Advances in Dementia Imaging David Clopton, MD, and Thomas Jason Druzgal, MD, PhD


side effect of our aging population is an increasing incidence of dementia. Historically, the role of imaging in dementia has been directed at ruling out the various treatable etiologies. Now a variety of imaging techniques are available or under development for evaluating the structural, biochemical, and functional changes seen in neurodegenerative disease. The advent of these new imaging techniques can help differentiate diseases that have overlapping symptomatology and offers the possibility of diagnosing conditions before they become clinically apparent. The following review is intended to discuss the currently available imaging tools specific to dementia and to introduce some research techniques that may play a clinical role in the future. Given our emphasis on new and emerging techniques, this review is necessarily restricted to the most common causes of dementia, namely Alzheimer disease (AD), vascular dementia (VaD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD).

Alzheimer Disease AD is the most common cause of dementia in the elderly.1 The disease behaves as a progressive neurodegenerative disorder associated with disruption of neuronal function and gradual deterioration in cognition, function, and behavior.2 Current theories on the pathophysiology of AD involve the accumulation of the protein amyloid-β (Aβ), dysregulation of tau protein phosphorylation, and accumulation of intracellular neurofibrillary tangles and toxic versions of soluble tau. Neurofibrillary tangles have been associated with neuronal degeneration that progresses in characteristic stages from the entorhinal cortex to the neocortex.3 The characteristic progressive atrophy beginning in the medial temporal lobes, and the abnormal presence of Aβ, are the major targets for imaging. Current imaging techniques for AD can be broadly characterized as those that focus on structural changes and those that focus on detecting the functional changes associated with the development of disease. Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA. Address reprint requests to: T. Jason Druzgal, MD, PhD, Department of Radiology and Medical Imaging, University of Virginia, PO Box 800170, Charlottesville, VA 22908. E-mail: [email protected]

0037-198X/12/$-see front matter & 2014 Elsevier Inc. All rights reserved.

Structural Changes Structural MRI As mentioned, AD is associated with progressive brain tissue loss in a specific pattern starting from the entorhinal cortex to the neocortex.3 Therefore, atrophy starting in the entorhinal cortex has been recognized as a structural biomarker of AD. Additionally, hippocampal atrophy (more specifically, the rate of hippocampal atrophy) is a risk factor for cognitive decline and dementia in normal aging and for progressing from mild cognitive impairment (MCI) to AD.4 The most established structural marker, hippocampal atrophy, is most easily evaluated by visual assessment on high-resolution coronal imaging (Fig. 1). Grading scales have been developed that show excellent sensitivity and specificity (80%-85%) to visually distinguish patients with AD from healthy controls5; however, these have limited sensitivity in early disease. Methods of assessing hippocampal volume loss on structural magnetic resonance imaging (MRI) have progressed from visual assessment to manual hippocampal volumetry, more recently to Food and Drug Administration–approved software packages that automatically segment the brain and measure relevant brain parenchymal volumes (Fig. 2). Despite these advances and the promising data reported on hippocampal volume thus far, medial temporal atrophy is not sufficiently accurate on its own to serve as an absolute criterion for the clinical diagnosis of AD at the MCI stage. To link MRI findings more solidly to the presence of AD pathology, there has been an increased interest in using structural MRI in conjunction with biochemical markers found in cerebrospinal fluid. A recent study showed that the combination of visually rated medial temporal atrophy and cerebrospinal fluid biomarkers had an impressive prediction of progression to AD (94% positive predictive value).6 High-Field MRI The use of 7-T MRI provides more advanced visualization of the macrostructures of the hippocampus and basal ganglia compared with the conventional 3-T scanners. The idea behind the use of high-field MRI is that neuronal death is actually a late manifestation of AD. There is a growing hypothesis that AD is actually a disease of synaptic loss,7 thought to occur very early within the Cornu Ammonis (CA1) apical neuropil, which receives axons projecting from the 53

D. Clopton and T. Jason Druzgal


Figure 1 Coronal T2-weighted MRI through the temporal lobes demonstrates severe atrophy of the bilateral hippocampi in Alzheimer dementia. (Used with permission from Amirsys, Inc.)

entorhinal cortex.8 This theory is supported by a study using 7T MRI showing that selective thinning of the CA1 apical neuropil layer relative to the CA1 cell body layer occurs in subjects with mild AD.9 The modality has promise, as thickness of the CA1-SRLM (stratum radiatum or stratum lacunosum-moleculare) was shown to be better than overall hippocampal volume at distinguishing AD from normal controls.9 It is important to say that although this study was quite sensitive at distinguishing AD from normal controls, considerable overlap between the groups existed. Diffusion Tensor Imaging Diffusion tensor imaging (DTI) is an MRI technique that provides information reflecting the integrity of tissue microstructure within the white matter tracts. DTI may provide some utility in differentiating AD-type dementia from VaD and Lewy body dementia. The most commonly used indices for measuring the degree of degeneration have been fractional anisotropy (FA), which quantifies the degree of directionality of the movement of water molecules, and mean diffusivity, which

quantifies overall movement of water molecules without regard to direction. Lower FA values and increased mean diffusivity are thought to represent increased axonal degradation and myelin damage in the brain. AD patients have been shown to have elevated mean diffusion in the hippocampus and decreased FA values in the main limbic pathways connecting to the hippocampus.10 DTI may have some role in differentiating AD from VaD based on regional difference in decreased FA values and increased apparent diffusion coefficients (ADCs).11 Additionally, a recent article has suggested that the DTI may have some utility in predicted risk of neuropsychiatric symptoms, specifically irritability, in patients with MCI and AD.12

Functional Changes BOLD fMRI Blood oxygen level–dependent (BOLD) functional MRI (fMRI) works by measuring T2n signal changes that correlate with the ratio of oxyhemoglobin to deoxyhemoglobin, a marker for neural activity within a gray matter voxel. BOLD fMRI research

Figure 2 Age-related atrophy report from the NeuroQuant volumetric MRI software package. The report contains a colorized display of how the brain was segmented, absolute and relative volume of the hippocampi and inferior lateral ventricles, and age-matched reference percentiles for each volume. (Color version of figure is available online.)

Advances in dementia imaging in AD typically evaluates either brain function during performance of memory tasks or brain connectivity during the resting state. In fMRI studies employing memory tasks, the most robust finding is that both patients with AD and patients with mild MCI show varying impaired hippocampal activation and parietal deactivation related to memory functions.13 In contrast, fMRI studies performed during the resting state describe the temporal synchrony of activity in different parts of the brain, most commonly focusing on the default mode network (DMN). In healthy subjects, the DMN is active during resting periods but becomes quiescent during the active performance of cognitive processes; a recurring finding in the DMN of patients with AD is a lesser degree of deactivation during the active state. This finding of reduced DMN connectivity has been shown in patients with preclinical disease (specifically those with positive amyloid positron emission tomography [PET] scans) and in those with a higher risk of converting to AD dementia within 3-4 years.14 PET Imaging With 18FDG PET of the glucose analogue 2-[18F]-fluoro-2-deoxy-D-glucose (18F-FDG) is well established as a tool to monitor glucose metabolism, in both the body and in the brain. A progressive reduction in glucose metabolism has been shown to occur years in advance of clinical symptoms in patients with verified AD.15 Characteristic deficits in posterior temporoparietal, posterior cingulate, and inferior frontal regions have been shown on 18FDG-PET in patients with AD, which reflects underlying neuronal degeneration (Fig. 3). 18FDG-PET studies have even been able to predict which healthy elderly individuals would develop MCI and which of those with MCI would progress to AD.16,17 The most sensitive marker for predicting which healthy adults would develop MCI was hypometabolism in the medial temporal lobe.15 The earliest and most sensitive marker for predicting which patients with MCI would progress to AD was found to be regional hypometabolism in the posterior cingulate cortex.16,18

55 PET Imaging of the Cholinergic System PET techniques using the radioligands 11C-PMP and 11CMP4A have been developed to image the activity of acetylcholinesterase (AChE). Studies using these radioligands have shown that patients with AD exhibit decreased cortical AChE activity when compared with healthy controls, particularly affecting the medial temporal lobes.19 Additionally, decreased cortical levels of AChE have been shown in patients with MCI who eventually converted to AD, suggesting that a change in AChE activity might be useful as an early marker of disease.20 PET Imaging With Amyloid and Tau Protein-Specific Ligands Amyloid plaques and tau neurofibrillary tangles are established neuropathologic hallmarks of AD that accumulate in the brain years before symptoms of dementia develop.21 Detection of amyloid protein in the human brain is accomplished with PET using specific Aβ ligands, such as Pittsburgh compound B (11C-PiB), AMYViD (18F-florbetapir), and 18F-flutemetamol.22 The utility of amyloid-specific PET ligands has great sensitivity for patients with AD, but unfortunately the modality is not specific (There is a high false-positive rate in normal patients.) and does not trend with disease progression.23 With regard to differentiating normal patients from those with AD, 11C-PiB does have utility (Fig. 4), and it also helps in differentiating patients with AD from those with other neurodegenerative disorders.24 For example, patients with AD would have increased uptake, whereas patients with Parkinson and patients with frontal temporal dementia would have low uptake.25,26 Another amyloid imaging compound of interest is 18F-2-(1-{6-[(2-[fluorine-18]fluoroethyl)(methyl)amino]2-naphthyl}-ethylidene)malononitrile (FDDNP), which binds not only to amyloid plaques but also to the tau protein in neurofibrillary tangles.27 Studies using 18F-FDDNP PET have shown increased tracer uptake in both patients with AD and patients with MCI when compared with controls. In an initial

Figure 3 18FDG-PET source images in axial and coronal planes demonstrate decreased radiotracer uptake in both the temporal and parietal lobes. This pattern can be seen with Alzheimer dementia. (Image courtesy of Patrice Rehm, MD, University of Virginia.)


D. Clopton and T. Jason Druzgal have decreased levels of NAA primarily in the frontal and parietal cortex.32 AD can be also differentiated from frontotemporal dementia (FTD), prion disease, and Huntington disease by 1H-MRS.33-35 For example, in the case of FTD the NAA-Cr ratio was reduced in the posterior cingulate cortex to a greater degree in those with AD, whereas the patients with FTD displayed a greater decrease in the frontal region.33

Figure 4 11C-PiB PET imaging reveals increased cortical uptake of radiotracer in a patient with AD as compared with a control. The pattern of abnormal uptake (temporal-parietal junction, medial frontal lobes, posterior cingulate, and precuneus) is classically associated with AD. (Image courtesy of the University of Pittsburgh Amyloid Imaging Group.) (Color version of figure is available online.)

study, 18F-FDDNP uptake yielded 100% diagnostic separation between patients with AD and controls and 95% separation between patients with MCI and controls.28 The clinical utility of the 18F-labeled compounds would likely exceed that of 11C compounds, as their longer half-life allows them to be produced at remote sites. PET Imaging of Neuroinflammation The process of neurodegeneration in AD has been associated with microglial activation as an inflammatory response. In the setting of inflammation, microglia will express a specific peripheral benzodiazepine-binding receptor site. A PET ligand, 11 C-PK 11195 has been developed to bind to this receptor site, making it a potential marker for neuroinflammation.29 Increased 11C-PK 11195 binding was observed in patients with AD when compared with healthy controls, specifically involving the entorhinal, temporoparietal, and cingulate cortices.29 A separate study showed that the degree of cognitive decline, measured by Mini-Mental State examination scores in AD subjects, correlated with levels of cortical microglial activation measured by 11C-PK 11195.30 Proton Magnetic Resonance Spectroscopy Proton magnetic resonance spectroscopy (1H-MRS) allows for noninvasive evaluation of brain biochemistry by measuring the levels of specific tissue metabolites, including N-acetylaspartate (NAA), choline (Cho), creatine (Cr), lactate, myoinositol, and glutamate. NAA is considered to be a marker of neuronal integrity, and the ratio of NAA to Cr is lower in the gray matter of the hippocampus in patients with AD when compared with normal elderly controls (Fig. 5).31 AD can be differentiated from other types of dementia by 1 H-MRS. For example, patients with VaD have been found to

ASL MRI Arterial spin labeling (ASL) perfusion MRI is another promising method for assessing brain perfusion in cases of dementia based on the theory that regional metabolism and perfusion are linked. Therefore, arterial blood water labeled as an endogenous diffusible tracer for perfusion may act in a similar manner as 18FDG-PET and 99mTc-hexamethylpropyleneamine oxime (HMPAO) single-photon emission computed tomography (SPECT) to demonstrate functional deficiencies.36 A potential advantage of ASL is the elimination of the need for radioisotopes, limiting both the cost and exposure to ionizing radiation. Studies using ASL in patients with AD have shown regional hypoperfusion patterns similar to those using 18FDGPET and 99mTc-HMPAO SPECT,37 and that ASL may be capable of differentiating between patients with AD and healthy controls.38 Regional atrophy correction (which can be done in the same MRI scanner) has been shown to improve the accuracy of the study and could prove to be more accurate than functional studies performed with other modalities.39

Vascular Dementia VaD is the second most common cause of dementia, following AD.40 Originally called “multi-infarct dementia,”

Figure 5 1H-MRS performed demonstrates decreased N-aceylaspartate (NAA) levels in the hippocampus, resulting in a lower NAA-Cr ratio, a pattern associated with Alzheimer dementia. (Used with permission from Amirsys, Inc.)

Advances in dementia imaging VaD is an irreversible form of dementia caused by a series of minor infarcts in the brain. The etiology of VaD can be multifactorial, and the National Institute of Neurological Disorders and Stroke and the Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN) criteria were developed in 1991 with the goal of developing reliable, valid, and readily applicable criteria for the diagnosis of VaD.41 The key criterion is the need to establish a temporal relationship (3 months) between the vascular event and the onset of dementia in addition to computed tomography (CT) or MRI scan showing lesions confirming cerebrovascular disease.41,42 Neuroimaging offers several possible uses in patients with suspected VaD, including (1) confirming the diagnosis, (2) suggesting a

57 specific vascular cause, and (3) identifying potentially treatable early vascular damage that could lead to VaD.

Structural Changes Structural CT and MRI MRI has increased sensitivity relative to CT for the detection of the pathologic changes related to vascular disease. There are variable imaging appearances suggestive of VaD with findings ranging from large cortical infarcts, small infarcts in strategic regions, microhemorrhage, or widespread white matter lesions as typical for leukoaraiosis (Fig. 6).43 The severity of leukoaraiosis has been found to be directly related to the risk of essentially all causes of dementia.44 Lacunar infarcts involving

Figure 6 FLAIR (top row) and GRE (bottom row) MRI images from a patient with vascular dementia. The FLAIR images show nearly confluent signal abnormality in the hemispheric white matter. Microhemorrhages indicated by dark signal on the GRE sequence are concentrated in the deep brain parenchyma. FLAIR, fluid-attenuated inversion recovery; GRE, gradient recalled echo.

D. Clopton and T. Jason Druzgal

58 the thalami have been shown to significantly increase the risk of dementia.45 Enlarged perivascular spaces are associated with vascular risk factors, such as hypertension, and are considered a likely marker of cerebral small vessel disease.46 MRI also has utility in defining atrophy, as an important correlate of cognitive dysfunction and potential response to therapy.47 Gradient Recalled Echo and Susceptibility-Weighted Imaging MRI T2n gradient recalled echo or susceptibility-weighted imaging (SWI) MRI can be used to evaluate for the present of microhemorrhage within brain parenchyma. Although cerebral microhemorrhages are present in the healthy population (10% of the healthy elderly), an increased number of microhemorrhages in deep parenchymal and infratentorial locations has been associated with an increased risk of dementia (Fig. 6).48 In a 3-T SWI MRI study, the prevalence of small hypointense foci suggesting microbleeds was found to be 86% in those with VaD compared with 54% in those with DLB and 48% in those with AD. In AD and DLB there was a predilection for a lobar distribution of microhemorrhages; this distribution was seen less often in patients with VaD or MCI. In addition to dementia risk, mortality was increased in patients with both microhemorrhages and global cortical atrophy.49 Diffusion Tensor Imaging DTI to evaluate the integrity of white matter may be helpful in distinguishing between AD and subcortical ischemic VaD in patients with only mild white matter alterations on T2weighted images. Recently, regional difference in decreased FA values and increased ADC values has been shown between AD and VaD. Specifically, in VaD, ADC values were higher in the inferior-fronto-occipital fascicles, genu of the corpus callosum, splenium of the corpus callosum, and superior longitudinal fasciculus. Patients with AD had higher ADC in the temporal lobe and hippocampus, when compared with those with subcortical ischemic VaD.11

Functional Changes Nuclear Imaging With 18FDG-PET, 99mTc-HMPAO SPECT, and 99mTc-ECD SPECT The diagnosis of VaD is usually made with the combination of clinical history and structural imaging, without the need for functional imaging. However, VaD can be associated with AD; and in such cases, PET and SPECT can be used to distinguish the 2 pathologies. With regard to SPECT imaging, 2 radiotracers are commonly used to demonstrate regional brain perfusion: 99mTc-HMPAO (Ceretec) and 99mTC-ethyl cysteinate dimer (ECD) (Neurolite).50 On 99mTc-HMPAO SPECT imaging in patients with VaD, reduced perfusion in 1 or more arterial territories is classically seen, with basal ganglia perfusion defects being characteristic. In the case of both, patients with AD and patients with VaD, defects and reduced perfusion can be seen in both posterior temporoparietal regions and in 1 or more vascular territories.51 When combined with an acetazolamide challenge, SPECT regional cerebral blood flow (CBF) may also have utility in

differentiating VaD from AD.52 In patients with VaD, 18FDGPET often shows global reduction in cerebral metabolism with additional focal asymmetric areas of hypometabolism affecting cortical, subcortical, and cerebellar distributions. This metabolic pattern differs from AD in which there are areas of bilateral decreased metabolism in the parietotemporal lobes, with relative sparing of the subcortical structures.53

Lewy Body Dementia DLB is characterized clinically by Parkinsonian motor features, executive dysfunction, and visual hallucinations.54 DLB and Parkinson disease are both associated with dopaminergic cell loss and accumulation of α-synuclein particles that aggregate to form Lewy bodies.55 As would be expected, Parkinson disease dementia is clinically and pathologically similar to DLB, with the distinction that in Parkinson disease, motor symptoms predate cognitive decline by 12 months.56

Structural Changes Structural MRI Structural MRI has shown differences between DLB and AD with regard to regional atrophy. Patients with DLB tend to have greater atrophy in the striatum, midbrain, and hypothalamus with relative sparing of the hippocampus.57 MRI also has some utility in distinguishing DLB from Parkinson plus syndromes, some of which can also cause dementia. For example, progressive supranuclear palsy may show atrophy of the midbrain in a pattern resembling a “hummingbird” on sagittal images, and “Mickey Mouse” on axial imaging.58 In the case of multiple system atrophy (another synucleinopathy), T2weighted images may demonstrate linear hyperintensitiy crossing the pons (“hot-crossed bun sign”), representing degeneration of the pontocerebellar tracts.59 Diffusion Tensor Imaging The amygdala is one of the earliest and most severely affected structures in DLB pathology.60 The directionality of diffusion measured with FA has been shown to be decreased in the inferior longitudinal fasciculus, which carries projections from the amygdala to the visual cortex.61 DTI findings have shown that diffusivity in the amygdala is elevated in patients with DLB, but the gray matter density of the amygdala is normal, as opposed to AD in which the opposite is true.62 Additionally, diffusion changes in the cortical gray matter of patient's with AD have been found to be more severe and widespread when compared with those with DLB.63

Functional Changes Proton Magnetic Resonance Spectroscopy In patients with DLB undergoing 1H-MRS, the ratio of NAA-toCr concentration in the posterior cingulate gyrus is typically normal but is decreased in patients with AD, VaD, and FTD.64 In the posterior cingulate gyrus and precuneus, AD and DLB typically have elevated Cho-Cr ratios when compared with normal controls.65 This may be of utility as the Cho-Cr levels

Advances in dementia imaging have been shown to decrease with cholinergic agonist treatment raising the possibility of using Cho-Cr levels as a therapeutic marker for both AD and DLB.66 Nuclear Imaging With 18FDG-PET and Blood-Flow SPECT The appearance of AD and DLB can be very similar on 18FDGPET and 99mTc-SPECT regional CBF, with involvement of the parietotemporal areas in both diseases.67 However, reduced glucose metabolism in the primary visual cortex in patients with DLB has been shown to be a useful discriminator (Fig. 7).67 Another useful finding in differentiating DLB and AD is regional hypometabolism in the lateral occipital cortex, with relative preservation of the middle or posterior cingulate gyrus (cingulate island sign).68 Nuclear Imaging With Dopamine Transporter PET and SPECT 18 F-dihydroxyphenylalanine (DOPA) PET allows regional measurement of accumulation and metabolism of levodopa within the brain.69 Reduction in 18F-DOPA uptake has been shown in the striatum of patients with DLB in amounts similar to those with Parkinson disease.70 Using 18F-DOPA PET to differentiate DLB from AD has been shown to be a very effective with a reported sensitivity of 86% and specificity of 100%.71 Currently the most widely used dopamine transport radiotracer is 123I-I-fluoropropyl-carbomethoxy-3β-4-iodophenyltropane (FP-CIT) (DaTSCAN), which evaluates the function of the presynaptic dopamine transporter. In a study, 123I-FP-

59 CIT was more effective than clinical criteria in the diagnosis of DLB.72 The downside to 123I-FP-CIT is that it is not specific for DLB, showing abnormal uptake in multiple other dementias including FTD, Huntington disease, and Parkinson plus syndromes.73,74 Another dopamine transport tracer, 11Cdihydrotetrabenazine, has also been able to differentiate DLB from AD, with the distribution of 11C-dihydrotetrabenazine significantly decreased in the caudate nuclei and putamen in DLB when compared with patients with AD.75

PET Imaging With Amyloid-Specific Ligands As previously described, 11C-PiB PET can be used to reflect amyloid burden. When comparing the uptake of 11C-PiB between DLB and AD, the overall cortical uptake is similar with the distinction being a relative increased tracer uptake in the occipital region of DLB.76 Additionally, DLB has shown an overall higher cortical uptake when compared with both Parkinson disease and Parkinson disease with dementia.76,77

PET Imaging of the Cholinergic System PET imaging of AChE activity has also been applied to the investigation of DLB. The 11C-MP4A uptake reduction is more widespread and more severe, especially in the cortex, when compared with Parkinson disease. However, there are no significant differences between DLB and Parkinson disease dementia.78

Cardiac Sympathetic Imaging The autonomic nervous system is vulnerable to α-synuclein pathology and there has been increased attention on using 123Imetaiodobenzylguanidine (MIBG) cardiac imaging to differentiate DLB from AD.79 The idea is that cardiac denervation precedes loss of neuronal cell bodies in paravertebral ganglia with a centripetal dieback process before central nervous system involvement.80 A decrease in 123I-MIBG radiotracer uptake, reflecting cardiac sympathetic denervation, has been detected in DLB but not in AD.81 Recent studies have shown that cardiac denervation can be detected by 123I-MIBG in patients with preclinical dementia in DLB.82

Frontal Temporal Dementia

Figure 7 Axial 18FDG-PET demonstrates decreased radiotracer uptake in the bilateral parietal and posterior temporal lobes (arrows) in addition to the occipital lobes (open arrow). The degree of occipital lobe hypometabolism is more than would be expected with Alzheimer disease, and is suggestive of dementia with Lewy bodies. (Used with permission from Amirsys, Inc.) (Color version of figure is available online.)

Frontotemporal dementia (FTD) encompasses a group of diseases that result in degeneration of the frontal lobe or anterior temporal lobe or both. FTD is the third most common cause of degenerative dementia found in industrialized countries, (behind AD and DLB). Clinically FTD can be grouped into 3 main categories based on behavior patterns: behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD), and progressive nonfluent aphasia (PNFA). Symptoms sometimes overlap with those of AD leading to misdiagnosis, with both structural and functional imaging showing promise in differentiating the 2 entities.

D. Clopton and T. Jason Druzgal


Figure 8 Top row: axial T1 magnetization-prepared rapid acquisition with gradient echo (MPRAGE) shows differential atrophy of the frontal and temporal poles in a patient with frontal temporal dementia. Middle row: 18FDG-PET imaging in the same patient shows severe hypometabolism in the temporal poles and to a lesser degree in the frontal poles and parietal lobes. Bottom row: 18F-florbetapir PET imaging shows little Aβ in the cortex of this FTD patient in comparison with the typical uptake in patients with AD. (Image courtesy of Mykol Larvie , MD, Massachusetts General Hospital.) (Color version of figure is available online.)

Structural Imaging CT and MRI Both CT and MRI can show structural changes in patients with FTD (MRI with greater sensitivity). Patterns of atrophy vary depending on the subtype of FTD but predominantly involve the temporal and frontal poles (Fig. 8). In the SD subtype, a severe “knife-edge” pattern of atrophy is nearly always found in the anterior temporal lobes.83 The corpus callosum can also be involved in the pattern of atrophy with the degree of severity favoring the anterior portion.84 This finding is in contradistinction to the callosal atrophy seen in AD, which tends to be more posterior.84 Both the behavior variant form and semantic form both have characteristic gray matter loss in the ventromedial frontal regions, the bilateral insula, and the left anterior cingulate cortex.85 Patients with the PNFA form have been shown to have selective atrophy in the left perisylvian region.86 There may be utility in the ability to recognize these structural changes, with studies showing the ability to differentiate bvFTD from normal controls.87 Additionally, cortical thickness measurements have also shown the ability to demonstrate differences in regional atrophy between AD and bvFTD.88 Diffusion Tensor Imaging DTI can be used to evaluate the changes in both white matter and gray matter in patients with FTD. A study showed that the changes in diffusion across the different subtypes of FTD closely mimicked their respective atrophy

patterns.89 This same study demonstrated damage within the white matter tracts that connect the atrophic regions, supporting the idea that the subtypes of FTD involve distinct brain networks.89 DTI has been shown capable of differentiating FTD from AD owing to a characteristic pattern of white matter degradation in the frontal lobes of patients with FTD, in a pattern distinct from AD.90

Functional Imaging Nuclear Medicine Imaging With 18FDG-PET and 99mTcHMPAO SPECT Just as the atrophy patterns vary depending on the clinical subtype of FTD, patterns of hypometabolism evident on nuclear medicine imaging are also different. Specifically, frontal hypometabolism is associated with the bvFTD, temporal hypometabolism is associated with SD, and left perisylvian hypometabolism is associated with PNFA.91 When differentiating FTD from AD, 18FDG-PET can be useful (Fig. 8); 1 historical cohort study that included postmortem validation showed 18FDG-PET to be more accurate than clinical judgment when differentiating AD from FTD.92 To demonstrate that hypoperfusion in the frontal and temporal regions may be highly predictive of FTD over AD, 99mTc-HMPAO SPECT has also been used.93 ASL MRI ASL MRI of patients with FTD shows a pattern of hypoperfusion consistent with PET and SPECT findings, with bilateral

Advances in dementia imaging


Neuroimaging methods commonly used to detect in vivo brain changes associated with demena Structural MRI: Used to evaluate volumetric grey maer change, specifically focusing of atrophy in the hippocampus as a structural biomarker of AD. Atrophy in frontal and temporal poles may help separate AD from FTD. High Field Structural MRI: 7T MRI shows very early changes in the hippocampal CA1 apical neurophil as a potenal early structural marker of AD. Diffusion Tensor Imaging: DTI is an MRI technique to assess microstructural brain changes within the white maer fibers of the brain. This technique may have ulity in differenang AD type demena from VaD and DLB. Funconal MRI: fMRI uses blood-oxygen-level dependent (BOLD) signal to make inferences about neuronal acvity. Paents with AD show decreased fMRI acvity during performance of memory tasks and abnormal resng state fMRI connecvity between brain regions. 18 FDG-PET: A nuclear medicine technique that measures glucose metabolism within the brain. Most demenas show decreased glucose consumpon but the paerns may be different between AD, DLB and FTD.

PET CT of the Cholinergic System: The acvity of acetylcholinesterase (AChE) can be followed with radioligands like 11C-PMP and 11C-MP4A. Decreased AChE acvity may be useful as an early marker in AD. PET CT with Amyloid and Tau Specific Ligands: Use of 11C-PiB, 18F-florbetapir , and 18Fflutemetamol to image Aβ, or F-18 FDDNP to image Tau protein, may have uliy in predicng progression from MCI to AD and differenang AD from DLB and FTD. PET CT of Neuroinflammaon: 11C-PK 11195 , a ligand for a binding receptor associated with neuroinflammaon, may have ulity in disnugishing healthy adults from AD paents, and evaluang the physiologic correlates of cognive decline. Proton MR Spectroscopy: A non-invasive way to evaluate brain biochemistry, with specific ulity in evaluang NAA as a marker of neuronal integrity. Paerns of decreased NAA have been shown in various types of demena, and 1H-MRS may have ulity in disnguishing between them. Arterial Spin Labeling: An MRI method for assessing brain perfusion by looking at arterial blood water as an endogenous perfusion tracer. ASL has potenal for disnguishing AD and FTD from normal control paents. Hemosiderin Sensive MRI Sequences: GRE and SWI sequences evaluate for microhemorrhage, which has been found with greater frequency in VaD paents, as compared to AD or DLB. Cardiac Sympathec Imaging: The use of 123I-MIBG to evaluate for cardiac denervaon, that has been shown to precede neuronal cell body loss in DLB, can help differenate between DLB and AD.

Figure 9 Summary chart.

regions of reduced CBF in the frontal cortex and insula.94 Interestingly, this same study showed reciprocal regions of hyperperfusion in the precuneus or posterior cingulate, with the suggestion that this may reflect a compensatory mechanism.94 The ASL technique has shown some possible utility in differentiating bvFTD from AD—with upto 87% accuracy.95

clinical use and several other techniques are poised to make the transition from the laboratory to the medical clinic. The incidence of dementia is on the rise with the growth of our elderly population, and as treatments advance, we can expect a growing need for more advanced imaging techniques to aid the diagnosis and management of these diseases.



This review summarizes multiple emerging imaging techniques that may allow for earlier diagnosis of dementia and better differentiation of the various causes of dementia (Fig. 9). Many of these techniques have already made their way into routine

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Advances in dementia imaging.

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