Neuroimaging in non-Alzheimer dementias

Clinical Neuroscience Research 3 (2004) 383–395 www.elsevier.com/locate/clires

Neuroimaging in non-Alzheimer dementias Sarah Tomaszewski Fariasa,*, William J. Jagusta,b a Department of Neurology, University of California Davis, Davis, CA, USA School of Public Health and Helen Wills Neuroscience Institute, University of California, Berkeley

b

Abstract An accurate etiological diagnosis in patients presenting with symptoms of cognitive decline is becoming progressively more important as new approaches to treatment are developed. Neuroimaging technology may play an important role in assisting in the diagnosis of various dementing disorders. A variety of neuroimaging methods have demonstrated varying degrees of sensitivity and specificity to the anatomical or physiological brain changes that accompany various dementing disorders. In addition to the clinical application of these techniques for diagnostic purposes, they also offer the opportunity to examine structural, functional, and biochemical changes in the brain that will lead to new insights regarding the pathophysiology of various dementias and advance our understanding about brain-behavior relationships. This paper reviews neuroimaging studies relevant to several of the most common non-Alzheimer’s disease dementias including dementia with Lewy bodies, vascular dementia, frontotemporal dementia, primary progressive aphasia and semantic dementia. The particular imaging techniques covered will include high resolution structural imaging with magnetic resonance imaging and functional neuroimaging techniques such as single photon emission computed tomography, and positron emission tomography. q 2004 Elsevier B.V. All rights reserved. Keywords: Neuroimaging; Dementia; Lewy body dementia; Vascular dementia; Frontotemporal dementia; Primary progressive aphasia; Semantic dementia

1. Introduction An accurate etiological diagnosis in patients presenting with symptoms of cognitive decline is increasingly important as new approaches to treatment are developed. Although neuroimaging traditionally has been used primarily as a means of excluding reversible causes of dementia such as normal pressure hydrocephalus and brain tumors, it is now being proposed as a means to identify biological markers associated with specific dementia types. A variety of neuroimaging methods have demonstrated varying degrees of sensitivity and specificity to the anatomical or physiological brain changes that accompany various dementing disorders. These methods include high resolution structural magnetic resonance imaging (MRI) and functional neuroimaging techniques such as single photon emission computed tomography (SPECT) and positron emission tomography (PET). Although the focus of this entire issue, as well as this particular article, is on non-Alzheimer’s dementias, the neuroimaging findings in Alzheimer’s disease (AD) will * Corresponding author. Address: 4860 Y Street, Suite 3700, Sacramento, CA 95817, USA. Tel.: þ 1-916-734-6442; fax: þ1-916-456-9350. E-mail address: [email protected] (S. Tomaszewski Farias). 1566-2772/$ - see front matter q 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.cnr.2004.04.005

first be briefly summarized for comparative purposes. This is primarily because in clinical settings the differential diagnosis is most often AD versus other non-AD dementias. The remainder of this article will review neuroimaging studies relevant to several of the most common non-AD dementias including dementia with Lewy Bodies (DLB), vascular dementia (VaD), frontotemporal dementia (FTD), primary progressive aphasia (PPA), and semantic dementia (SD). Although there are a large variety of new neuroimaging techniques, this article is limited to examining only the most widely used methods including structural MRI, PET and SPECT.

2. Alzheimer’s disease Alzheimer’s disease is almost always part of the differential diagnosis when examining someone with a late life dementia. Pathologically, it is associated with neurofibrillary tangles that are most prevalent in the temporal lobe and neocortical association areas and relatively less abundant in primary sensory and motor cortices, brain stem nuclei and the basal ganglia [1]. Neuropathology first appears in the hippocampus and subiculum, followed by entorhinal cortex, inferior temporal gyrus, and finally

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neocortical regions, particularly in the parietal cortex [1,2]. Given this topographic distribution of pathology, it would be expected that structural and functional neuroimaging should show similar characteristic regional abnormalities. MRI studies. Although a large series of studies has documented that global cerebral atrophy is significantly greater in AD compared to normal aging, due to the variability in atrophy seen with normal aging the diagnostic usefulness of such a finding is minimal. Because the medial temporal lobes are pathologically affected early in the course of AD and because episodic memory loss is such an early and pervasive symptom of AD, structural imaging of the hippocampus and related regions has been the focus of much attention. Initial reports using MR imaging of hippocampal size in AD patients relative to controls showed very large reductions in hippocampal volume (on the order of 50%) resulting in very high sensitivity and specificity for classification [3,4] and this finding has been supported in a multitude of studies using a variety of different methods to quantify the volume of medial temporal lobe structures (Fig. 1). However, as will be discussed at several points in this paper, the diagnostic accuracy of hippocampal atrophy

in AD is lower when comparing AD to other dementia types rather than to normal controls. PET studies. The classic pattern of temporoparietal hypometabolism in AD is now a highly replicated finding [5 –8] (Fig. 2). It is associated with a high level of diagnostic accuracy (close to 90%) when compared to normal controls. However, as discussed throughout this article, lower levels of accuracy are usually obtained when comparing AD with other types of dementia. In PET studies the reductions in glucose metabolism accompanying AD occur early in the course of the disease in individuals who have mild degrees of cognitive impairment without a full dementia syndrome [9], as well as in individuals who are cognitively normal but have genetic predispositions to develop AD [10]. Metabolic deficits are not necessarily bilateral, but can be unilateral or markedly asymmetric and often correlate with the nature of the neuropsychological deficits [5,11 – 14]. Significantly reduced glucose metabolism in posterior cingulate cortex in AD has also been documented and this is one of the brain regions most severely hypometabolic in early and presymptomatic stages of the disease [10]. SPECT studies. SPECT studies of blood flow have also replicated the findings of functional reductions in posterior

Fig. 1. MR images of a patient with AD (top) and a normal aged subject (bottom). These images show generalized atrophy in AD and also considerable hippocampal atrophy in the AD subject but not in the normal subject (arrows).

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Fig. 2. FDG-PET images of a patient with AD (top) and a normal aged subject (bottom). Arrows demonstrate glucose metabolism in the temporal lobes (left) and the parietal lobes (right) which is clearly reduced in the AD patient.

temporal and parietal cortices that are reported using PET [15 – 17]. In general however, SPECT tends to have lower sensitivity and specificity for the identification of AD compared to PET imaging [18 –22]. Studies using SPECT investigating the difference between AD and normal controls have achieved rather high degrees of sensitivity and specificity for the diagnosis of AD, with values ranging from 80 to 90% [23,24].

3. Dementia with Lewy bodies Dementia with Lewy bodies (DLB) is increasingly recognized and there is now a large body of literature describing the associated clinical findings. The current diagnostic criteria emphasize a triad of symptoms including parkinsonism, persistent visual hallucinations, and fluctuating cognitive impairment [25]. Several studies have suggested that the cognitive profile in DLB differs somewhat from AD in that memory tends to be less impaired, while visuospatial processing may be worse [26,27]. However, clinical differentiation of DLB from AD remains

problematic. The difficulties in accurately diagnosing DLB must be kept in mind when evaluating brain imaging studies of patients without autopsy confirmation of diagnoses. MRI studies. In keeping with both the clinical findings of relatively preserved memory and pathological studies indicating relatively less involvement of the medial temporal lobe in DLB as compared to AD [28], a number of recent volumetric studies have indicated that there may be less medial temporal lobe atrophy on magnetic resonance imaging in DLB. In one study, hippocampal volume in DLB was intermediate to groups of AD patients and normals [29], while another group reported DLB patients to have hippocampal volumes equivalent to those of VaD patients but larger than those of AD patients [30]. These studies replicate findings from research using both visually-based ratings of medial temporal lobe atrophy [31] and voxelbased morphometry [32] in showing relative preservation of medial temporal lobe structures in DLB compared to AD. Several studies also suggest that amygdala volumes may also be relatively preserved compared to AD [29,30,32] and VaD [30].

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Several other brain regions have been investigated in DLB. An early study using CT scanning found that preferential frontal lobe atrophy occurs in DLB [33], however this finding has not been reproduced in more recent studies using MR techniques [31,32,34]. In another study, caudate volume was investigated because of the prominent Parkinsonian symptoms that accompany the disorder [35]. The lack of significant caudate atrophy compared to AD in this study supports the prominence of a neurochemical, as opposed to a structural, lesion in this disorder. Finally, there has been one serial MRI study examining rate of whole brain atrophy in DLB compared to both AD and VaD [36]. All three groups showed accelerated rates of atrophy over a 1-year period compared to age matched controls. Although there was some suggestion that atrophy rate in DLB (1.4% per year) may be slightly less than in AD (2%) and VaD (1.9%), these differences were not statistically significant and the finding is at odds with some other data suggesting that cognitive decline may be faster in DLB compared to AD [37]. The only variable that predicted atrophy was baseline severity of dementia as measured by the MMSE. PET studies. The most consistent functional imaging abnormality associated with DLB has been hypometabolism in the occipital lobe using PET [38 –40]. This is not associated with preferential atrophy in posterior brain regions [41,42], suggesting a functional rather than a structural basis. Several groups have shown pronounced reductions in the primary and association visual cortices in clinically diagnosed DLB [38] as well as in autopsy confirmed cases of DLB [39,43]. In all of these studies DLB could be distinguished from AD with a sensitivity of approximately 80% and a specificity of about 90%. In order to further define some of the potential neuropathological correlates of this occipital hypometabolism, Higuchi and colleagues [38] examined postmortem brains of patients with DLB, AD, and normal controls and found extensive spongiform changes and gliosis throughout the white matter with relative sparing of the gray matter in DLB. Such pathology was most abundant in the occipital regions and statistically different from the AD group and seemed to parallel the reduced glucose metabolism in this area. These finding are at odds with the relative distribution of the lewy bodies themselves (with comparatively high densities in the limbic and frontal cortex compared to the occipital cortex [44]). SPECT studies. SPECT results parallel PET studies showing hypoperfusion in the occipital lobe of DLB patients compared to other forms of dementia including AD [45 –47]. At least one study has suggested that the only difference in rCBF between DLB and AD is occipital hypoperfusion, with temporoparietal hypoperfusion abnormalities being common to both [47]. Other studies have suggested that medial temporal lobe blood flow deficits are not as great in DLB compared to AD [46] and such

findings are consistent with observations from structural imaging and neuropsychological studies. Summary. In conclusion, structure brain imaging in DLB shows relative preservation of medial temporal lobe volumes in comparison to AD, while brain function in DLB shows pronounced reductions in occipital lobe metabolism and perfusion. These findings appear to parallel the relatively less severe amnesia seen in DLB, and could also underlie the prominence of visuospatial deficits and/or visual hallucinations, although this has not been definitively shown.

4. Vascular dementia Some estimates suggest that VaD is the second most common type of dementia after AD [48,49]. It is caused by cerebrovascular pathologic changes that affect the cerebral cortex, subcortical white matter, subcortical nuclei (particularly the basal ganglia and thalamus), or a combination of these regions [50,51]. However, VaD is a heterogeneous disorder that is not well defined, with little consensus as to criteria for its clinical and pathological diagnosis. Diagnostic confusion extends to the neuropathological and vascular mechanisms that lead to VaD. Much of the confusion results from the frequent coexistence of vascular and AD pathology, raising questions as to the mechanisms of dementia with stroke and even casting doubt on the importance of vascular disease in causing dementia. As such, it has been suggested that neuroimaging may play an especially important role in improving diagnostic accuracy and obtaining a better understanding of the pathophysiology of VaD [52]. Recently, attention has been drawn to a subcortical variant of VaD which is related to small vessel disease and is pathologically characterized by lacunar infarction, focal and diffuse ischemic white matter lesions, and incomplete ischemic infarctions [53]. MRI studies. There is general consensus that MR imaging is sensitive to the presence of cerebrovascular disease [54] and notably VaD is the only dementia in which structural brain imaging plays a major role in supporting the diagnosis. This adds to the already substantial problem of diagnostic uncertainty when one evaluates studies of clinical cohorts, since the requirement for abnormal imaging introduces a selection bias into studies. However, this requirement is somewhat controversial and the diagnostic value of imaging criteria has not yet been thoroughly validated [55]. An additional problem is that while structural imaging can define the presence of cerebrovascular lesions, structural imaging can neither exclude AD as a factor in contributing to the dementia nor can it define the significance of the contribution of the vascular lesions in producing cognitive impairment and dementia. Several studies have examined the degree of both global and region-specific atrophy in VaD compared to normal

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controls and groups of other dementia types. Most studies suggest that global or whole brain atrophy is greater in VaD compared to normal controls [56]. However, compared to AD, some studies have suggested that moderate to severe atrophy is less common in VaD [57,58]. In terms of regional patterns of atrophy, several authors have found no specific pattern of selective atrophy separating VaD from various other dementias including AD and DLB [30,57,59]. Although hippocampal atrophy has also been reported in patients clinically diagnosed with VaD [59,60], concomitant AD is impossible to exclude in clinical samples. In view of the circularity involved in diagnosing and studying VaD patients with the same imaging modality, it is not surprising that studies have repeatedly reported higher prevalence of lacunar infarction and white matter hyperintensities (WMH) in VaD than other dementias [59,61,62]. However, an increase in the presence of both WMH and lacunes in VaD has also been reported in studies wherein imaging was not used to define diagnostic groups [63]; however, the diagnostic sensitivity of these radiological markers for VaD was low. Extensive white matter abnormalities have been reported in AD [62,64,65], and FTD [66], as well as in VaD [59,61]. These studies can be interpreted as showing that WMH may not invariably reflect vascular pathology, or that clinical diagnoses are inaccurate. In keeping with these data, Charletta and colleagues [58] found that the presence of white matter lesions was common in both VaD (100%) and AD (93%); however, lacunar and cortical infarcts were significantly more common in VaD. Several studies have attempted to examine the relative importance of WMH and lacunes in contributing to clinical presentation. Some studies have found no correlation between either lacunes or deep white matter lesions and global cognitive functioning [67], despite the fact that both blood flow and glucose metabolism in the cortex and white matter [67] and various measures of atrophy [59] were associated with cognition. However, when more specific measures of cognition have been examined in VaD (rather than global screening measures of cognition), aspects of executive functioning and processing speed have been found to correlate with degree of WMH [68 – 70]. Further, this pattern of association was essentially the same in participants with and without lacunes [69]. In general, however, many cognitive variables (i.e. memory and language) tend to be more strongly associated with cortical atrophy and measures of hippocampal atrophy than with either WMH or lacunes [68 –71]. Finally, several studies have examined how abnormalities on MRI change over time in VaD. The Australian Stroke Prevention Study [72], the largest study to examine such change, reported that semi-quantitative ratings of WMH progressed in 17.9% of normal individuals over a 3year period, although this did not influence measures of cognitive function. Two other studies found increases in WMH volume over time in normals [73] and in a mixed sample of both normals and mild to moderately demented

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individuals [74]. In addition to WMH change over time, atrophy increases over time in patients with VaD though not at rates faster than DLB or AD [74]. PET studies. There have now been a number of studies examining patterns of rCBF associated with VaD. Several studies have suggested that VaD may be associated with a pattern of reduced rCBF in the frontal cortex [52,75], a pattern that would be consistent with the pronounced attention/executive dysfunction in VaD noted in neuropsychological studies [76,77] and which may have its pathological basis in disruption of subcortical-frontal projections. Sultzer and colleagues [75] examined 11 patients with VaD with exclusively subcortical vascular lesions on MRI and found frontal hypometabolism to be the most common metabolic deficit in those with lacunar infarcts of basal ganglia or thalamus. The asymmetry of hypometabolism correlated with asymmetry of subcortical infarction. While some studies suggest preferential frontal involvement in VaD, other studies have found that VaD may be associated with more widespread metabolic abnormalities [78 –80]. For example, Yao et al. [79] studied five patients with Binswanger’s disease and found marked decreases in both rCBF and CMRO2 in the parietal, frontal and temporal cortices in addition to large reductions in rCBF and CMRO2 in the white matter when compared to normal controls. Mielke and colleagues [80] compared VaD to AD, finding that cortical hypometabolism was similar in VaD and AD (both showing reduced rCMRGI in temporoparietal and frontal association areas), while metabolism of subcortical structures including the basal ganglia and thalamus as well as the cerebellum were reduced only in the VaD patients. SPECT studies. Some studies using SPECT, like those using PET, have demonstrated generalized blood flow reduction in VaD compared to normal controls [81], while others have suggested a more focal (in many cases frontal) presentation. Yang et al. [82] found reductions that predominated in subcortical, frontal and temporal regions in VaD patients compared to controls, while Shyu et al. [56] found blood flow reductions in subcortical and frontal regions in mildly demented VaD patients and globally in those with more severe dementia. SPECT studies of the differential diagnosis of VaD vary considerably. In one study comparing AD, FTD and VaD [81], VaD was associated with reduced medial temporal perfusion compared to FTD, with no differences between VaD and AD. Others [83] reported bilateral anterior rCBF abnormalities significantly increased the odds of having FTD as opposed to VaD; whereas, bilateral posterior rCBF abnormalities significantly increased the odds of having AD as opposed to VaD. Patchy rCBF changes significantly increased the odds of a patient having VaD as opposed to AD, a finding that is consistent with a number of other studies that have also reported rCBF, cerebral oxygen, and glucose metabolism are decreased in a patchy manner in patients with VaD [5,84]. Other studies have not found

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a specific pattern of reduced blood flow that was diagnostic in the differentiation VaD from mild AD [81] VaD from AD and FTD [63]. The failure to differentiate VaD from AD in some of these studies could clearly reflect overlapping pathology. Summary. Structural MRI studies consistently show that both lacunes and WMH, although common in many dementia types as well as in cognitively normal older adults, are seen with increased frequency in VaD. However, the use of these variables as diagnostic markers of VaD makes interpretation of these results problematic. The functional neuroimaging changes associated with VaD are still controversial but many studies indicate subcortical lesions seem to preferentially result in frontal cortical hypometabolism. Other studies have shown no specific regional pattern, with patchy areas of hypometabolism. Given the heterogeneity of VaD, it is not surprising that there is marked variability in the metabolic abnormalities associated with the disease. It is likely that some of this variability is a function of the location of the vascular pathology, as well as the presence of concomitant Alzheimer pathology in many cases.

5. Frontotemporal lobar degeneration Frontotemporal lobar degeneration (FTLD) includes three distinct clinical syndromes: (1) the frontal variant, often referred to as FTD, in which changes in social behavior and personality predominate, (2) Primary Progressive Aphasia (PPA) in which the phonological and syntactical components of language are affected, and (3) semantic dementia (SD) in which there is a breakdown in the conceptual database which underlies language production and comprehension, although deficits in nonverbal

semantic knowledge are also frequently present [85]. The fact that spongiform degeneration, gliosis and neuronal loss are the most common pathological findings in FTD, PPA and SD has lead several researchers to suggest that all of these disorders share an underlying etiology but that the clinical phenotype of FTLD will vary depending on the brain region primarily affected. For example, Neary and colleagues [86] reported on two brothers, one of whom developed a progressive language disorder with behavioral disturbances developing only late in the course of the disease and had reduced perfusion extending throughout the left hemisphere on SPECT, and predominant left frontotemporal atrophy. The other brother developed severe personality and behavioral disturbances early in the course, showed reduced perfusion bilaterally in the anterior hemispheres (more marked on the right) using SPECT, and had bilateral frontotemporal atrophy. In both cases the histological findings were similar, revealing severe loss of large cortical neurons, spongiform changes affecting the outer cortical laminae, and mild gliosis without Pick or Lewytype inclusions or neurofibrillary tangles. Despite the notion that histopathological findings such as these represent the majority of cases of FTD, PPA and SD, other pathological findings have been reported including AD [87], Pick’s Disease [88], and even Creutzfeld-Jakob’s disease [87,89]. 5.1. Frontotemporal dementia (Frontal variant) MRI studies. Not surprisingly several studies have noted increased atrophy in frontal lobe structures in FTD compared to other patient groups (Fig. 3). Although the situation is not as problematic as in VaD, selection bias can influence results since individuals with more striking focal atrophy revealed on MRI are more likely to be included in FTD cohorts. Compared to AD, FTD patients show bilateral

Fig. 3. MR images of a patient with frontotemporal dementia (frontal variant) showing atrophy of anterior temporal and frontal lobes bilaterally.

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Fig. 4. FDG-PET images of a patient with frontotemporal dementia (frontal variant) showing profound glucose hypometabolism in frontal and anterior temporal lobes.

frontal atrophy [90,91] as well as anterior temporal lobe atrophy [91]. Although FTD is associated with less severe episodic memory deficits compared to AD, visually based MRI studies have not supported a notable difference in hippocampal atrophy between these two groups [63]. More sensitive studies using volumetric analysis have found that FTD and AD show equally severe entrorhinal atrophy, while the posterior hippocampus is less severely atrophic in FTD as compared to AD [90,92]. Finally, longitudinal data [93] show that atrophy in the frontal lobes progresses more rapidly in FTD patients than AD patients, although rates of atrophy in posterior brain regions are comparable. PET studies. A number of studies have shown that FTD is associated with predominant hypometabolism in the frontal and anterior temporal lobes (Fig. 4) [40,94,95]. Hypometabolism of the parietal lobes has also been reported [94], but is generally less severe than the metabolic abnormalities observed in AD [95]. SPECT studies. Reduction in frontal lobe rCBF using SPECT is now also a highly consistent finding across a large number of studies when comparing FTD both to normals as well as individuals with other dementia types [96 – 100]. Several studies have suggested that this frontal hypoperfusion is useful in differentiating FTD from AD [101,102]. Such findings have been reported even in cases where it was clearly documented that functional imaging had not influenced diagnostic decisions [100]. Furthermore, perfusion abnormalities may be seen before atrophy is evident [99,103], although behavioral changes may precede SPECT abnormalities [104]. Finally, there have been a few studies examining the relation between specific clinical characteristics of FTD and perfusion abnormalities with findings suggesting that right anterior hypoperfusion on SPECT imaging is associated with prominent behavioral disturbances, while left-lateralized hypoperfusion was related to language disturbances [105,106]. Some research has also shown that measures of executive functioning correlate with frontal and temporal blood flow [107], while other studies have not found a relationship between cognition and SPECT [108]. Summary. Although frontal atrophy has been described in association with FTD, it may not be evident early in

the course of the disease (particularly on visual inspection). Additionally, more widespread atrophy (including hippocampal atrophy) may be present during the course of the disease. Decreased metabolism and perfusion in the frontal lobes is a highly consistent finding whether measured by PET or SPECT, although early behavioral symptoms may occur in the absence of obvious metabolic abnormalities. Both temporal and parietal lobe hypoperfusion have also been reported in a number of studies, although it has not always been demonstrated. 5.2. Primary progressive aphasia PPA is a syndrome that most typically has been characterized as including nonfluent speech, agrammatisms, and anomia. However, there is wide variability in the exact nature of the language disorder that can be present, ranging from a purely motoric or speech production deficit (sometimes referred to as aphemia) to either a primary expressive or receptive, or mixed receptive or expressive language dysfunction. Initial studies grouped all patients with early language/speech symptoms under the rubric of PPA, making it difficult to interpret how the exact nature of the presentation may relate to the localization of neuropathologic or neuroimaging findings. More recently a few studies have attempted to subdivide patients based on the particular clinical presentation (i.e. fluent vs. nonfluent), although such methods of categorization have been primarily qualitative, making replicability of findings difficult. Neuropathological reports on nearly 50 cases of PPA have now been reported in the literature and have identified abnormalities in frontal, perisylvian and temporal cortices [109 – 112]. According to a recently published summary, 60% of the cases showed nonspecific focal atrophy or neuronal loss with gliosis lacking distinctive histopathology, 20% showed tau-positive, intracytoplasmic bodies of Pick’s disease, and less than 20% showed AD pathology [113]. MRI studies. Studies that have included structural imaging in patients initially presenting with progressive and rather isolated language deficits have generally found prominent left hemisphere atrophy, most typically being noted in the superior and middle temporal lobe gyri and

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perisylvian areas [114 – 116]. Evidence of frontal lobe atrophy has been reported in some but not all cases [115] as well as within the left inferior parietal lobule [113]. A pattern of nonfluent language dysfunction tends to correlate with predominantly left frontal and perisylvian atrophy, while the fluent group showed left temporal atrophy involving the superior, middle, and inferior temporal gyri, hippocampus and parahippocampal gyrus on MRI and these patterns of atrophy are generally accompanied by similar patterns of metabolic abnormalities [113,117]. However, studies have not supported a strong association between the degree of specific quantitatively assessed language deficits (i.e. confrontation naming) and whole brain or regional brain atrophy [113]. PET studies. The currently available PET data in PPA is essentially limited to case studies. The available data suggest that metabolic abnormalities tend to predominate in the left hemisphere, with variability in the degree of involvement of frontal and temporal areas, and in some cases parietal areas [118 – 120]. There is some suggestion that the exact nature of the language deficit may be related to the site of hypometabolism (i.e. cases of predominant articulatory or word production deficits and oral motor apraxia have been associated with a prominent left frontal metabolic deficit [117,120]) but very limited information is as yet available. In a few cases it has been noted that PET abnormalities were observed when structural imaging was only minimally abnormal or normal [118,119], suggesting that functional imaging may have an increased sensitivity to the changes associated with PPA. SPECT studies. Results using SPECT in PPA coincide with those reported using PET. In the majority of cases PPA is associated with predominantly a left rCBF reduction [121, 122,116] within the frontal, temporal and parietal areas. One study to date has examined the association between perfusion deficits in PPA and clinical symptoms, finding that degree of dsynomia was strongly correlated with reduced frontotemporal 99mTc-HMPAO uptake [123]. Summary. Although primarily in the form of case studies, available MRI data seem to consistently show predominant

atrophy in the left hemisphere, with variability in frontal, temporal and parietal regions. Even when atrophy is not clearly visualized on structural images, functional focal deficits have been reported using both PET and SPECT imaging. The common finding is left temporal hypoperfusion with variable extension to other lobes, including frontal and parietal areas. Although some right-sided abnormalities have been found in a few cases, the metabolic state of the right hemisphere has most often been within normal or near normal limits. Thus, resting functional imaging data primarily reflected the clinical focality of PPA. 5.3. Semantic dementia Although case descriptions of patients with a selective impairment of semantic knowledge were first reported in 1975 by two independent groups [124,125], it has not been until much more recently that this syndrome, now referred to as semantic dementia (SD), has been the focus of more systematic investigation. This is due in large part to the work of Neary and others [85] who have developed specific diagnostic criteria. Using their current diagnostic system, patients with SD present with impairment in naming and loss of word meaning. Speech is fluent with normal articulation and prosody and relative preservation of syntax. Often these patients have surface dyslexia and dysgraphia. Impaired face and object recognition may also be present in the absence of visuoperceptual deficits. Compared to AD, episodic memory (particularly for recent life events) is relatively preserved early in the course, although verbal memory may be affected by anomia. As noted previously, many cases of SD had been previously lumped under PPA and thus at this point it is fairly difficulty to draw definitive conclusions regarding either clinical or neuroimaging differences between PPA and SD. MRI studies. Studies of regional patterns of atrophy in SD compared to both age-matched controls and AD patients indicate that SD is associated with pronounced atrophy in the temporal pole that is most often bilateral, but is typically greater on the left than the right (Fig. 5) [126 –128]. Atrophy

Fig. 5. MR images of a patient with semantic dementia, demonstrating left anterior temporal atrophy.

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can also extend into the inferior and middle temporal and fusiform gyri [126 – 128]. A number of studies have now also found that the amygdala, entorhinal cortex, and hippocampus are also involved [127,128]; but as opposed to AD in which atrophy is largely symmetric, SD patients show asymmetric atrophy involving primary the left hemispheric structures. Additionally, the SD group showed an anterior to posterior gradient in the distribution of the temporal lobe atrophy, with more marked anterior atrophy, while the AD group did not show a similar distribution [128]. This anterior/posterior gradient of the amygdala and hippocampal regions is also found when comparing SD to the frontal variant of FTD [129]. SPECT and PET studies. At the current time there are essentially no group studies examining the use of either PET or SPECT in patients with well characterized SD. There have been several case reports. One study found that, in a single subject, rCBF as measured by SPECT was normal [130], while in another series of five patients brain imaging by SPECT scan implicated the left temporal region in all cases [131]. In another, larger case series, mean rCBF values were similar in both SD and FTD with greatest reduction in the frontal and anterior temporal cortices bilaterally, while PPA was associated with a more unilateral (left) deficit in the frontal and temporoparietal regions [132]. Two studies have examined PET activation during various semantic decision making tasks in patients with SD, both showing reduced left posterior inferior temporal activation coupled with increased left anterior superior and inferior frontal activation, as well as increased activation of the homologous right anterior language areas [130,133]. Summary. Neuroimaging studies of SD are extremely limited at this point. Available data suggests that structural imaging tends to show atrophy that is most pronounced in the anterior temporal poles (left greater than right). Atrophy of medial temporal lobe structures has also been reported with greater left involvement and an anterior to posterior gradient. Unfortunately, it seems too premature at this point to draw any strong conclusions about the pattern of functional neuroimaging findings associated with SD.

6. Summary Brain imaging with both structural and functional neuroimaging techniques has the potential to provide clinicians with information that can help determine specific dementia diagnoses. There is emerging consensus related to a number of different findings. Hippocampal atrophy, although highly associated with AD, has been found in other dementia types. There seems to be somewhat less hippocampal atrophy in DLB as compared to AD, and FTD is associated with an anterior – posterior gradient not seen in AD. Temporal and parietal hypometabolism or hypoperfusion using PET and SPECT are consistent findings

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associated with AD and can be particularly helpful in differentiating AD from FTD, which demonstrates frontal and anterior temporal hypoperfusion. Despite the fact that DLB is not associated with increased occipital atrophy, hypoperfusion of the occipital lobe in DLB has been replicated by a number of studies. Although the existing studies provide considerable data supporting the utility of these techniques, problems remain. Both DLB and VaD are plagued by conceptual and methodological problems related to clinical diagnosis. The diagnostic reliability of DLB is low and thus, without autopsy confirmation, study results are difficult to interpret and different findings across studies may relate primarily to diagnostic issues. There have been a number of diagnostic criteria proposed for VaD, all of which have weaknesses and none of which are universally accepted. One important issue with regard to VaD is that of the etiologic role of WMH and lacunar infarcts in dementia. Such radiological markers can be seen in normal older adults and are common in essentially all dementia types. Although these changes are generally associated with risk factors for cerebrovascular disease, their occurrence in individuals without cerebrovascular risk factors, along with their somewhat unclear pathological correlates necessitates caution in interpreting these findings as indicative of VaD. Finally, there is very little data examining structural, and particularly functional imaging in the non-frontal variants of FTD—PPA and SD. What is available is limited to case reports. Additionally, future studies need to more specifically define the nature of the language-related deficits in groups of patients labeled as PPA and SD in order to better characterize the association between patterns of localized brain dysfunction and specific language deficits. Thus, the current state of neuroimaging in nonAlzheimer dementias is intimately related to conceptual and diagnostic issues. Lack of reliable and valid diagnostic criteria somewhat limit the interpretation of available imaging data in many different diseases, and overlaps between these ‘non-AD’ dementias and AD are well described. Nevertheless, many trends have been reviewed in this article that are consistent across studies from different laboratories. These data, while not always validated by the most rigorous standards, can provide some guidance to clinicians in some cases requiring ancillary tests for differential diagnosis. As knowledge accrues from clinical, pathological and imaging studies over the next few years, it seems likely that the role of structural and functional imaging in dementia diagnosis will become clarified.

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