worsen over time; when vascular lesions are located in strategic regions; and when well-defined vasculopathies known to cause dementia are proven, such as CADASIL or CAA. In other circumstances, it is possible that patients may have a combination of degenerative and vascular pathology.180,181

Imaging Findings in Vascular Dementia

The NINDS-AIREN criteria consider structural neuroimaging crucial for the diagnosis of VaD,34 and operational definitions for the radiologic part of these criteria were recently proposed, both in terms of topography and severity of lesions (Table 2).182

T2-6
TABLE 2:
Operational Definitions for the Imaging Guidelines of the National Institute of Neurological Disorders and Stroke (NINDS) - Association Internationale pour la Recherche et l'Enseignement en Neurosciences (AIREN) Criteria for Vascular Dementia (VaD)

T2-weighted MR sequences are far more sensitive for the detection of CVD than CT,183 although CT was found to be more specific than MR in predicting subsequent symptomatic CVD.124 In addition, the sensitivity of T2-WI for detection of thalamic lesions in patients with probable VaD is superior to FLAIR (Fig. 7), and given the great clinical importance of these lesions, FLAIR should not be used as the only T2-weighted sequence.184

F7-6
FIGURE 7:
Axial T2-weighted images showing a left tuberothalamic artery infarct (A), and two right-sided thalamic infarcts (C and E). (B, D, and F) Correspondent fluid-attenuated inversion recovery images do not reveal considerable thalamic abnormalities.

Hypointensity on T1-WI usually represents tissue destruction, and may be considered as a surrogate marker for complete infarcts. Therefore, lesions hyperintense on T2-WI and isointense on T1-WI may just correspond to demyelination.185,186 FLAIR has the additional advantage of easily identifying cystic lesions,187 and the combination of FLAIR with T1-WI may be useful to differentiate the more aggressive lesions from those that might have less power to cause cognitive impairment.186

Misclassification between lacunar infarcts and enlarged Virchow-Robin spaces may occur, but most of the enlarged Virchow-Robin spaces measure <2 mm, and normally surround perforating arteries entering the striatum in the anterior perforated substance.188,189 Their appearance in large numbers reflects focal brain atrophy around blood vessels and may lead to the so-called état criblé, especially in the basal ganglia (Fig. 8).188,190,191 Moreover, the association of enlarged Virchow-Robin spaces and white matter lesions with cognitive impairment occurs,192 and widening of Virchow-Robin spaces can be considered as a measure of focal atrophy.193

F8-6
FIGURE 8:
Axial fluid-attenuated inversion recovery images showing numerous enlarged Virchow-Robin spaces in the basal ganglia (état criblé) associated with extensive white matter lesions.

White matter changes on MR imaging are visible as diffuse hyperintense abnormalities on T2-WI, FLAIR, and PD-WI, without prominent hypointensity on T1-WI. On CT, white matter changes appear as mildly hypodense areas. Since their occurrence increases progressively with age, they are usually referred to as age-related white matter changes (ARWMC). ARWMC may be considered as a surrogate marker for small vessel disease.6,128 Moreover, they are associated with vascular risk factors as well as with other types of CVD.194-196 Since the original scale of Fazekas et al,127 several others were proposed for rating ARWMC. Currently, the most complete is that proposed by Wahlund et al, applicable both to CT and MR imaging.183 According to the NINDS-AIREN criteria, white matter changes alone may be sufficient to cause dementia when at least ¼ of the white matter is involved.34 Although this proportion has been defined arbitrarily, it is in accordance with the finding that only severe white matter disease is associated with cognitive dysfunction.197 Extensive and diffuse white matter changes affecting predominantly deep and periventricular white matter, but relatively sparing the U-fibers, occur in Binswanger's disease (Fig. 9).167

F9-6
FIGURE 9:
Axial fluid-attenuated inversion recovery images showing extensive and diffuse white matter lesions affecting predominantly deep and periventricular white matter, but relatively sparing the U-fibers, a pattern typical of Binswanger's disease.

In patients with CADASIL, diffuse white matter signal changes involving the U-fibers occur mainly in the temporal, temporopolar, and frontal regions (Fig. 10).198-200 Microbleeds, defined by some authors as hypointense foci (<5 mm) on T2-WI or gradient-echo T2*-WI,201,202 are present in a considerable proportion of these patients, as well as in patients with CAA.203,204 However, the most typical feature of CAA is the occurrence of cortical-subcortical (lobar) hemorrhages.204,205

F10-6
FIGURE 10:
Axial fluid-attenuated inversion recovery images revealing diffuse white matter signal changes involving the U-fibers, mainly in the temporal, temporopolar, and frontal regions of a patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Deep venous thrombosis and dural arteriovenous fistulae are vascular abnormalities that may rarely cause venous hypertensive encephalopathy or bilateral thalamic congestion (Fig. 11), and lead to dementia. MR or conventional angiography are crucial for their diagnosis.206-208 Conventional angiography is also very useful for the interventional therapy for these abnormalities.206,207,209

F11-6
FIGURE 11:
Axial fluid-attenuated inversion recovery image (A) showing bilateral thalamic hyperintensity due to venous congestion caused by a straight sinus thrombosis, confirmed by digital subtraction angiography (B) (courtesy of Luís Maia and Teresa Caixeiro).

ROLE OF NEUROIMAGING IN THE DIFFERENTIAL DIAGNOSIS OF DEMENTIA

Magnetic resonance studies performed to investigate the value of MTA for the differential diagnosis of dementia did not find unequivocal results. O'Brien et al210 carried out a study to determine the specificity of hippocampal atrophy for the differentiation between AD and other conditions associated with cognitive impairment, such as VaD and major depression. They found that ratings of MTA were useful to differentiate AD from other groups. Conversely, Laakso et al138 found that hippocampal atrophy was not specific to differentiate AD from VaD or PDD, although they could not rule out the coexistence of Alzheimer pathology in their VaD or PDD patients. More recently, Barber et al130,131 found different degrees of hippocampal atrophy occurring in AD, VaD, and DLB-the most severe in AD, the less severe in DLB, and although there was also a trend toward less atrophy in DLB compared with VaD, no significant volumetric difference between these two groups was observed. Most likely, these discrepancies reflect different populations' studies, illustrating that the diagnostic accuracy of MTA depends on disease severity.

SPECT and PET studies have been also applied to the differential diagnosis of dementia. Although they are considered useful for the differentiation between AD, VaD, and FTD, the discrimination between AD and DLB was found to be difficult based on cerebral metabolism and blood flow.211,212 In the future, VBM and serial volumetric studies evaluating global brain atrophy may also be useful for the differential diagnosis. However, one should always keep in mind that imaging overlap between different entities may reflect combination of different pathologies, or even result from differences in pathology distribution.213,214

The pattern of white matter signal abnormalities on MR is very important for the differentiation between ischemic lesions and inflammatory demyelinating lesions. Multiple sclerosis (MS) is the most common inflammatory demyelinating disease and occurs mainly in young people, but it may lead to cognitive dysfunction due to accumulation of white matter lesions, or due to occurrence of cortical and juxtacortical lesions.29 The most specific MR diagnostic criteria for MS were proposed by Barkhof et al,215 and currently a modification of them makes part of the guidelines from the International Panel on the diagnosis of MS.216 MR is also very important for the diagnosis of other disorders that may lead to dementia and primarily affect white matter, such as herpes simplex encephalitis, human immunodeficiency virus encephalitis, and progressive multifocal leukoencephalopathy.29

Apart from the imaging findings described for the most frequent diseases causing dementia, MR may still show specific imaging patterns of atrophy or signal abnormalities in other disorders. Atrophy of the striatum, most conspicuous on visual inspection in the caudate nucleus, is typical of Huntington's disease (Fig. 12),29 although putaminal atrophy is a better predictor of disease onset in presymptomatic subjects.217 Rapidly progressive brain atrophy, as well as striatal and cortical hyperintensity on FLAIR, PD-WI, or T2-WI (Fig. 13) preceded by signal abnormalities on diffusion-weighted imaging (DWI) occur in patients with Creutzfeldt-Jakob disease.218-221 Additionally, in the new variant of Creutzfeldt-Jakob disease, bilateral hyperintensity of the pulvinar is a very specific imaging finding.222

F12-6
FIGURE 12:
(A) Axial and (B) coronal T2-weighted images showing marked atrophy of the striatum, most conspicuous in the caudate nucleus, typical of Huntington's disease.
F13-6
FIGURE 13:
Axial proton density-weighted image of a patient with Creutzfeldt-Jacob disease showing hyperintensity in the striatum, periventricular white matter, septum pellucidum, and cerebral cortex, particularly in the claustrum, insula, and frontal lobe.

Normal pressure hydrocephalus (NPH) is a rare disorder that, even more rarely, causes dementia. By definition, it includes the clinical triad of gait disturbance, urinary incontinence, and dementia. Gait impairment is the cardinal symptom, while mental deterioration may be subtle or even unrecognized. Initially, NPH was considered to be an idiopathic form of communicating hydrocephalus, but currently other forms of communicating hydrocephalus, and even a few noncommunicating forms make part of its spectrum.223-225 MR is the best imaging modality to evaluate the pulsatile motion of cerebrospinal fluid (CSF) in the cerebral aqueduct, either visually, as a low intensity signal on T2-WI (flow void), or using quantitative phase-contrast measurements. In NPH, both flow void and phase-contrast measurements are increased due to reduced ventricular compliance,226,227 and it seems that only when they are prominently increased there is prediction of a positive response to shunt therapy.225,228-230 Given the frequent coexistence of NPH with deep and periventricular white matter ischemic changes,231,232 it is matter of controversy whether NPH alone represents a true disease entity causing dementia.

NEW MAGNETIC RESONANCE TECHNIQUES AND MOLECULAR IMAGING

The big future challenge of neuroimaging techniques in the diagnosis of dementia will be to demonstrate pathologic processes occurring at a microscopic level, and therefore help to recognize subjects at risk for developing dementia before the occurrence of atrophy as an indicator of substantial tissue loss.

Neuronal loss and dysfunction are the major pathologic consequences at the cellular level. Proton MR spectroscopy (MRS) is reliable to demonstrate these abnormalities, by means of showing low levels of N-acetylaspartate-the metabolite considered to be a neuroaxonal marker.233-252 Additionally, most single voxel proton MRS studies performed in the parieto-occipital cortex of AD patients have also shown high levels of myo-inositol, a finding believed to represent gliosis or increased tissue osmolality.233,234,237,244 The same results were found in the frontal lobe of FTD patients.239 Furthermore, phosphorous MRS studies have shown low levels of phosphocreatine and high levels of phosphomonoesters in the early stages of AD,238,246,253,254 but their meaning is uncertain. In spite of the reported findings, the role of MRS for the diagnosis of dementia is limited,242,252 mainly because the technique is difficult to standardize and can not be used on an individual basis. Perhaps in the future, the chemical shift imaging approach may become more important as a diagnostic tool, since the regional distribution of metabolites can be evaluated.

Perfusion-weighted imaging (PWI) is an MR technique that constitutes a good alternative to nuclear medicine for the evaluation of microvascular changes in patients with dementia.255,256 The experience with PWI is still limited, and most studies have used a rapid gradient-echo T2*-weighted sequence during intravenous injection of a paramagnetic contrast bolus. This dynamic susceptibility contrast (DSC) PWI shows a degree of temporoparietal hypoperfusion in AD patients comparable to the degree of hypometabolism revealed by PET, even after correction for brain atrophy. In addition, whereas the sensitivity of both DSC-PWI and PET to detect changes is comparable, DSC-PWI is much more rapid, and has the advantage of avoiding ionizing radiation.257,258 In the future, DSC-PWI may be useful for diagnostic purposes or even tried to identify persons at risk for developing dementia.

Arterial spin labeling (ASL) represents an alternative MR technique to evaluate brain perfusion, and obviates the use of an exogenous contrast bolus injection. ASL uses water as a freely diffusable tracer and inverts the inflowing water proton spins in the arterial blood to obtain a measure of flow.259 One ASL study comparing AD patients with control subjects demonstrated blood flow decreases in AD occurring in the temporal, parietal, frontal, and posterior cingulate cortices.260

Functional MR imaging (fMRI) is a powerful research technique to evaluate brain activation on the basis of local changes in blood deoxyhemoglobin concentration-the so-called blood oxygen level dependent (BOLD) effect.261 Usually, the BOLD effect is measured in relation to various stimuli and tasks, but a new fMRI approach applied to study brain connectivity during a “no task condition” is currently under development.262 Findings of fMRI studies applied to dementia include decreased activation in the medial temporal lobe of AD patients during learning tasks requiring the encoding of new information, as well as loss of frontal activation in FTD patients during a working memory task.263,264 In the future, the major application of fMRI perhaps will be to identify patients at risk for developing dementia. So far, fMRI studies undertaken to identify patients at risk for developing AD (carrying the APOE-ε4 allele) showed conflicting results. They found either decreased or increased brain activation in regions involving the temporal lobe, which possibly means these regions are either already affected subclinically or trying to assume a compensatory role.265,266

Diffusion-weighted MR imaging is a technique sensitive to the microscopic motion of water molecules in tissue.267 It is already very important in clinical practice for the diagnosis of recent onset ischemia, and may detect recent infarcts responsible for the so-called “stepwise decline” in patients with VaD.268 Moreover, the apparent diffusion coefficients of the temporal white matter and hippocampus are higher in MCI and AD patients than in control subjects, probably due to decreased axonal density, disruption and loss of axonal membranes or myelin, and to wallerian degeneration secondary to gray matter pathology.269-271 High b value DWI is more sensitive to white matter degeneration than conventional DWI.272

Diffusion tensor imaging (DTI) enables the measurement of directionality (anisotropy) of the microscopic motion of water, and allows visualization of white matter tracts due to the longitudinal diffusion of water in fibers.273 Decreased fractional anisotropy was found in the temporal lobes and deep posterior white matter of AD patients,269,270,274 and a reduction in the integrity of association white matter tracts, such as the splenium of the corpus callosum, superior longitudinal fasciculus, and cingulum, also occurs in AD.275 Increases of water diffusion and a parallel loss of anisotropy in hyperintensities identified on T2-WI, in normal-appearing white matter, and in normal-appearing gray matter (especially the thalamus) were found in CADASIL,276,277 as well as increases of water diffusion in lesions and normal-appearing white matter in patients with ARWMC.278 Therefore, DTI may provide a better index of white matter damage than conventional MR imaging.

Magnetization transfer (MT) is an MR technique that modulates image contrast by selectively saturating protons bound to macromolecules (eg, proteins) using off-resonance radiofrequency (RF) pulses.279 The difference of signal intensity with and without application of the RF pulses can be measured as an MT ratio (MTR). When there is protein destruction, bound protons become less suppressed by the RF pulses, and the MTR decreases.280 This occurs in patients with AD, PDD, PSP, and ARWMC.281-284 Since microscopic abnormalities extend beyond the macroscopic lesions visualized on conventional MR images,284 MT may be helpful to evaluate diffuse brain damage in patients with dementia.

Studies about T1 and T2 relaxation time measurements in elderly patients with or without dementia are scarce. Age-related increases of T1 relaxation times in the white matter, putamen, and thalamus were found,285 as well as increases of T1 relaxation times in the temporoparietal white matter of AD patients.286 Concerning T2 relaxation time measurements, the results from studies in patients with AD are conflicting. Some studies found prolongation of the T2 relaxation times in the temporoparietal white matter, hippocampus, and amygdala,286-288 as well as a correlation between this prolongation and the severity of dementia,287,288 while other studies did not find any use for T2 relaxometry in the diagnosis of AD.289-291 Both T1 and T2 relaxation times are dependent on the free water content. Therefore, the CSF may contribute to increase the relaxation times, particularly in patients with brain atrophy. One study using a bi-exponential model to separate brain tissue water from CSF showed reduction of the T2 relaxation times in the right hippocampus of AD patients, and proposed that these patients may have a reduced water content in the brain tissue.292 These results are consistent with the neuropathological features of AD that increase tissue osmolality, such as the intraneuronal deposition of lipofuscin and neurofibrillary changes, as well as the extracellular deposition of β-amyloid.54

Magnetic resonance microscopy (MRM) requires higher field scanners, stronger gradients, and much longer sequences than conventional MR to create images with very high resolution. MRM is ideally suited for studying small animals and embryos, and may even depict images of single neurons in vitro.293-295 One MRM study in formalin fixed brain tissue sections of AD patients detected β-amyloid plaques using a 7.1 Tesla (T) magnet and gradient strengths as high as 850 mT/m, by means of a gradient-echo T2*-weighted sequence. This sequence created images with isotropic voxels of approximately 40 μm, and required scanning times as high as 20 hours.296 Another postmortem MRM study using a multislice fast-spin-echo T2-weighted sequence could also detect β-amyloid plaques in the brain of a transgenic mouse model of AD, with scanning times approaching what may be considered reasonable for in vivo imaging.297

Finally, molecular imaging represents an important advance of the neuroimaging techniques applied to the diagnosis of neurodegenerative diseases, due to the possibility of targeting non-invasively specific abnormal proteins that represent biologic markers of disease. Moreover, in the future, it may allow monitoring the effects of new therapies aimed at modifying the course of these diseases. Currently, most of the efforts are focused on the development of radioligands for in vivo detection of β-amyloid using PET and SPECT. However, the development of these new agents revealed to be a major challenge, since the employed molecules should not be toxic, must be labeled by a radioactive tracer, must be able to cross the blood-brain barrier, and then must specifically bind to β-amyloid. The molecular imaging probes examined for PET include derivatives of histologic dyes for β-amyloid (Congo red and thioflavins), stilbene derivatives, acridine analogues, serum amyloid protein (SAP), and the radiofluorinated 6-dialkylamino-2-naphthylethylidene (DDNP) analogues. In addition, rhenium complexes, Congo red derivatives, SAP, antibodies to amyloid, and fragments of β-amyloid itself have been examined for SPECT.45,46 The DDNP derivative 2-(1-{6-[2-[18F]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (18FDDNP), and the thioflavin T derivative 11C labeled Pittsburgh Compound-B were shown to label β-amyloid in living humans, both visualized by PET.298,299 Moreover, 18FDDNP also targets NFTs,300 and prion plaques301 in human autopsy brain tissue. Very recently, novel compounds were presented for in vivo imaging of β-amyloid with PET,302,303 as well as dual agents that may be employed both with PET and SPECT.304 MRM also enables imaging of β-amyloid after injection of magnetically labeled peptides in transgenic mice,305,306 and because MR provides much higher spatial resolution than PET or SPECT without ionizing radiation, it may become a good alternative to nuclear medicine.

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Keywords:

Aging; Alzheimer disease; amyloid; atrophy; brain; brain diseases; cerebrovascular disorders; dementia; diagnosis; differential diagnosis; emission computed tomography; emission computed single-photon tomography; entorhinal cortex; hippocampus; Lewy bodies; magnetic resonance imaging; memory; pathology; x-ray computed tomography

© 2004 Lippincott Williams & Wilkins, Inc.