Curr Neurol Neurosci Rep (2014) 14:489 DOI 10.1007/s11910-014-0489-x

NEUROIMAGING (DJ BROOKS, SECTION EDITOR)

Imaging Frontotemporal Lobar Degeneration Janine Diehl-Schmid & Oezguer A. Onur & Jens Kuhn & Traugott Gruppe & Alexander Drzezga

# Springer Science+Business Media New York 2014

Abstract The term frontotemporal lobar degeneration (FTLD) refers to a group of neurodegenerative disorders that target the frontal and temporal lobes. It accounts for approximately 10 % of pathologically confirmed dementias but has been demonstrated to be as prevalent as Alzheimer’s disease in patients below the age of 65. The 3 major clinical syndromes associated with FTLD include behavioral variant frontotemporal dementia, semantic and nonfluent variants of primary progressive aphasia. The more recently introduced term logopenic variant appears to represent an atypical form of Alzheimer’s disease in the majority of cases. The neuropathology underlying these clinical syndromes is very heterogeneous and does not correlate well with the clinical phenotype. This causes great difficulties in early and reliable diagnosis and treatment of FTLD. However, significant advances have been made in recent years via the application of magnetic resonance imaging and positron emission tomography All authors contributed equally. This article is part of the Topical Collection on Neuroimaging J. Diehl-Schmid Department of Psychiatry and Psychotherapy, Technische Universität München, München, Germany O. A. Onur Department of Neurology, University of Cologne, Köln, Germany O. A. Onur Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Center Jülich, Jülich, Germany J. Kuhn Department of Psychiatry and Psychotherapy, University of Cologne, Köln, Germany T. Gruppe : A. Drzezga (*) Department of Nuclear Medicine, University of Cologne, Kerpener Str. 62, 50937 Köln, Germany e-mail: [email protected]

imaging methods as biomarkers. The current review aims to provide a synopsis on the value of magnetic resonance imaging-based and molecular imaging procedures in FTLD. Keywords Frontotemporal lobar degeneration . FTLD . Imaging . PET . MRI . fMRI . fcMRI . Connectivity . Amyloid . Tau . Atrophy

Introduction Frontotemporal lobar degeneration (FTLD) is an umbrella term for a heterogeneous group of familial and sporadic neurodegenerative disorders that primarily affect the frontal and temporal lobes. Since its first description by Arnold Pick in 1892, the term “frontotemporal dementia” has been subject to multiple revisions regarding its classification into the taxonomy of neurodegenerative diseases, which also emphasizes the difficulty managing this disease. Three major clinical subtypes can be distinguished based on the early and predominant symptoms and signs: (1) behavioral variant frontotemporal dementia (bvFTD), 2) the language variants of FTLD, and (3) overlapping syndromes. Regarding the last, it is noteworthy that up to 15 % of FTLD patients develop symptoms of motor neuron disease or atypical Parkinsonian syndromes, corticobasal syndrome, and the progressive supranuclear palsy syndrome. As these are all hybrid expressions, they form a complex and heterogeneous subgroup of FTLD and will not be included into the present review. Demographic Data Only a limited number of studies that allow estimation of the prevalence and incidence of FTLD are available. While FTLD is a common cause of young-onset dementia, within the

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population as a whole FTLD is a rare disorder [1] and classified as an orphan disease (Orpha number ORPHA282 of www.orpha.net). The estimated prevalence is 15–22/100,000 [2]. Compared with Alzheimer’s disease (AD), the age of onset in FTLD is earlier, with a mean age of onset of about 58 years [3]. Patients have been described with an onset even in their thirties [4]. The diagnosis is often delayed by several years after first medical advice is sought [5]. FTLD is a malignant disorder that leads to death on average 3 to 10 years after diagnosis [4, 6]. Genetics Up to 40 % of FTLD patients have a history suggestive of familial transmission; about 10 % of the patients show an autosomal dominant inheritance pattern [7]. Mutations in several genes have been identified as causal. Mutations in the microtubule-associated protein tau (MAPT) gene account for up to one-fifth, and mutations in the progranulin (GRN) gene account for up to one-fourth of familial cases [8••]. Recently, abnormal expansion of a hexanucleotide repeat in the chromosome 9 open reading frame 72 (C9orf72) gene has been found to be a common genetic cause of FTLD accounting for about 20 % of familial cases [9]. Mutations of the valosin containing protein gene and chromatin modifying protein 2B gene are responsible for a minority of familial FTLD cases. Neuropathology The neuropathologic classification is based on the identification of intracellular protein inclusions. Three broad subdivisions have been recognized: (1) FTLD with MAPT– positive inclusions; (2) FTD with tau-negative, transactive response DNA-binding protein 43 (TDP-43)–positive inclusions; and (3) a small proportion of cases characterized by fused in sarcoma protein-inclusions [10••]. Clinical Presentation bvFTD is the most common subtype and is—according to the revised diagnostic criteria [11••] —characterized by early decline and a progressive deterioration of social behavior and personal conduct, as indicated by early disinhibition, apathy or inertia, loss of sympathy or empathy, perseverative and stereotyped or compulsive behaviors, and hyperorality or dietary changes. As the patients often perform well on standard neuropsychological tests of memory, language, attention, and visual spatial ability in the first years of their disease, diagnosis can be difficult. The semantic and nonfluent variants of primary progressive aphasia (svPPA and nfvPPA) [11••], 2011 #7847}, form the language variants of FTD. They are

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initially characterized by a breakdown in language function. The most prominent clinical finding in svPPA is a progressive semantic impairment. Patients lose conceptual knowledge about the world, which affects their ability to understand the meaning not only of words but also of visual perceptions, sounds, odors, etc. Patients are significantly impaired in word comprehension and confrontation naming; speech, however, is fluent and grammatically correct [12••]. Nonverbal memory and perceptual and visuospatial abilities are preserved in the earlier stages of the disease process. nfvPPA is a disorder of language expression and of motor speech with agrammatism and effortful halting speech while other cognitive domains are spared in the early stages of the disease [12••]. Although primary progressive aphasia (PPA) is primarily a disorder of language, behavioral alterations very similar to bvFTD occur also during the course of PPA. Behavioral disturbances in svPPA include loss of embarrassment, irritability, disinhibition, selfishness, exclusive preferences for food, neglect of hygiene, stereotyped, perseverative, and compulsive behaviors [13, 14]. In nfvPPA, very mild behavioral disturbances are often obvious but should not dominate the clinical picture in the early disease stages. However, severe behavioral alterations may occur in advanced disease stages [12••, 15]. svPPA and nfvPPA are categorized as PPA. Recent International Consensus Criteria suggest a third type of PPA syndrome that does not fit the criteria for svPPA or nfvPPA, termed logopenic variant (lvPPA) [12••]. In this syndrome, patients present with phonological disorders as well as impaired word retrieval and sentence repetition, whereas motor speech, grammar, and comprehension are relatively intact. It has been shown that lvPPA is often a manifestation of AD— confirmed using beta-amyloid imaging—rather than because of typical FTLD-pathology [16]. In practice, the clinical phenotypes of the different FTLD syndromes can be overlapping, and these disorders can also be confused with AD. Correlation studies between clinical findings and post mortem histopathologic evaluation consistently reveal poor specificity of clinical classification with regard to the prediction of the underlying neuropathology [17••, 18 20]. Thus, even in an expert setting, clinical classification may not be sufficiently reliable. Furthermore, it is well accepted that the onset of neurodegenerative pathology occurs years to decades in advance of first clinical symptoms, which naturally limits the value of clinical assessment with regard to early diagnosis. Given this, there is a clear need for suitable biomarkers and modern imaging tools have a great potential to fill this gap.

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Magnetic Resonance Imaging-Based Techniques in FTLD There have been a considerable number of volumetric magnetic resonance imaging (MRI) studies in FTLD designed to detect grey matter atrophy and atrophy patterns with the aim of differentiating between the subtypes (Figs. 1 and 2).

Fig. 1 PET- and MRI-findings for three types of FTLD. Top: behavioural variant frontotemporal dementia (bvFTD), middle: semantic variant of progressive aphasia (svPPA), bottom logopenic variant of progressive aphasia (lvPPA). For each syndrome on the left side of the illustration: Axial slices of [18 F]FDG, structural MRI and fusion of both. Right side: Surface rendered display of hypometabolism (top) and results of amyloid-imaging (bottom). All images were acquired at the Technische Universität München, Munich/Germany on an integrated Siemens mMR system (funded by the German Research Foundation/DFG). R: Right side of the brain, L: Left side of the brain

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Most studies have targeted bvFTD and shown that even within this subgroup different patterns of atrophy occur. Based on a cluster analysis, it was proposed that it is possible to distinguish between 4 different patterns [21]. The first 2 patterns show predominantly frontal atrophy with 1 of the patterns restricted to the frontal area, whereas the second

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Fig. 2 Typical patterns of grey matter atrophy in patients with different FTLD subtypes. Atrophy patterns are overlaid on the coronal (top row), sagittal (middle row) and axial slices (bottom row) of the Montreal Neurological Institute (MNI) template. Top and bottom rows: Right on

the figure is right side of the brain. Middle row: Left on the figure is dorsal and right on the figure is rostral in the brain. Used with permission of Agosta et al. [104].

pattern shows extended atrophy in the temporal lobe. The 2 other patterns show either temporal lobe atrophy alone or more widespread atrophy covering the temporofrontoparietal area. Another feature of this pattern is its asymmetrical character. Recently, a meta-analysis using the method of anatomical likelihood estimate was published in which the peak coordinates of structural imaging studies were taken from several studies covering 417 patients resulting in maps with probabilities for every voxel [22••, 23]. Interestingly, this analysis did not reveal the temporal lobe as a primarily affected area but rather highlighted the frontomedian cortex, the basal ganglia, the anterior insulae, and the thalamus. This could be due to the method as only local maxima and not the entire clusters were analyzed. However, if the temporal lobes were to represent a primarily affected region, peak maxima should have been detected in some of the studies. Furthermore, a meta-analysis using a different approach (the voxel-based meta-analytic tool ES-SDM) also revealed grey matter volume decrease primarily in frontal areas, in the insula, and the striatum [24]. In a separate meta-analysis using likelihood estimates svPPA was associated with atrophy in the left subcallosal area,

the left anterior superior temporal sulcus, the middle temporal gyrus, in both amygdalae, and the inferior part of the temporal poles [25]. For nfvPPA, the analysis revealed alterations in the left hemisphere in the Broca’s area (pars opercularis of the inferior frontal gyrus), the upper part of the temporal pole, the lentiform nucleus, and the middle frontal gyrus [25]. A recent longitudinal study has reported that in svPPA the atrophy emerges fastest in temporal areas, whereas in nfvPPA the frontal areas were targeted [26]. In addition, the asymmetry increased over time. In another longitudinal study using tensor-based morphometry similar results were reported. BvFTD was associated with alterations frontally, svPPA in the fusiform gyrus and nfvPPA in the parietal lobe [27]. In summary, depending on the clinical phenotype, different atrophy patterns for the subtypes are detectable at a group level. These patterns might be helpful in classification of the subtypes. However, longitudinal studies show this particular imaging approach is not powerful enough to enable early detection and classification of disease at a single subject level. An alternative approach in neuroimaging is to divide FTLD patients according to their genotype, rather than with regard to clinical symptoms. Carriers of a mutation in the C9orf72 gene show symmetric atrophy of frontal regions extending to other

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lobes and the cerebellum. In MAPT mutation carriers, atrophy can be observed in anteromedial temporal areas, orbitofrontal areas, and the fornix, whereas GRN mutations are associated with temporo-parietal and inferior frontal atrophy [28, 29••]. Further, the pattern in MAPT mutations is symmetrical but in GRN mutations asymmetrical [28]. With this approach presymptomatic family members of mutation carriers can be investigated. This gives an opportunity to seek for very early signs of the disease and to build a foundation for early diagnosis (and potentially treatment) in the future. As images can be acquired even in presymptomatic stages, longitudinal studies can be performed to optimize our understanding of the disease development [30] and to assess effects of interventions. Besides cortical thickness and grey matter volume, the integrity of the fibers and tracts is of particular interest in the assessment of neurodegeneration. This can be assessed by means of diffusion-tensor-imaging (DTI). Fractional anisotropy is a measure of directionality of water flow—fiber tracts restrict water diffusion along a particular axis. A high fractional anisotropy value means restricted diffusion along tracts which serve as a barrier while a low value reflects free diffusion in all directions. In addition, levels of diffusivity (mean, radial, and axial) can be computed. Hence, assessing the diffusion of water along structures gives the opportunity to track integrity of the connections within the brain. Whereas bvFTD is associated with wide ranging and bihemispheric alterations of tracts connecting frontal and temporal areas such as the anterior superior and inferior longitudinal fasciculus, the inferior fronto-occipital fasciculus, the anterior cingulate, and parts of the corpus callosum [29••, 31], PPA cases show more focal and asymmetric changes. svPPA causes changes in the left uncinate fasciculus and the left inferior longitudinal fasciculus [29••, 32]; nfvPPA causes changes in the left arcuate fasciculus and superior longitudinal fasciculus [29••, 32, 33]. As valid tools for meta-analysis of DTI data are not yet established, pooled analyses across several studies are not currently available. Besides the above-mentioned imaging techniques, other less commonly used MRI-approaches may allow the detection of specific changes in FTLD. For example, magnetic resonance spectroscopy, which provides an estimation of brain metabolite levels, has the potential to characterize neurodegenerative disorders beyond the measurement of atrophy/ structural changes. So far, MRI spectroscopy has had a limited application in FTLD, however. In a small study, 2 bvFTD patients showed an increase of myo-inositol, a marker for gliosis in the cingulate cortices whereas 3 svPPA patients showed a reduced N-acetylaspartate peak, a marker of neuronal integrity, in frontal and temporal areas [34]. In another study, reduction of N-acetylaspartate was observed in the dorsolateral prefrontal cortex and the motor cortex in 26 patients suffering from FTLD [35]. Comparing different

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dementia syndromes, however, revealed no significant differences between FTLD and AD [36, 37]. Another MRI-method with clinical potential is arterial spin labelling (ASL) MRI, which provides a measure of cerebral blood flow coupled to brain metabolism [38]. In comparison to AD, patients with FTLD showed bilateral frontal hypoperfusion, whereas hypoperfusion targeted posterior regions like the posterior cingulate, the medial parietal regions, and the precuneus in AD patients [39]. Generally, the patterns detected through ASL have been demonstrated to be similar to changes in metabolism reported using positron emission tomography (PET) imaging with 18 F-fluorodeoxyglucose (18 F-FDG) [39]. As access to MRI is widely available, ASL imaging might represent a future alternative to FDGPET. This option may gain importance in multimodal imaging approaches, eg, using novel integrated PET/MR imaging instrumentation (see below chapter multimodal imaging).

Functional Magnetic Resonance Imaging Functional magnetic resonance imaging (fMRI) detects changes in neuronal activation both at rest and during specific tasks compared with a control condition. The principle of these so-called “activation studies” is based on the blood oxygen level dependency (BOLD) effect (ie, the concept that neuronal activity leads to deoxygenated hemoglobin in draining venules, which is more paramagnetic than oxygenated hemoglobin). Because of the effect of neurovascular coupling, neuronal activation is assumed to lead to an increased flow of oxygenated blood in the corresponding brain regions, causing a change in local magnetic field [40]. Activation studies in FTLD disorders have only infrequently been performed. Rombouts and colleagues demonstrated an attenuated activation of the frontal cortex during working memory performance in patients with early frontotemporal dementia as compared to patients with early Alzheimer's disease[41]. A study of Wilson and colleagues demonstrated that the increase in activation of the posterior inferior frontal cortex, observed in healthy controls processing increasing sentence complexity, was not detectable in nfvPPA patients [42]. In another activation study, in svPPA a lack of activation in superior temporal regions was observed during reading compared with controls [43]. However, apart from insights on the pathophysiological nature of different forms of FTLD, a clinical utility of MRI activation studies for the assessment of FTLD has not been established. Resting state fMRI can be used to detect functional connectivity between different brain areas (often referred to as functional connectivity MRI/fcMRI). The concept of this approach is based on the idea that communicating brain areas demonstrate slow synchronized oscillations of BOLD signal which are correlated over time. Consequently, functionally

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connected brain regions reveal patterns of synchronous fluctuations in BOLD-signal, which reflect different functional networks [44]. This approach is of major interest because more recent theories of neurodegeneration postulate that different types of neurodegeneration differentially affect these predefined networks of the brain (network degeneration hypothesis). Seeley and colleagues were able to demonstrate that patterns of atrophy in different neurodegenerative disorders including bvFTD, svPPA, and nfvPPA, clearly mirrored disruption of common functional connectivity networks seeded on the basis of the disease specific atrophy-peaks in healthy controls [45••]. Two functional networks are of particular interest with regard to FTLD [30]. The first one is the so-called default mode network (DMN). This network comprises a group of brain regions deactivated during cognitively demanding tasks requiring externally oriented attention. Later imaging studies showed that this network can reliably be identified during resting conditions and it is considered to be involved in internally focused cognitive processes (eg, planning of future behavior etc.). Anatomically, this network includes the medial prefrontal cortex, posterior cingulate, angular gyri, and precuneus. The second network of interest is the salience network, which is thought to moderate the need for behavioral change and possibly control the activity in other networks. Anatomically, this network connects the frontal lobes with the limbic system and contains the anterior cingulate, insula, striatum, and amygdala [46]. Previous studies regarding bvFTD using fcMRI have shown a decreased connectivity within the salience network [47••, 48 50]. Day and colleagues reported that increased left insular fractional amplitude of low-frequency fluctuations predicted a worsening of behavior as shown by an increase of the frontal behavioral inventory scores [51]. Regarding DMN function, previous studies have consistently demonstrated decreased connectivity in this network in AD and its pre-stages [52 54]. However, in FTLD findings regarding DMN connectivity have been more variable. Some studies have shown an increased connectivity of the default mode network in bvFTD in the presence of decreased frontolimbic connectivity [47••, 48]. However, as summarized by Rohrer and colleagues [30], other studies found variable decreases of connectivity within the DMN [49, 50]. These contradictory findings may in part arise from the use of different methodology, the inclusion of different subtypes [30], or different stages of the disease because an increased connectivity within the DMN has been described in symptomatic patients but not in presymptomatic patients [47, 55, 56]. It has been postulated that decreased functional integrity of the salience network may contribute to the failure to deactivate the DMN [46]. A recent study employing small world analysis (assessment of clustering of regions and their connectivity in the brain) detected a lack of cortical hubs in the

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frontal cortices in bvFTD [57]. A study focusing on functional connectivity and the genetic background in bvFTD has shown that there was no significant difference in frontoinsular connectivity within the salience network between nonsymptomatic MAPT, and GRN carriers and healthy participants. However, decreased connectivity was observed especially in the anterior midcingulate cortex in GRN carriers compared with MAPT carriers and healthy participants [55]. In svPPA patients, reduced connectivity of the left anterior temporal lobe has been consistently demonstrated [58••, 59]. Furthermore, Agosta and colleagues observed a reduced leftlateralized nodal degree (a measure of connectivity to the rest of the brain) not only in the inferior and ventral region of the temporal lobe but also within the occipital cortices, in frontal cortex bilaterally, left amygdala and/or hippocampus, and left caudate nucleus [58••]. In summary, studies on functional connectivity in FTLD demonstrate that anatomical regions affected by the specific phenotypes show impaired integration in functional connectivity networks, possibly reflecting on-going neurodegeneration within these networks and, thus, supporting the network degeneration concept.

FDG-PET [18 F]FDG-PET is a marker of cerebral glucose metabolism providing a measure of neuronal synaptic activity [60]. In numerous studies, including in vivo imaging vs post mortem neuropathologic evaluation, FDG-PET has demonstrated proven utility for the early and reliable diagnosis of neurodegenerative disorders by allowing the detection of specific hypometabolic patterns reflecting regional neuronal dysfunction (Fig. 1). FDG-PET can be regarded as an established imaging tool licenced for the differentiation between AD and FTLD-syndromes [20]. Furthermore, specific hypometabolic patterns have also been described in the different FTLD-subtypes [61 65]. A characteristic finding in bvFTD patients is hypometabolism of the frontal cortex frequently extending into the anterior temporal regions. Schroeter and colleagues confirmed this in a group of 417 bvFTD patients using a data driven meta analysis which identified the frontomedial cortex as the main affected area besides basal ganglia, anterior insula, and thalamus [22]. In svPPA less pronounced frontal abnormalities but a more distinct hypometabolism in the temporal regions (usually bilaterally) has been described [66, 67]. Compared with the findings in bvFTD and svPPA, nfvPPA and lvPPA patients usually show pronounced asymmetry in the observed patterns of hypometabolism. NfvPPA is characterized by an involvement of left frontal cortical regions (often including Broca’s area) [68••]. Interestingly, in a small series of 2 left-handed patients with nfvPPA, right dominant

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hypometabolism has been demonstrated, potentially reflecting involvement of the right hemisphere in language processing in these patients [69]. In lvPPA, hypometabolic regions have been described within the left lateral temporal and parietal lobe with additional involvement of precuneus and posteriofrontal lobe [70 73]. It has been reported that a significant proportion of lvPPA patients show amyloid-aggregation pathology detected with amyloid-imaging (see next section) and so probably represent an atypical phenotype of AD [68••]. However, a subgroup of typical lvPPA patients has also been demonstrated to be amyloid-negative, some of those being GRN-carriers and some non-GRN carriers. Importantly, a differentiation between amyloid-positive/negative lvPPApatients and between GRN-carriers or noncarriers is not possible on the basis of the pattern of hypometabolism alone as this has been described to be similar in these different subcategories (although in small groups) [70]. Concerning the new consensus criteria for diagnosis of PPA, Matias-Guiu and colleagues demonstrated that FDG PET had a sensitivity of 60 % and a positive predictive value of 78.5 % for differentiating the subtypes of PPA [74••]. In summary, FDG-PET represents a well-established and reliable tool for differentiating FTLD from AD and distinguishing subtypes of FTLD. However, genetic and/or neuropathologic subtypes cannot be reliably differentiated with FDG PET as they can show overlapping patterns of neuronal dysfunction.

Beta-Amyloid PET The introduction of PET-tracers for amyloid imaging demonstrated that molecular imaging of abnormal protein aggregations underlying neurodegenerative pathology in vivo is feasible [75 77]. The 11C-labeled Pittsburgh Compound B (PiB), a neutral thioflavin derivative, is currently the best established compound but several 18 F-labeled tracers with a longer halflife permitting broader distribution have been introduced and some have now achieved approval of the Food and Drug Administration and the European Medicines Agency. Although the currently available tracers exhibit some differences regarding their specific properties (nonspecific binding, target to cerebellar uptake ratios etc.), their general features can be considered to be comparable [78]. Importantly, it has been demonstrated that these tracers bind with high affinity specifically to amyloid-deposits and not to intracellular proteinaggregates such as tau-neurofibrils and alpha synuclein [79 85]. With regard to FTLD, the application of in vivo amyloidimaging is limited to the detection or exclusion of amyloidpathology. In the majority of FTLD-cases, tau- or TDP-43positive and amyloid-negative histopathology is expected. Several studies have demonstrated that a differentiation between AD and FTLD can be successfully performed in at least

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80 % of cases using amyloid PET [64, 86, 87••, 88, 89]. Similarly, in studies focusing on clinically defined subtypes of FTLD such as svPPA or bvFTD, amyloid-PET predominantly revealed normal findings, i.e. no evidence of amyloiddeposition [64, 86, 88]. However, in some studies small percentages of amyloid-positive cases were reported in FTLD. [86, 88, 89]. Without histopathologic proof, these findings could reflect either mixed pathology or a clinical misdiagnosis. Serrano and colleagues report on a positive amyloid-scan in a patient with clinical FTLD. Post mortem histopathologic examination confirmed the co-existence of amyloid plaques with TDP-43-positive histopathology. This demonstrates that mixed pathology can be present in FTLD and the authors conclude that a positive amyloid-scan does not necessarily establish AD as the sole cause of disease [90]. A number of studies have confirmed the imperfect correlation of clinical diagnoses of FTLD with the underlying disease pathology [17••, 18 20]. A particularly interesting subgroup are the patients with lvPPA. It has been described that up to 50 % of these patients may represent an atypical form of AD [12••, 17••, 19]. Consistently, amyloid-imaging studies demonstrated tracer retention similar to AD patients in the majority of lvPPA, whereas in nfvPPA and svPPA amyloid-negative findings were observed [68, 91]. However, a subgroup of amyloid-negative lvPPA patients has also been described [70]. These findings indicate that amyloid-imaging may be valuable for differentiating distinct subgroups of causal pathology in lvPPA, which cannot be distinguished on the basis of the clinical assessment alone. In general, amyloid-imaging may have utility for discriminating between FTLD and AD. It may serve in the detection of amyloid-positive FTLD-cases caused by AD with an atypical appearance or cases with mixed pathology.

Outlook: Tau-PET In addition to amyloid-imaging, PET tracers specific for imaging tau protein deposits in vivo, are being developed, which are of potential relevance for research in the field of FTLD. The following compounds are currently available as candidates for tau-imaging and have undergone first in man studies: 18 F-THK5117, 18 F-THK5105, 18 F-T807, 18 F-T808, and 11C-PBB3 [92]. PET studies with 18 F-THK5117 and 18 FTHK5105 indicate superior properties of 18 F-THK5117 in terms of signal-to-noise ratios [92 95]. Comparing 18 F-T808 to 18 F-T807, substantial defluorination was seen in some cases for T-808, which makes 18 F-T807 preferable [92, 96]. The first in vivo data acquired with these tracers in AD, mild cognitive impairment and healthy controls indicates a pattern of uptake compatible with tau binding and an association between the intensity of tracer retention and the severity of

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dementia, which is in line with the assumption that taupathology correlates tightly with cognitive deficits [97]. Comparing the first human tau-PET findings with [11C] Pittsburgh Compound B amyloid-imaging data in the same patients revealed substantially different tracer distribution patterns [92, 98] consistent with differences in the distribution of tau and amyloid-pathology in AD, known from histopathologic studies [99]. No systematic studies on the application of tau-imaging in the different forms of FTLD have been published so far. A major difficulty in this context may be found in the different tau-isoforms detected in the different FTLD-subtypes and the yet unknown binding behavior of the available tau-tracers to this isoforms in vivo [100].

Multimodality Imaging A recent advance in imaging is to employ multimodal approaches to obtain a more comprehensive picture of the type and extent of neurodegenerative disease. This refers on the one side to the combination of different MR sequences. For example, in 1 study DTI was combined with measures of cortical thickness to distinguish between AD and bvFTD [101]. In another study using voxel-based morphometry, DTI, and ASL it could be shown that the changes detected through ASL were not totally overlapping with changes detected by voxelbased morphometry and DTI [102]. In detail, atrophy without hypoperfusion was observed in the premotor cortex whereas atrophy with hypoperfusion could be seen in the right prefrontal cortex and the bilateral medial frontal lobe. This indicates that the observed abnormalities are complementary and that their combination may lead to better diagnosis. A particularly interesting option with regard to multimodal imaging is the advent of modern integrated PET/MR instrumentation allowing the acquisition of PET and MRI data at the same time. This may open a new opportunity to capture causal molecular pathology (tau/amyloid), metabolic abnormalities, changes in receptor status, perfusion, connectivity and brain structure/volume in a one stop diagnostic procedure. This provides a great potential for the assessment of neurodegenerative disorders for several reasons. (1) The patterns of metabolic/perfusion and structural abnormalities observed as measures of neuronal injury/ dysfunction in the different forms of FTLD correspond well to the diagnostic appearance but do not allow reliable conclusions on the underlying pathology (see example lvPPA above). (2) On the other hand, classification by means of molecular imaging may (eg, allow excluding amyloid-aggregation pathology as a possible

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cause of disease) but it will not be helpful with regard to disease staging and assessment of pattern/extent of neuronal dysfunction. Therefore the combination of both imaging categories (molecular pathology and neuronal injury) as possible with PET/MR may form an ideal diagnostic pairing [103]. Combining different aspects of disease may increase sensitivity and specificity and help to achieve robust findings even in small samples. Multimodal imaging might enlarge our understanding of the disease and provide strategies to distinguish the subtypes from each other. Potentially, this may lead to alternative or supportive diagnostic algorithms. Multimodal imaging approaches have not been systematically evaluated with regard to their superiority to individual diagnostic procedures. Some initial studies, however, indicate that the combination of amyloid- and FDG-PET may improve the differentiation between AD and the FTLD-syndromes and the differentiation between amyloid-positive and -negative forms of progressive aphasia [68, 87]. Generally, it can be expected that the collection of multimodal information will lead to a more reliable characterization of neurodegeneration from different angles, thus, improving early and reliable diagnosis, prognostic judgment, and therapy selection with less focus on the symptomatic appearance of these disorders. Thus, if available, PET/MR may represent the method of choice for the diagnostic imaging assessment of neurodegeneration including FTLD.

Conclusions Neither clinical phenotype, histopathologic assessment, nor genotyping on their own appear to allow an unequivocal classification of the different FTLD syndromes and their overlapping subtypes. This hampers the diagnostic work-up and defines the need for suitable supporting biomarkers. Modern imaging procedures may shed light on the involved pathophysiological parameters in vivo. This includes the assessment of molecular pathology such as amyloid- and/or tau-aggregation, neuronal dysfunction, functional and structural connectivity, and atrophy. In particular, the intelligent combination of these imaging tests, as possible today by means of integrated PET/MR technology, may open a new window toward the characterization of FTLD in vivo, allowing to noninvasively provide information on the “endophenotype” of the disease. This may lead to improved understanding of the involved pathophysiological mechanisms, to earlier and more reliable diagnosis and, thus, potentially to the selection of suitable targeted therapies.

Curr Neurol Neurosci Rep (2014) 14:489 Acknowledgments We wish to thank Hannah Lockau, MD for careful revision of the manuscript and Sue Permagne, MD, PHD for helpful comments. Compliance with Ethics Guidelines Conflict of Interest Janine Diehl-Schmid and Traugott Gruppe declare that they have no conflict of interest. Oezguer A. Onur was supported by the Koeln Fortune Program / Faculty of Medicine, University of Cologne. Jens Kuhn has occasionally received honoraria outside the submitted work from AstraZeneca, Lilly, Lundbeck Otsuka Pharma and Schwabe for lecturing at conferences and financial support to travel. He received financial support for IIT-studies from Medtronic Europe SARL (Meerbusch, Germany). Alexander Drzezga reports consulting/speaker honoraria from GE Healthcare, AVID/Lilly, and Piramal, outside the submitted work. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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