Neuroimaging in Dementia

INTRODUCTION

Neuroimaging tools are excellent techniques for evaluating anatomic and functional changes in the brain. The most commonly used neuroimaging technique for evaluating brain changes in dementia is structural MRI, which allows researchers and clinicians to assess both anatomic location and extent of brain atrophy in people with dementia, as well as rule out nondegenerative causes of cognitive impairment. Based on the hydrogen atom spin in water molecules in a strong magnetic field, MRI techniques can also be used to assess integrity and connectivity patterns of brain white matter, extent of and connectivity patterns of brain function during a cognitive task or at rest, cerebral blood flow (CBF), extent and location of cerebrovascular damage, presence and severity of cerebral microbleeds, restricted diffusion in prion diseases, and much more.

The second most commonly used neuroimaging technique to study dementia is positron emission tomography (PET). PET uses radioactive small molecules, called tracers, that bind to a target of interest in the tissue of interest. In dementia, PET imaging yields information about ongoing biological processes including brain metabolism, protein aggregation, neurotransmitter systems, neuroinflammation, and other processes. A similar technique, known as single-photon emission computed tomography (SPECT), can be used to measure changes in dopaminergic systems in patients with dementia with Lewy bodies (DLB) or Parkinson disease dementia (PDD). For PET, the major targets are brain levels of key hallmark proteinopathies known to be involved in dementia (eg, amyloid, tau), levels of neurotransmitter receptors and transporters, and glucose metabolism (ie, with fludeoxyglucose [FDG]-PET).

This article reviews neuroimaging findings in selected slow and rapidly progressive dementias, including Alzheimer disease (AD), vascular cognitive impairment, DLB and PDD, frontotemporal lobar degeneration (FTLD) spectrum disorders, and Creutzfeldt-Jakob disease (CJD). It also briefly discusses the potential assistance in differential diagnosis provided by imaging techniques to distinguish dementia types when symptoms are overlapping.

ALZHEIMER DISEASE

AD is the most common age-related dementia and is characterized by the widespread deposition of abnormal amyloid-β (Aβ) in extracellular plaques and tau in intracellular neurofibrillary tangles.¹ Patients with AD also show widespread neuronal loss, gliosis, and immune cell activation, mostly of microglial cells. AD is characterized by progressive cognitive decline, particularly in the memory domain but also in other cognitive domains (eg, executive function, language). Patients with AD show a loss of ability to perform activities of daily living, such as balancing a checkbook, remembering to take medications, and eventually even how to properly dress or bathe themselves. Patients with AD may also show neuropsychiatric symptomatology, including depression, anxiety, and agitation. Currently, three classes of treatments are US Food and Drug Administration (FDA) approved for AD: acetylcholinesterase inhibitors (ie, galantamine, rivastigmine, donepezil), an N-methyl-d-aspartate (NMDA) receptor antagonist (memantine), and, most recently, a new medication that is an Aβ-directed antibody that clears Aβ (aducanumab). However, to date, none of these have conclusively been shown to prevent or reverse cognitive decline associated with AD.

Current literature suggests that abnormal protein accumulation, neurodegeneration, and cognitive decline occur over many years to decades. Further, findings suggest that there is a temporally ordered cascade of abnormal changes in various biomarkers of AD as described in the hypothetical ordering of biomarkers proposed by Jack and colleagues² (figure 9-1). The Jack hypothesis suggests that the first abnormalities are seen in amyloid measured by using either CSF or PET, followed by changes in tau (on CSF or PET) and functional brain changes. Next, abnormal brain atrophy is observed, followed by the clinical symptoms of memory loss and dementia. The long time course between when amyloid and tau abnormalities are detectable and the onset of dementia allows for the characterization of patients who are cognitively normal but show significant amyloid and sometimes tau deposition (preclinical AD), as well as patients with mild impairment in cognition and amyloid and tau deposition (prodromal AD or mild cognitive impairment [MCI] due to AD). These stages of disease show different levels of abnormalities on imaging, as discussed later.

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FIGURE 9-1. Hypothetical ordering of Alzheimer disease (AD) biomarkers. The hypothetical ordering of AD biomarkers suggests that the earliest observerable change is increased amyloid deposition, detected first using cerebrospinal fluid (CSF) measures and then by positron emission tomography (PET). Next, changes in tau pathology are observed, as measured by CSF and more recently PET, followed by neurodegenerative changes, measured using structural magnetic resonance imaging (MRI) or fludeoxyglucose (FDG). Finally, changes in cognition are observed with the onset of prodromal AD (ie, mild cognitive impairment [MCI]). All processes are hypothesized to follow a sigmoidal pattern, with initially low levels progressing rapidly once they begin to rise, followed by a plateau at a maximal point.Aβ = amyloid-β; Max = maximum; Min = minimum.Reprinted with permission from Jack CR Jr, et al, Lancet Neurol.2 © 2013 Elsevier Inc.

A recent development in characterizing older adults at risk for AD is the amyloid, tau, neurodegeneration (A/T/N) staging system (table 9-1³).⁴ This system categorizes patients by their amyloid status (positive or negative), tau status (positive or negative), and neurodegeneration (positive or negative). The definition of amyloid and tau positivity can be determined by using either CSF or plasma levels of Aβ and phosphorylated tau (pTau) or through PET imaging with tracers that detect Aβ and tau deposition. Neurodegeneration status is more difficult to define because it exists on a spectrum, and some atrophy due to aging is seen in older adults. However, cutoff values for positive or negative neurodegeneration have been established for MRI-based assessments of hippocampal and cortical atrophy, as well as for glucose hypometabolism as measured by FDG-PET. Through the A/T/N characterization system, clinicians or researchers can categorize older adults who are cognitively normal and have preclinical AD as A+, T+ or T-, and N+ or N-. In addition, older adults with cognitive impairment can be categorized as having MCI or dementia due to either AD pathophysiology (A+/T±/N±) or non-AD pathology (A-/T±/N±). Overall, the A/T/N classification system allows researchers and potentially clinicians to better characterize disease burden at the level of the individual and provide a better prediction of disease course and ultimately treatment based on the presence of specific proteinopathies.⁴

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TABLE 9-1. Amyloid, Tau, and Neurodegeneration Biomarker Classifications by Cognitive Impairment Status^a

MRI Findings in Clinical, Prodromal, and Preclinical Alzheimer Disease

Patients with AD show marked changes on most biomarker measures used for clinical care and research. Patients with AD show widespread degeneration on structural MRI both subcortically, including in the hippocampus, amygdala, basal ganglia, and basal forebrain, and cortically, with the greatest changes in the medial and lateral temporal lobes (figure 9-2a⁵).⁶ Changes in subfields of the hippocampus are also evident in patients with AD, including significant atrophy in the subiculum, presubiculum, CA1, CA2/3, and CA4/dentate gyrus.⁷ Quantification of cortical atrophy rates in patients with AD suggests an accelerated rate of atrophy, with loss of up to 4.7%/year in the hippocampus and 2%/year in the cortex relative to the approximate normal rate of loss of 1.4% in the hippocampus and less than 1% in the cortex of cognitively normal adults.⁸ A recent method for examination of brain white matter myelination uses the ratio of a T1-weighted image intensity value and a T2-weighted image intensity value to assess myelin on a voxel-by-voxel basis. This method, the T1-weighted–to–T2-weighted ratio (T1/T2), shows alterations in cortical white matter in AD, particularly in the temporal lobe, suggesting a loss of myelination in patients with AD.⁹

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FIGURE 9-2. Neuroimaging biomarkers in patients with mild cognitive impairment (MCI) or Alzheimer disease (AD). Patients with MCI present with varying amounts of amyloid and tau positivity, whereas patients with AD more commonly are amyloid and tau positive. For example, the patient with AD (A) is representative of most patients with probable AD, with amyloid positivity (A, second column, arrow), tau positivity (A, fourth column, arrows), and marked medial temporal lobe neurodegeneration (A, first column, arrow) and hypometabolism (A, third column, arrows). Patients with MCI are more variable. In this example, one patient with MCI (B) shows slight medial temporal lobe neurodegeneration (B, first column, arrow) and lateral parietal glucose hypometabolism (B, third column, arrows) in the presence of high amyloid deposition (B, second column, arrow) but minimal tau (B, fourth column, arrows). However, another patient with MCI (C) shows widespread amyloid (C, second column, arrow) and tau (C, fourth column, arrows) deposition, as well as medial temporal lobe atrophy (C, first column, arrow) and parietal hypometabolism (C, third column, arrows). Neurodegeneration (column 1) and tau deposition (column 4) are shown in a coronal view, amyloid deposition (column 2) is shown in a sagittal view, and hypometabolism (column 3) is shown in an axial view. Note: all example images are taken from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset.Aβ+ = amyloid-β positive; CN = cognitively normal older adult; FDG = fludeoxyglucose; L = left; MRI = magnetic resonance imaging; PET = positron emission tomography; tau- = tau negative; tau+ = tau positive;Reprinted with permission from Risacher SL, et al, Handb Clin Neurol.5 © 2019 Elsevier Inc.

Other MRI techniques have shown significant impairment in brain structure and function in patients with AD. Diffusion-weighted imaging (DWI) has demonstrated atrophy in widespread cerebral white matter tracts in posterior regions, the corpus callosum, and temporal lobe white matter tracts including the cingulum bundle, uncinate fasciculus, fornix, and superior and inferior longitudinal fasciculi.¹⁰ Brain function is generally measured via functional MRI (fMRI) with blood oxygenation level–dependent (BOLD) imaging and can be done either at rest (resting-state fMRI) or during performance of a cognitive or other task (task-based fMRI). Results from task-based fMRI studies in AD show decreased or even absent activation in the medial temporal lobe, frontal and parietal lobes, and posterior cingulate during episodic memory tasks.¹¹ Resting-state fMRI studies have also shown widespread impairments in patients with AD, including altered deactivation of the default-mode network, a network of brain regions that are active during a rest state and deactivate on initiation of a cognitive task.¹² Other brain networks such as the salience network and dorsal attention network also show abnormalities in patients with AD.¹² CBF can be measured semiquantitatively using arterial spin labeling MRI techniques. CBF has previously been shown to be reduced in patients with AD relative to those who are cognitively normal, particularly in temporoparietal regions and the hippocampus.¹³ Finally, susceptibility-weighted imaging (SWI) techniques analyzed by using a technique called quantitative susceptibility mapping, which is thought to reflect iron deposition in the brain, have demonstrated alterations in patients with AD in the caudate and amygdala that reflect higher levels of iron deposition in these regions.¹⁴ Some individuals with AD also show cerebral microhemorrhages on SWI or similar imaging techniques, which is usually linked to the amount of amyloid deposition, particularly in conditions such as cerebral amyloid angiopathy (CAA).¹⁵

Amnestic MCI is considered a prodromal stage of AD in many cases, with progression of approximately 50% of patients to a diagnosis of AD dementia within 5 years (illustrated in case 9-1). Neuroimaging measures have provided additional evidence of MCI as a transition stage between normal cognition and dementia, showing AD-like patterns of degeneration on structural MRI and deposition of amyloid and tau on molecular imaging that are often less severe than in clinical AD dementia but still markedly different from those in cognitively normal patients. Structural MRI in patients with MCI shows focal atrophy in the medial and lateral temporal lobes, most especially in the entorhinal cortex and hippocampus, which is intermediate in severity between patients who are cognitively normal and patients with clinical AD dementia (figures 9-2b and 9-2c).⁶ Structural MRI measures of medial temporal lobe atrophy are also good at predicting future conversion from MCI to AD within a few years.⁶ Longitudinally, patients with MCI show more rapid volume loss in the hippocampus and cortex relative to cognitively normal patients but not as severe as the rate of loss seen in patients with clinical AD dementia.⁸ Finally, the T1/T2 ratio demonstrates reduced myelin in the bilateral inferior parietal lobule and hippocampus.⁹

Advanced MRI metrics of brain structure and function also show intermediate impairments in patients with MCI that are often reflective of the severity and pattern of symptomatology. DWI measures show white matter degeneration in MCI in tracts that are myelinated later in cerebral development and temporal lobe white matter tracts, including the cingulum, fornix, and superior and inferior longitudinal fasciculi, as well as the corpus callosum.¹⁰ Studies have suggested that these measures of white matter integrity can also predict progression of MCI to AD. Task-based fMRI studies show mixed results in patients with MCI, perhaps linked to varying severity of MCI. Similar mixed results have been seen in resting-state fMRI studies, with differences due to heterogeneity and differential severity.¹² Less impaired patients with MCI may show compensatory hyperactivation in the medial temporal lobe and greater deactivation of the default-mode network during memory tasks and at rest, whereas more impaired patients show patterns of activity similar to those of patients with AD. Arterial spin labeling studies have shown a similar pattern of hyperperfusion in milder forms of MCI and hypoperfusion in more impaired patients with MCI.¹³ Finally, quantitative susceptibility mapping has shown mixed results in patients with MCI with one study suggesting increased values representing areas with more iron in cortical regions but not subcortical regions, whereas others found no significant differences in iron deposition in MCI.¹⁴

Patients with preclinical AD, including cognitively normal patients with significant amyloid deposition (Aβ+ cognitively normal) and cognitively normal patients carrying at least one apolipoprotein E (APOE) ε4 allele (APOE ε4+ cognitively normal), also show subtle changes in MRI measures of brain structure and function. Studies of structural MRI in preclinical AD have shown mixed findings, with some suggesting mild atrophy in subregions of the hippocampus known to degenerate early in the disease course (eg, subiculum, presubiculum), whereas others have found minimal atrophic changes.⁷ Patients with preclinical AD also show an accelerated rate of brain atrophy relative to Aβ- or APOE ε4- cognitively normal patients, especially in those who subsequently convert to a diagnosis of MCI or AD dementia.¹⁶ Individuals with preclinical AD also showed a reduced T1/T2 ratio in the right inferior parietal lobule relative to controls without preclinical AD, suggesting altered myelination in this region in the earliest stages of AD.⁹

Advanced neuroimaging techniques have also been applied to preclinical AD populations and suggested ongoing pathologic changes occurring before the onset of cognitive symptoms. Specifically, DWI studies have found white matter integrity loss in tracts known to be affected in MCI and clinical AD, including the cingulum and corpus callosum.¹⁷ Task-based fMRI studies in preclinical AD have shown altered activation during memory tasks, as well as both increased and decreased brain connectivity on resting-state fMRI and changes in cortical hubs and modularity.¹⁸ Arterial spin labeling studies in preclinical AD have shown that APOE ε4+ cognitively normal patients show areas of both hyperperfusion and hypoperfusion relative to APOE ε4- cognitively normal people, with hyperperfusion in the medial temporal lobe, precuneus, and insula and hypoperfusion in the inferior parietal lobe and middle temporal gyri.¹⁹

Metabolic and Molecular Imaging Findings in Clinical, Prodromal, and Preclinical Alzheimer Disease

FDG-PET studies in patients with AD show hypometabolism in the lateral parietal, temporal, and secondary visual association cortices, with frontal lobe hypometabolism later in the disease and relative sparing of the primary visual cortex and sensorimotor cortex (figure 9-2a).²⁰ As described later, this pattern is distinct from that seen in DLB, PDD, and frontotemporal dementia, assisting with diagnosis in cases with overlapping symptomatology. In fact, the Centers for Medicare & Medicaid Services approves reimbursement for FDG-PET in cases with an uncertainty of diagnosis; FDG-PET provides considerable improvement of diagnostic certainty in patients (approximately 50% to 60%).²¹

On amyloid-specific molecular imaging, patients with AD show widespread amyloid deposition throughout the cortex and later in the striatum (figure 9-2a).²⁰ Stages of amyloid pathology in AD have been described and validated with postmortem data, namely that amyloid deposition begins in medial parietal and frontal regions, then progresses to encompass most of the cortex, finally showing cortical and subcortical amyloid deposition in the striatum.²² However, given that amyloid deposition can be found in other dementias and even in cognitively normal patients, the diagnostic use of amyloid imaging is best for ruling out AD by a negative scan rather than for use as a positive diagnostic test.

Tau PET imaging is also widely used in research, and one tracer has been approved by the FDA for clinical use ([¹⁸F]flortaucipir). Patients with AD show characteristic tau deposition in the medial and lateral temporal and parietal lobes, as well as frontal lobe deposition in more advanced cases (figure 9-2a). Significant tau PET tracer uptake is seen in the temporal, parietal, and frontal lobes, whereas the primary sensory and motor cortices are relatively spared.²³ Higher baseline tau PET burden is associated with faster rates of future atrophy, as well as the topographic pattern of where atrophy occurs.²⁴ Studies have shown that tau PET techniques are able to recreate the topographic patterns of tau deposition, described in seminal work by Braak and Braak,²⁵ from neuropathologic assessment, especially in Braak stages IV to VI.²⁶ As tau PET signal and distribution are more closely associated with symptoms of AD than amyloid, tau PET scans provide important information in both classic and atypical presentations of AD (described in more detail later). Longitudinally, patients with AD dementia show accelerated rates of tau accumulation relative to patients with MCI and those who are cognitively normal.²⁷ The recent development of additional tracers to study synaptic loss (eg, [¹¹C]UCB-J) and neuroinflammation (eg, mitochondrial 18-kDa translocator protein tracers) has provided additional information in patients with AD dementia. These modalities demonstrate synaptic loss in areas known to show neurodegeneration in AD (ie, medial and lateral temporal lobes) and increased neuroinflammation across the cortex.^28,29

Similar to MRI findings, patients with MCI tend to have intermediate levels of molecular imaging changes relative to cognitively normal people and patients with AD. Patients with MCI show hypometabolism in temporoparietal, posterior cingulate, and parietal regions on FDG-PET, which can predict future progression to dementia (figures 9-2b and 9-2c).³⁰ As might be expected, 50% to 75% of patients with MCI show widespread amyloid deposition, most prominently in the medial parietal and frontal lobes.³¹ Patients with MCI who are amyloid positive show poorer cognition and a faster rate of cognitive decline and progression to dementia than those who are amyloid negative (figures 9-2b and 9-2c).³² Tau PET studies in patients with MCI show increased signal primarily in the bilateral medial and lateral temporal lobes, with some patients showing deposition in the parietal and secondary visual association areas (similar to Braak stages V and VI).²³ Amyloid-positive patients with MCI show greater tau deposition than amyloid-negative patients with MCI, with very few individuals showing high tau deposition in the absence of amyloid deposition.³³ In fact, amyloid-negative patients with tau positivity in the cortex have recently been postulated to be false-negative amyloid PET cases.³⁴ Longitudinal studies have suggested that patients with MCI show a more pronounced rate of accumulation of tau relative to cognitively normal people. Finally, patients with MCI show increased neuroinflammation but only minimal changes in synaptic density.^28,29

Approximately 25% of cognitively normal people older than 65 years show high levels of amyloid deposition. People who are APOE ε4+ and cognitively normal are considerably more likely to show amyloid deposition than people who are APOE ε4- and cognitively normal.¹⁶ Amyloid deposition in cognitively normal people is associated with a higher risk of cognitive decline.³⁵ FDG-PET studies in patients with preclinical AD show mixed results, with some studies showing hypometabolism in AD-like distribution (ie, medial temporal lobe, temporoparietal, cingulate) and others showing hypermetabolism in the prefrontal cortex and temporal lobe.³⁶ The considerable heterogeneity of this group regarding disease stage, likelihood, proximity to an impaired diagnosis (ie, MCI or AD dementia), and any additional risk factors is likely to affect the consistency of the findings. Finally, Aβ+ cognitively normal patients show higher levels of tau deposition and faster rates of tau accumulation than Aβ- cognitively normal patients.²³ Tau in preclinical AD can also be staged similarly to the Braak staging seen in patients with MCI and AD.³⁷

New Developments in Alzheimer Disease Neuroimaging

One major area of development in the field of AD is the development of blood-based tests for amyloid and tau, as well as neurodegeneration. Recent advances in fluid assays have led to the development of sensitive plasma-based biomarkers for detection of amyloid and tau along the continuum of AD. Multiple plasma pTau assays for different phosphorylation sites (pTau181, pTau217, pTau231) have been developed and show excellent prediction of clinical diagnosis, as well as the presence of cerebral amyloid and tau deposition. Studies have shown higher levels of pTau and lower Aβ42/Aβ40 ratios in patients with MCI and AD relative to cognitively normal patients.³⁸ In addition, strong associations between cerebral measures of amyloid and tau (CSF or PET) and plasma pTau and Aβ42/Aβ40 ratios have been seen across groups from preclinical AD to clinical AD stages. These measures are being rapidly developed for clinical use and show excellent ability to improve differential diagnosis and diagnostic accuracy, particularly for detecting cerebral amyloid and tau deposition across disease stages.

Patterns of tau and amyloid spread have also been a topic of recent investigations. The patterns of tau deposition seen on PET, which are a set of anatomically dispersed regions in primarily the temporal and parietal lobes, are often similar to the canonical Braak stages.²⁵ Recent studies have suggested that, instead of spreading locally in neighboring regions, tau may propagate through the brain along functionally and structurally connected networks.³⁹ This spreading and the associated neuronal loss is thought to be a major factor in the development of cognitive decline because the deposition of the pathologic proteins causes global network failure. Cross-sectional tau PET studies have reported that areas of high tau deposition tend to follow characteristic patterns that significantly overlap with intrinsic functional and structural networks. Specifically, the earliest tau deposition appears to be in the entorhinal cortex, followed by the amygdala, hippocampus, parahippocampal gyri, fusiform, lateral temporal lobe, and finally to the wider cortex. Longitudinal studies using tau PET support these hypotheses, as Aβ+ patients show a higher rate of tau accumulation in more intrinsically connected regions. Overall, this seeding theory of tau spread fits the current data, but larger and longer longitudinal studies are needed to fully understand this hypothesis.

Amyloid data do not fit the propagation model as well as tau PET but do show areas of early versus late amyloid deposition.⁴⁰ Early regions of amyloid deposition, such as the anterior temporal lobe, frontal lobe, medial parietal lobe, cingulate, and precuneus, generally precede later regions, such as the insula, other cortical regions, and the striatum. However, the model of amyloid spread is not as strongly supported by the current data, which suggests that amyloid follows a sigmoidal rate of change over time with low to high deposition rate transition occurring approximately 15 to 17 years before the onset of clinical symptoms.⁴¹ Future studies allowing a better understanding of these processes will be crucial for designing treatments to interfere with the spread and deposition of these pathologic proteins in at-risk patients.

Heterogeneity in Patients With Alzheimer Disease

Despite the consistency of results described above, heterogeneity in cognition and imaging findings is common in patients with AD. One type of heterogeneity is the age of onset of dementia, which can be broadly classified as early-onset AD, with an age of onset younger than 65 years, or late-onset AD, with an age of onset at 65 years or older.¹ Early-onset AD is considerably rarer than late-onset AD with only approximately 5% of all patients with AD showing onset before age 65. However, patients with early-onset AD have been shown to have more severe findings on both MRI and metabolic and molecular imaging measures relative to patients with late-onset AD, with more global atrophy, amyloid deposition, and tau deposition at the same level of cognitive impairment.⁴² A recent multisite longitudinal neuroimaging study to investigate early-onset AD, the Longitudinal Early-Onset Alzheimer’s Disease Study, will provide additional information about the clinical and biomarker course of these patients.⁴³

Heterogeneity in the pattern of cognitive symptoms and anatomic patterns of atrophy and tau deposition has also been widely discussed. Although most patients with AD present initially with memory impairments, other presentations with predominant language impairment, visuospatial impairment, and executive impairment are also seen. Patients with early-onset AD are more likely to show nonmemory-predominant cognitive impairment.⁴⁴ Rare subtypes of early-onset AD that present with visuospatial impairment (posterior cortical atrophy) and language impairment (logopenic variant primary progressive aphasia [PPA]) show similar patterns of amyloid deposition to those seen in traditional early-onset AD. However, tau deposition and atrophy patterns in posterior cortical atrophy and logopenic PPA show distinct patterns that match the dominant cognitive symptoms. Namely, posterior cortical atrophy is characterized by tau deposition, hypometabolism, and atrophy in posterior brain regions (ie, parietal and occipital lobes), whereas logopenic variant PPA shows left more than right hemisphere tau deposition, hypometabolism, and atrophy, particularly in temporoparietal regions.⁴⁵

An additional atypical amyloid-related disorder is CAA, in which amyloid deposition primarily occurs in the vessel walls of small cerebral arteries and capillaries rather than in the extracellular space. Although commonly co-occurring with AD, primary CAA features a symptomatic and spontaneous local hemorrhage that can cause focal neurologic symptoms, headache, and altered consciousness.⁴⁶ MRI findings in CAA show cerebrovascular damage, most especially microhemorrhages and cortical superficial siderosis that can be assessed by using T2* or SWI sequences or both. Further, because CAA is an amyloid-based disorder, amyloid PET scans demonstrate high amyloid deposition,⁴⁷ particularly in the occipital lobe, which is generally indistinguishable from positive amyloid scans from traditional AD with parenchymal amyloid. Finally, a tau PET study indicated increased tau deposition in regions with microbleeds and cortical superficial siderosis in patients with CAA.⁴⁸

Heterogeneity occurs in late-onset AD, although not as commonly or as severely as in early-onset AD. Heterogeneity in cognitive symptoms affecting nonmemory domains can be seen in late-onset AD (figure 9-3⁴⁴).^49,50 Patients with these nonmemory-predominant presentations show different atrophy and FDG hypometabolic patterns than those seen in “traditional AD,” which correspond to their domain of most impairment (eg, more posterior in visuospatial-predominant late-onset AD, left more than right in language-predominant AD).^51,52 In addition to the cognitive-defined heterogeneity, tau deposition and atrophy patterns have notable heterogeneity following a pattern previously described in neuropathologic studies. In fact, by using both tau deposition on PET and MRI-based assessments of atrophy patterns, the definition of two or three AD subtypes can be described that differ from the traditional AD atrophy pattern.^44,50 Specifically, recent studies in patients with amyloid-positive MCI and AD dementia have suggested the presence of multiple subtypes, including patients with minimal tau deposition or atrophy in any region, patients with a limbic-predominant presentation defined as focal and severe tau deposition and atrophy in the limbic regions with minimal cortical atrophy, and a hippocampal-sparing pattern defined as a heavy tau deposition or severe atrophy in the cortex with relative sparing of tau deposition and atrophy in the hippocampus and medial temporal lobe. Previous studies have suggested important clinical differences between these subtypes, including a faster clinical progression, lesser likelihood of carrying an APOE ε4 allele, and earlier age of onset in hippocampal-sparing AD than traditional AD or limbic-predominant AD. Future treatments developed for AD should consider consistent efficacy in these different subtypes of AD, and perhaps personalized treatments will be needed to address the heterogeneity seen across patients.

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FIGURE 9-3. Conceptualization of heterogeneity in Alzheimer disease (AD). Patients with AD can show heterogeneity in multiple domains, including the patterns of tau deposition, atrophy, and clinical presentation. For example, Vogel and colleagues49 identified four subtypes (A) of tau distribution that mirror those previously seen in studies of brain atrophy.50B (top), Heterogeneity of phenotypes can be found in late-onset AD, which may often be characterized as a less severe version of the clinically defined atypical variants in early-onset AD, such as logopenic variant primary progressive aphasia (lvPPA), posterior cortical atrophy (PCA), or behavioral variant AD (bvAD). B (bottom), Often these heterogeneous atypical phenotypes can be conceptualized as occurring along four different age-associated spectra, such that “atypical” late-onset AD presentations are less extreme expressions of early-onset AD phenotypes. C, The causes of these atypical variants are unknown; however, they are hypothesized to be the result of one or more of three different scenarios, including (1) structural variations in axonal connectivity patterns resulting in pathology following an individual network, (2) vulnerabilities in certain regions that cause faster and more severe pathology accumulation in those sites, and (3) the different presentations representing different biological or biophysical diseases causing differential regional spread.CBS = corticobasal syndrome; L temporal = lateral temporal; MTL = medial temporal lobe; PCA = posterior cortical atrophy; S = subtype.Reprinted with permission from Vogel JW and Hansson O, Trends Neurosci.44 © 2022 Elsevier Inc.

VASCULAR COGNITIVE IMPAIRMENT

Vascular cognitive impairment defines dementias that are caused by changes in the cerebrovascular system, including subcortical ischemic vascular dementia, multi-infarct dementia, hemorrhagic dementia, and genetic forms of vascular cognitive impairment such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).⁵³ The most common type of vascular cognitive impairment is subcortical ischemic vascular dementia, which is often secondary to cardiovascular risk factors such as hypertension, hyperlipidemia, diabetes, and obesity. In subcortical ischemic vascular dementia, cognitive changes are dependent on the location and severity of cerebrovascular damage, strokes, or both. Clinically, patients with vascular cognitive impairment most commonly show impaired executive function and processing speed, as well as potentially headaches, motor changes, apathy, depression, and incontinence, depending on the location and severity of the cerebrovascular insult.

MRI Findings in Vascular Cognitive Impairment

Patients with subcortical ischemic vascular dementia and other types of vascular cognitive impairment most commonly show white matter hyperintensities throughout the white matter of the brain as visualized by T2-weighted or fluid-attenuated inversion recovery (FLAIR) imaging.⁵⁴ Other pathologies that can be visualized on MRI include lacunes, prominent perivascular spaces, and cerebral microhemorrhages (figure 9-4). Although these pathologies can be seen in normal aging, the pathology in vascular cognitive impairment or subcortical ischemic vascular dementia is much more severe and widespread than that seen in cognitively normal patients. In addition, patients with vascular cognitive impairment show more extensive white matter hyperintensities and subcortical infarcts and fewer microhemorrhages than patients with CAA. Brain atrophy is also observed globally in gray matter and white matter and is correlated with the extent of white matter hyperintensity burden.⁵⁵ DWI studies have also described differences in white matter integrity in vascular cognitive impairment, even in “normal appearing white matter,” which are areas of the white matter that do not show apparent cerebrovascular pathology macroscopically and on MRI. Reduced white matter integrity in both projection and association fibers in vascular cognitive impairment is associated with severity of dementia, cognitive impairment, motor symptoms, and extent of cerebral atrophy.⁵⁶ Both task-based and resting-state fMRI studies have shown alterations in activation and connectivity in patients with vascular cognitive impairment, namely reduced activation during task performance and reduced connectivity of the regions of the cingulate, parietal, and frontal lobes.^57,58 Increased brain connectivity has also been reported, which is associated with the extent of cognitive impairment. Arterial spin labeling studies have shown that a larger white matter hyperintensity burden was associated with lower CBF globally, which was less significant in vascular cognitive impairment without dementia.⁵⁹ Finally, quantitative susceptibility mapping has demonstrated higher susceptibility values in vascular cognitive impairment relative to those in cognitively normal patients, especially in the striatum, suggesting greater iron deposition in the caudate and putamen of patients with vascular cognitive impairment.¹³ The determination of whether ischemic burden is the primary cause of cognitive impairment or a secondary factor in a clinical patient is difficult considering the high frequency of cerebrovascular disease comorbidity with other disease-causing pathologies. If the patient is negative for other types of copathologies that can be measured in vivo (ie, amyloid, tau) and displays a heavy ischemic burden, that may suggest that the cerebrovascular damage is the primary causative pathology. However, given the current lack of in vivo biomarkers for other important neurodegenerative pathologies (eg, transactive response DNA-binding protein 43 [TDP-43], α-synuclein), some uncertainty remains about concluding that observed vascular damage is the sole cause of cognitive decline.

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FIGURE 9-4. Example axial MRI scans of vascular cognitive impairment–related pathology. Abnormalities on structural MRI in vascular cognitive impairment are shown on fluid-attenuated inversion recovery (FLAIR) and susceptibility-weighted imaging (SWI). A, One example FLAIR image shows white matter (WM) hyperintensities (white arrows) in periventricular and subcortical WM regions. B, Another FLAIR scan shows a lacunar infarct (red arrow) along with WM hyperintensities (white arrows). C, An example SWI scan shows cerebral microhemorrhages (also known as microbleeds) in the basal ganglia and thalamus (blue arrows).Modified with permission from Razek A and Elsebaie N, Clin Imaging.54 © 2021 Elsevier Inc.

Metabolic and Molecular Imaging in Vascular Cognitive Impairment

Fewer studies have investigated molecular imaging tools in vascular cognitive impairment because the primary methods for diagnosis and monitoring of vascular cognitive impairment are MRI based. FDG-PET imaging has demonstrated that patients with vascular cognitive impairment have multifocal hypometabolism, which often presents in an asymmetric or scattered pattern or both.⁶⁰ This hypometabolism can be cortical or subcortical or both and found near arteries or watershed regions of the brain. Unlike in AD, patients with vascular cognitive impairment may show pronounced hypometabolism in the primary sensorimotor cortex. Amyloid and tau PET studies generally show minimal tracer binding, which can distinguish vascular cognitive impairment from CAA.⁵³

COMORBIDITY OF CEREBROVASCULAR DISEASE WITH OTHER DEMENTIA PATHOLOGIES

The majority of dementia cases that come to autopsy have more than one pathologic finding, most commonly AD pathology and small vessel disease, especially in older patients.⁶¹ In life, AD often presents as mixed dementia, reflecting the presence of AD pathophysiology and one or more other suspected pathologies. At this time, only AD and vascular pathologies can be visualized in vivo, because other notable pathologies (eg, α-synuclein, TDP-43, fused in sarcoma [FUS]) can be assessed only at autopsy. Patients with mixed AD and vascular pathologies show greater levels of white matter hyperintensities and more advanced white matter degeneration on structural MRI and DWI relative to those with AD only or vascular cognitive impairment only.⁶² Mixed dementia cases have also been shown to have more rapid degeneration in motor function, such as gait and grip strength.⁶³ Cerebrovascular risk factors in both cognitively impaired patients and cognitively normal patients provide additive risk for cognitive decline, although this may vary by ethnicity, as well as more prominent perivascular spaces and white matter hyperintensities on MRI.⁶⁴ Overall, the mixed dementia cases are an important and frequently observed phenomenon that should be considered during the development of novel therapeutic interventions and pharmaceuticals.

PARKINSON DISEASE DEMENTIA AND DEMENTIA WITH LEWY BODIES

Lewy bodies, which represent pathologic protein aggregations of α-synuclein, are the main pathologic characteristic of Parkinson disease (with or without dementia), DLB (illustrated in case 9-2), and multiple system atrophy (MSA).⁶⁵ These pathologic aggregates may also co-occur in patients with other primary proteinopathies (eg, AD, FTLD) or cerebrovascular damage, leading to mixed pathology, as well as cognitive and motor symptoms. PDD and DLB are diseases along the same continuum with the distinguishing factor being the sequence of onset of motor versus cognitive symptoms. In other words, motor symptoms are diagnosed first in PDD and followed by cognitive impairment, whereas DLB is defined as the opposite (cognitive symptoms came before the motor symptoms). Therefore, the authors of this article discuss these diseases simultaneously, noting that patients with PDD tend to have less severe cerebral pathologies than patients with DLB.⁶⁶ DLB-associated and PDD-associated cognitive decline is primarily observed in executive function, attention, and higher-order visuospatial processing domains, which can fluctuate in severity, as well as visual hallucinations and delusions, rapid eye movement (REM) behavior disorder, and parkinsonian symptoms. MSA is a class of rare Lewy body–related diseases, including olivopontocerebellar atrophy, Shy-Drager syndrome, and striatonigral degeneration. Patients with MSA show parkinsonian symptoms of varying severity, cerebellar ataxia, and prominent autonomic dysfunction in the case of Shy-Drager syndrome.⁶⁷ These patients are now divided into parkinsonian type MSA and cerebellar ataxia type MSA, based on their predominant symptoms.

MRI Findings in Dementia With Lewy Bodies, Parkinson Disease Dementia, and Multiple System Atrophy

Patients with DLB show cortical atrophy on structural MRI, particularly in the insula, middle and posterior cingulate, superior temporal-occipital areas, lateral orbitofrontal lobe, other regions of the frontal lobe, inferior parietal lobe, temporal lobe, and occipital lobe. Patients with PDD show atrophy in similar regions, with less severity in cortical regions than that in patients with DLB.⁶⁶ Relative to patients with AD, patients with DLB and PDD show relative sparing of the medial temporal lobe (figure 9-5a). Approximately half of patients with DLB show marked amyloid deposition, suggesting comorbid pathologies.⁶⁹ Aβ+ patients with DLB and PDD show more global atrophy than Aβ- patients with DLB and PDD, as do patients with DLB and PDD with comorbid cerebrovascular disease represented by a higher white matter hyperintensity burden.⁶⁶ Longitudinally, patients with DLB and PDD show a faster rate of atrophy in the medial temporal lobe, lateral temporal lobes, and temporal-occipital areas, which is generally more severe in DLB than PDD.⁷⁰ MRI in patients with MSA shows atrophy of the cerebellum, pons, thalamus, substantia nigra, and parietal and occipital lobes.⁷¹ One characteristic (but nonspecific) sign of MSA can be found by using T2-weighted imaging, which shows a cruciform hyperintensity in the pons that is known as the hot cross buns sign.⁷² Longitudinally, patients with MSA, relative to cognitively normal patients, show increased atrophy rates in the cerebellum, pons, and midbrain, which are associated with declines in cognition⁷³ and the development of extrapyramidal, cerebellar, and autonomic features.

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FIGURE 9-5. Imaging findings in dementia with Lewy bodies (DLB) relative to Alzheimer disease (AD). A, Representative structural coronal MR images show relatively spared hippocampal volume in the patient with DLB relative to the patient with AD dementia. B, Areas of glucose hypometabolism are highlighted (blue to red scale), with the hottest colors showing the areas with the most loss of glucose metabolism. The patient with DLB shows glucose hypometabolism in the primary occipital lobe and parietal lobe, whereas the patient with AD shows mostly lateral parietal and frontal hypometabolism. C, [¹²³I]FP-CIT single-photon emission computed tomography (SPECT) imaging of dopamine transporters shows significant reductions in dopaminergic transmission in the striatum of the patient with DLB, with preserved function in the patient with AD.[¹⁸F]FDG = fludeoxyglucose; PET = positron emission tomography.Modified with permission from Walker Z, et al, Lancet.68 © 2015 Elsevier Inc.

Advanced MRI studies have also shown alterations in white matter integrity, brain function, CBF, and iron deposition in patients with DLB, PDD, and MSA. In patients with DLB and PDD, DWI studies demonstrate significant loss of white matter integrity in the corpus callosum, longitudinal fasciculi, and frontal, parietal, and occipital white matter, with more severe findings seen in DLB relative to PDD.⁷⁴ Reduced structural connectivity in the default-mode network and visual networks are also seen in DLB and PDD.⁷⁴ Patients with MSA show reduced white matter integrity in the brainstem, cerebellar, and subcortical regions on DWI, which is associated with the severity of ataxia symptoms.⁷⁵ Task-based fMRI studies have observed altered activation in patients with DLB and PDD during visual and executive tasks, including reduced activation in occipital-temporal areas and hyperactivation in the superior temporal sulcus.⁷⁶ Patients with PD and MCI showed reduced activation during a working memory task in the middle frontal gyrus and parietal lobule relative to PD patients without cognitive impairment and cognitively normal people.⁷⁷ A task-based fMRI study in patients with MSA demonstrated reduced activation in motor control areas during a grip force task.⁷¹ Resting-state fMRI studies in DLB and PDD show reduced functional connectivity in motor-related regions, executive control network, salience network, frontoparietal network, and the default-mode network.⁷⁸ Patients with MSA also show altered connectivity on resting-state fMRI studies with areas of both increased and decreased connectivity in motor and sensory regions.⁷⁹

Arterial spin labeling studies in DLB and PDD show hypoperfusion in the cuneus, precuneus, anterior cingulate, and parietal-occipital cortices, as well as the cerebellum and caudate, with relative sparing of the posterior cingulate compared with patients with AD (ie, cingulate island sign).⁸⁰ Patients with PD without dementia who convert from normal cognition to MCI have hypoperfusion in the prefrontal cortex and anterior cingulate, which is associated with cognitive function.⁸¹ Patients with MSA have hypoperfusion in the cerebellum, particularly those with cerebellar ataxia type MSA versus parkinsonian type MSA.⁸²

Quantitative susceptibility mapping studies have demonstrated increased iron deposition in PDD and DLB, specifically in the brainstem, thalamus, globus pallidum, putamen, and hippocampus, whereas patients with MSA show greater iron deposition in the putamen and brainstem.¹³ In addition, the SWI scans used to perform quantitative susceptibility mapping also provide imaging of iron deposition in nigrosomes, which are small bundles of dopaminergic cells in the substantia nigra pars compacta.⁸³ When intact, this area shows a hyperintense signal that resembles the tail of a swallow, called the swallow tail sign. Patients with DLB show a loss of the swallow tail sign on SWI scans.⁸⁴

Metabolic and Molecular Imaging in Parkinson Disease Dementia, Dementia With Lewy Bodies, and Multiple System Atrophy

FDG studies in PDD and DLB show hypometabolism in the striatum, cerebellum, frontal and parietal lobes, and the occipital lobe, including the primary visual cortex, with relative sparing of the hippocampus (figure 9-5b).⁸⁵ One of the more distinctive patterns in DLB and PDD is the presence of the cingulate island sign, which is a relative preservation of metabolism in the posterior cingulate relative to the surrounding parietal and occipital lobes. Patients with MSA have decreased glucose metabolism in the cerebellum and putamen that does not correlate with dopaminergic changes.⁸⁶ Amyloid PET studies have demonstrated amyloid deposition in more than half of patients with DLB but with lesser severity than in patients with AD.⁶⁹ Patients with PDD less frequently show amyloid positivity than those with DLB. However, compared with patients with AD, patients with PDD and DLB show more tracer uptake in the primary visual cortex, which is associated with a faster decline in visuospatial function and progression to dementia. Patients with MSA rarely have a positive amyloid PET. Tau PET studies in PDD and DLB show increased tau in the inferior temporal gyrus and precuneus, predominantly in patients with DLB who are amyloid positive.⁸⁷ An MSA case study also showed increased tau deposition in the striatum, midbrain, thalamus, and brainstem, as well as frontal, parietal, and temporal lobes.⁸⁸ However, tau deposition in these disorders is likely secondary to comorbid amyloid pathology rather than the Lewy body pathology. Finally, a 2021 conference report demonstrated in vivo use of a novel PET tracer called ACI-12589 that is sensitive and specific to α-synuclein in patients with DLB, PDD, and MSA.⁸⁹

Unique to DLB and other Lewy body diseases, PET and SPECT measures of dopaminergic neurotransmission represent excellent biomarkers for differential diagnosis.⁹⁰ Specifically, SPECT and PET studies targeting the dopamine transporter (DAT) with [¹²³I]FP-CIT and dopamine receptors (ie, D2 receptors) have shown reduced tracer binding in the striatum and cortex in DLB and PDD, which can differentiate DLB from AD (figure 9-5c).⁹¹ Some anatomic specificity of dopaminergic alterations has also been observed in PDD and DLB, with decreased DAT binding in the caudate associated with cognitive symptoms, whereas DAT reductions in the putamen are associated with motor symptoms. In MSA, DAT-SPECT shows reduced binding in the striatum that is associated with disease severity and duration in parkinsonian type MSA but not in cerebellar ataxia type MSA.⁸⁶ However, none of the imaging measures of dopaminergic neurotransmission can distinguish between different parkinsonian syndromes (eg, DLB, PDD, MSA).

FRONTOTEMPORAL LOBAR DEGENERATION

As the name implies, FTLD diseases feature degeneration of primarily the frontal or temporal lobes or both. Broadly, FTLD disorders can be classified into two forms based on symptomatology: (1) behavioral variant FTLD, in which patients show behavioral disturbances, along with cognitive decline in executive function and, later in the disease, multiple cognitive domains; and (2) PPAs, which feature language impairments of multiple types. One language-predominant FTLD syndrome is semantic dementia, in which patients show aphasia characterized by impairment in semantic memory and single-word comprehension and, later in the disease, behavioral symptoms similar to behavioral variant FTLD. Another is progressive nonfluent aphasia (illustrated in case 9-3), featuring speech production difficulties with agrammatism, phonemic errors, and anomia. Finally, logopenic variant PPA is a variant of AD (described earlier) with characteristic word-retrieval problems, phonologic errors, and impaired repetition.⁹²

In addition, several FTLD syndromes can feature extrapyramidal or motor symptoms⁹² with the FTLD and parkinsonism spectrum. The first disorder is corticobasal degeneration (CBD),⁷² which features cognitive impairment, mostly in executive function or aphasia, and markedly asymmetric apraxia, akinesia, limb rigidity, focal myoclonus, dystonia, and alien limb syndrome. Another parkinsonian FTLD is progressive supranuclear palsy (PSP), which features symmetric bradykinesia, truncal rigidity, postural instability, pseudobulbar syndrome with dysarthria and dysphagia, and supranuclear palsy of vertical gaze, as well as cognitive and/or behavioral changes.⁷² Finally, FTLD with motor neuron disease, also called FTLD-amyotrophic lateral sclerosis (FTLD-ALS), demonstrates progressive muscle weakness and wasting, hyperreflexia, spasticity, and respiratory failure, as well as behavioral and cognitive symptoms.⁹³ Pathology associated with FTLD is generally caused by pathologic deposition of either tau or TDP-43, a TAR DNA-binding protein. Behavioral variant FTLD, progressive nonfluent aphasia, CBD, and PSP are most commonly associated with tau deposition, whereas semantic dementia and FTLD-ALS are commonly associated with TDP-43 deposition (or in rare cases deposition of FUS protein). Onset of FTLD most commonly occurs before the age of 60, although it can happen later in rare cases. A longitudinal multisite observational clinical and biomarker study, called The ALLFTD Study, is ongoing and will provide new data about important biomarker and pathologic findings in this group of diseases.⁹⁴

MRI Findings in Frontotemporal Lobar Degeneration

Patients with behavioral variant FTLD show frontal and temporal lobe atrophy, including the frontomedial cortex, basal ganglia, anterior insula, thalamus, anterior cingulate, orbitofrontal cortex, and deep gray matter structures (figure 9-6⁹⁵).⁹⁶ However, the atrophy pattern observed in behavioral variant FTLD can vary by underlying pathology (ie, tau versus TDP-43).⁹⁷ Studies of patients with behavioral variant FTLD due to tauopathy demonstrate atrophy in the prefrontal cortex, temporal lobe, anterior cingulate, and insula, which is typically bilateral but with slightly left more than right atrophy. In extreme cases (eg, Pick disease), the atrophy of the frontal lobes is so pronounced that it gives them a knifelike appearance. Patients with behavioral variant FTLD with TDP-43 pathology show frontal, temporal, and parietal atrophy, which tends to be asymmetric (either side can be predominant). Differentially, parietal atrophy is greater in patients with TDP-43 behavioral variant FTLD, whereas the frontal atrophy in behavioral variant FTLD due to tauopathy is usually greater than that seen in TDP-43 forms. Longitudinally, patients with behavioral variant FTLD show an increased atrophy rate in the frontal and temporal lobes, regardless of underlying pathology.⁹⁸ Alternatively, patients with semantic dementia show focal atrophy of the anterior inferior temporal lobe, with an asymmetric (left more than right) pattern (figure 9-6).⁹⁶ Patients with semantic dementia also show atrophy in the left subcallosal area, temporal lobe, amygdala, hippocampus, and perirhinal cortex. Longitudinally, patients with semantic dementia show a high rate of progressive atrophy in the left more than right temporal lobe.⁹⁸

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FIGURE 9-6. Atrophy and hypometabolism in frontotemporal dementia spectrum disorders. The two columns on the left show group-level differences between patients with the indicated clinical frontotemporal lobar degeneration (FTLD) syndromes compared with cognitively normal controls visualized on three-dimensional rendered surfaces of the brain (atrophy on MRI). The two columns on the right show hypometabolism in the three FTLD syndromes displayed as z score deficit maps for individual patients compared with controls.agPPA = agrammatic primary progressive aphasia; bvFTD = behavioral variant frontotemporal dementia; FDG = fludeoxyglucose; MRI = magnetic resonance imaging; PET = positron emission tomography; SD = semantic dementia.Modified with permission from Whitwell JL, Prog Mol Biol Transl Sci.95 © 2019 Elsevier Inc.

Patients with progressive nonfluent aphasia show asymmetric perisylvian and anterior insular atrophy with the dominant language hemisphere most affected (usually the left hemisphere in right-handed people) (figure 9-6). In addition, atrophy is observed in the frontal operculum (eg, Broca area), temporal pole, lentiform nucleus, inferior and middle frontal gyri, premotor cortex, and the dorsolateral prefrontal cortex, spreading to other frontal, parietal, and temporal lobes, as well as the caudate and thalamus in later stages. If the progressive nonfluent aphasia is caused by a tauopathy, patients have more severe temporal atrophy than in other forms.⁹⁷ Longitudinally, the frontal lobe of patients with progressive nonfluent aphasia shows a high rate of atrophy that is twice as fast as even patients with AD.⁹⁸

Patients with CBD show asymmetric atrophy of the frontal and parietal lobes without sparing of the primary motor and sensory cortices, as well as the basal ganglia contralateral to the side most affected with rigidity and apraxia (figure 9-7a).⁹⁹ Alternatively, structural MRI studies in patients with PSP show significant midbrain atrophy, particularly in comparison with the neighboring pons, which is more severe than that seen in CBD (figure 9-7b).⁹⁹ This atrophy pattern, which is characteristic for PSP, has been described as the hummingbird sign on a sagittal view and the Mickey Mouse sign or morning glory sign on an axial view.¹⁰⁰ Patients with PSP also show atrophy in the posterior frontal lobe, premotor cortex, supplementary motor area, caudate nucleus, brainstem, and cerebellum.⁹² Longitudinally, patients with CBD and PSP show accelerated cortical and subcortical atrophy rates, with faster atrophy in CBD than in PSP.¹⁰¹ Finally, patients with FTLD-ALS show atrophy in the frontal and temporal lobes, as well as the anterior cingulate, occipital lobe, and precentral gyrus, which is more severe in patients with FTLD-ALS than in patients with ALS and no FTLD symptoms.⁹⁷

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FIGURE 9-7. Structural MRI in corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). Axial sections from a structural MRI scan from a patient with CBD (A) show atrophy in the frontal and parietal lobes (arrows), while sagittal and axial views of a structural MRI scan (B) from a patient with PSP show two hallmark findings, the hummingbird sign, which represents midbrain atrophy relative to the pons (box), and the Mickey Mouse sign or morning glory sign, which represents atrophy of the midbrain (arrows).Modified with permission from Risacher SL and Saykin AJ, Handb Clin Neurol.5 © 2019 Elsevier Inc.

Abnormalities in patients with FTLD have also been observed on advanced MRI techniques, such as DWI, fMRI, arterial spin labeling, and quantitative susceptibility mapping. DWI studies in behavioral variant FTLD show reduced white matter integrity in the salience network, a set of interconnected regions that includes the anterior cingulate and insula, as well as tracts connecting the frontal and temporal lobes, including the anterior superior longitudinal fasciculus, inferior longitudinal fasciculus, inferior frontal-occipital fasciculus, uncinate fasciculus, anterior cingulum, and parts of the corpus callosum.¹⁰² Diffusion tensor imaging studies of patients with semantic dementia have shown significant white matter integrity loss in the left uncinate fasciculus, left inferior longitudinal fasciculus, and left parahippocampal white matter, with the lowest integrity values in the left anterior temporal lobe.¹⁰² Patients with progressive nonfluent aphasia show white matter degeneration on DWI in frontoparietotemporal pathways, including the uncinate fasciculus, arcuate fasciculus, parts of the superior longitudinal fasciculus, and the superior motor pathway.¹⁰² Decreased white matter integrity in patients with progressive nonfluent aphasia is primarily seen in the regions with gray matter atrophy, including the left perisylvian region, inferior frontal gyrus, insula, and supplementary motor area. In patients with CBD, DWI studies show a loss of white matter integrity in the motor regions of the thalamus, precentral and postcentral gyri, and the bilateral supplementary motor area.¹⁰² Alternatively, patients with PSP show decreased white matter integrity on DWI studies in the superior longitudinal fasciculus, thalamus, cingulum, primary motor cortex, supplementary motor area, and frontal-orbital white matter.¹⁰² Reduced structural connectivity in the cerebellothalamic network is also observed in patients with PSP. Patients with CBD show longitudinal white matter integrity loss in the basal ganglia and cortex, whereas patients with PSP show white matter loss in the superior cerebellar peduncles and caudate.¹⁰³ Finally, patients with FTLD-ALS show reduced white matter integrity on DWI studies in the frontal and temporal lobes, corpus callosum, corticospinal tract, inferior longitudinal fasciculus, inferior frontal-occipital fasciculus, and uncinate fasciculus, which are associated with poorer cognition.¹⁰⁴ Longitudinal DWI studies in FTLD-ALS show progressive degeneration of white matter motor tracts.¹⁰⁵

Task-based fMRI studies in behavioral variant FTLD have shown attenuated frontal activation during working memory, as well as abnormalities during facial expression tasks.¹⁰⁶ In resting-state fMRI studies, patients with behavioral variant FTLD demonstrate significantly reduced salience network connectivity, which predicts worsening behavioral symptoms and dementia, and changes in default-mode network connectivity, although reports have been conflicting.¹⁰⁷ Patients with behavioral variant FTLD also show disrupted internetwork connectivity and a lack of frontal lobe cortical hubs on resting-state fMRI.¹⁰⁸ In task-based fMRI studies, some patients with semantic dementia show impaired activation in temporal regions during reading,¹⁰⁹ whereas others show normal activation.¹¹⁰ Other task-based fMRI studies have shown impairments in patients with semantic dementia on a variety of language-related tasks, including sound processing, autobiographic memory, and surface dyslexia.¹⁰⁹ Resting-state fMRI studies in patients with semantic dementia show reduced functional connectivity of the left anterior temporal lobe and frontolimbic circuitry, with increased connectivity in local prefrontal cortex networks.¹⁰⁷ Reduced left lateralized functional connectivity in the temporal, occipital, and frontal lobes, as well as in the amygdala, hippocampus, and caudate, were also observed in patients with semantic dementia.

Alternatively, patients with progressive nonfluent aphasia show reduced activation in the posterior inferior frontal cortex during sentence complexity, reading, and comprehension tasks in task-based fMRI studies.¹¹¹ Resting-state fMRI studies in progressive nonfluent aphasia show alterations in the inferior frontal and insular speech and language network, as well as language networks more broadly.¹¹²

Patients with FTLD with motor symptoms also show functional deficits during task-based fMRI of motor tasks. Reduced activation in the premotor cortex, with a corresponding increase in parietal activation, was observed in patients with CBD during a limb apraxia task,¹¹³ whereas patients with PSP have shown altered activation during both a grip-force task and a mental-imagery task (imagining lying, standing, walking, or running), including reduced activation in the basal ganglia, primary motor and premotor cortex, and frontal and temporal lobes.¹¹⁴ In patients with CBD, a resting-state fMRI study found disruption of multiple resting-state networks, including the lateral visual and auditory networks.¹¹⁵ Resting-state fMRI studies in patients with PSP have shown decreased functional connectivity in the thalamus, caudate, anterior cingulate, dorsolateral prefrontal cortex, supramarginal gyrus, temporal-occipital cortex, supplementary motor area, and cerebellum. Other resting-state fMRI studies in patients with PSP have demonstrated reduced functional connectivity in the default-mode network and salience network, along with the thalamus, striatum, cerebellum, and premotor cortex.¹¹⁵ Finally, task-based fMRI studies in patients with FTLD-ALS have demonstrated reduced activation in the frontal lobe, insula, and thalamus during an executive task, in the frontal lobe during an emotional task, and in the frontal lobe, anterior cingulate, supramarginal gyrus, temporal lobe, and occipitotemporal regions during a verbal fluency task.¹¹⁶ A resting-state fMRI study in presymptomatic FTLD-ALS demonstrated increased functional connectivity between the cerebellum and precuneus, cingulate, and middle frontal lobes.¹⁰⁴

Studies using arterial spin labeling to measure CBF in FTLD syndromes have demonstrated hypoperfusion in areas that largely overlap with the patterns of atrophy seen in each disease subtype. Specifically, patients with behavioral variant FTLD show hypoperfusion in the frontal and temporal lobes, as well as the anterior cingulate cortex.¹¹⁷ Patients with semantic dementia show left more than right temporal lobe hypometabolism, including in the anterior temporal lobe, middle temporal gyrus, and fusiform gyrus.¹¹⁸ Alternatively, an arterial spin labeling study in patients with progressive nonfluent aphasia demonstrated hypoperfusion in the left temporal lobe, insula, frontal pole, and perisylvian region.¹¹⁸ CBD and PSP both show hypoperfusion in cortical and subcortical regions, as well as the midbrain, relative to that seen in cognitively normal patients.¹¹⁸ Finally, patients with FTLD-ALS show hypoperfusion in the left frontal and temporal lobes relative to that in patients with ALS without cognitive impairment and cognitively normal people.¹¹⁹ Quantitative susceptibility mapping studies of iron deposition in FTLD syndromes have primarily been focused on the syndromes with motor symptoms, including CBD, PSP, and FTLD-ALS.¹³ Specifically, patients with PSP show increased iron deposition in the striatum, midbrain, and brainstem, whereas patients with CBD show increased susceptibility (representing increased iron) in the corticomedullary junction and superficial gray matter. Finally, patients with FTLD-ALS have consistently shown increased iron deposition in the motor cortex, striatum, brainstem, and hippocampus relative to patients with non-FTLD ALS and cognitively normal patients.

Metabolic and Molecular Imaging in Frontotemporal Lobar Degeneration

The majority of molecular imaging studies in FTLD have been performed with FDG-PET or tau PET tracers because amyloid PET shows no significant signal in patients with FTLD of any type (aside from logopenic variant PPA, discussed earlier). Patients with behavioral variant FTLD show symmetric frontal hypometabolism on FDG-PET, even in the absence of visually apparent atrophy on MRI, which later spreads to the anterior cingulate, parietal lobe, and temporal lobe (figure 9-6).¹²⁰ The basal ganglia, insula, and thalamus have also shown hypometabolism in patients with behavioral variant FTLD.

FDG-PET studies in semantic dementia have identified reduced metabolism in the left anterior temporal lobe but less significant frontal lobe hypometabolism than in other forms of FTLD (figure 9-6).¹²⁰ Alternatively, patients with progressive nonfluent aphasia show asymmetric (usually left more than right) frontal cortical hypometabolism in the language-dominant hemisphere, including in the Broca area (figure 9-6).¹²⁰ Interestingly, left-handed patients may show the reverse pattern, with right more than left frontal hypometabolism, because this may be their language-dominant hemisphere.¹²¹

FDG-PET studies in CBD show asymmetric hypometabolism in the posterior frontal lobes, paracentral lobule, sensorimotor cortex, thalamus, basal ganglia, middle cingulate, parietal lobe, and substantia nigra, whereas studies in PSP show notable hypometabolism of the prefrontal cortex, caudate, pallidum, thalamus, mesencephalon, and subthalamic nucleus.¹²² Thalamic hypometabolism in patients with PSP has been associated with increased postural instability and falls.¹²³ Finally, patients with FTLD-ALS show hypometabolism in the frontal lobe, superior temporal lobe, parietal lobe, occipital lobe, and insula,¹¹⁶ which is more severe in FTLD-ALS than in ALS without FTLD.¹²⁴ Amyloid PET scans have shown minimal binding in any subtype of FTLD unless comorbid AD pathology exists.

Tau studies in patients with FTLD have shown binding of tracers in multiple phenotypes, including sporadic and familial behavioral variant FTLD, progressive nonfluent aphasia, CBD, PSP, and even in semantic dementia, which is usually linked to TDP-43 deposition (figure 9-8). Sporadic behavioral variant FTLD shows tau deposition in the basal ganglia, anterior cingulate cortex, and insula in about 50% of cases assessed in vivo, perhaps reflecting the variability in the underlying pathology (ie, tau versus TDP-43).¹²⁵ However, familial MAPT mutations, which result in behavioral variant FTLD secondary to pathologic tau deposition, show high tau signal in the bilateral temporal lobes, anterior cingulate cortex, hippocampus, frontal lobe, and basal ganglia.¹²⁶ The extent of tau in MAPT mutations is correlated with greater atrophy and varies by tau isoform. Multiple studies in patients with semantic dementia have demonstrated tau tracer uptake in the anterior temporal lobe, fusiform gyrus, and insula, which overlaps with the expected regions of degeneration and TDP-43 deposition. This binding may represent off-target binding to TDP-43, which is the likely underlying pathology causing this condition, or binding to comorbid tau fibrils in the region.¹²⁵ Interestingly, a study in a patient carrying a familial C9orf72 mutation, which generally results in TDP-43 pathology, also showed tau PET tracer binding, suggesting nonspecific binding of the tracer.¹²⁷ A 2019 study also reported tau deposition in patients with progressive nonfluent aphasia in the left more than right inferior frontal gyrus.¹²⁵ Multiple studies have reported binding of several different tau tracers in patients with CBD or corticobasal syndrome in the premotor cortex, subcortical white matter, and basal ganglia, which was shown to increase in intensity longitudinally with disease progression and found to be more significant in regions contralateral to the more affected side of the body.¹²⁵ Finally, tau tracer in the basal ganglia, midbrain, and other subcortical regions was observed in patients with PSP, which was shown to correlate with the amount of clinical impairment in some cases and not in others.¹²⁸

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FIGURE 9-8. Axial [¹⁸F]flortaucipir positron emission tomography (PET) in frontotemporal dementia spectrum disorders. Imaging of a patient with behavioral variant frontotemporal dementia (bvFTD) shows mild tracer uptake (arrows) in the frontotemporal lobes, whereas the imaging of the patient with semantic dementia (SD) shows tracer deposition (arrow) predominantly in the left temporal lobe. The imaging of the patient with agrammatic (nonfluent) primary progressive aphasia (agPPA) shows slightly elevated tracer retention (arrow) in the left frontal lobe.SUVR = standardized uptake value ratio.Modified with permission from Whitwell JL, Prog Mol Biol Transl Sci.95 © 2019 Elsevier Inc.

CREUTZFELDT-JAKOB DISEASE AND OTHER PRION DISORDERS

Rapidly progressing neurodegenerative disorders caused by the accumulation of abnormal prion proteins can occur sporadically (sporadic CJD) (illustrated in case 9-4), from exposure to food (variant CJD) or tissues (iatrogenic CJD) containing the abnormal prion protein, or because of a genetic variation in the prion protein gene (PRNP; familial CJD), Gerstmann-Strӓussler-Scheinker disease, or fatal familial insomnia.¹²⁹ These diseases feature cognitive and motor dysfunction, although other presentations with various symptoms are possible. Specifically, most forms of CJD demonstrate a rapidly progressive dementia and a variety of cerebellar, motor, and extrapyramidal symptoms, as well as myoclonus and ultimately death.

Gerstmann-Strӓussler-Scheinker disease is characterized by impairments in executive function, dementia, and numerous motor symptoms including ataxia, balance problems, difficulty walking, incoordination, and sometimes parkinsonian changes. Fatal familial insomnia is primarily associated with a progressive insomnia that causes significant physical and mental decline and ultimately death.

MRI Findings in Creutzfeldt-Jakob Disease and Related Prion Disorders

The primary imaging biomarkers for prion disorders are MRI based, the most sensitive sequence being DWI. All forms of CJD can show restricted diffusion in the basal ganglia, cerebellum, and diffuse regions of the cortex (“ribboning”), most commonly affecting the frontal and parietal lobes (figure 9-9¹³⁰).¹³¹ Cortical involvement is more often asymmetric and does not correspond to arterial perfusion territories. The thalamus may also show restricted diffusion in some cases, although more frequently in patients with variant CJD than sporadic CJD.¹³¹ Restricted diffusion in the pulvinar nucleus of the thalamus relative to the neighboring anterior putamen in patients with variant CJD is called the hockey stick sign because of the curvilinear signal abnormality. These measures of restricted diffusion have been shown to be associated with disease duration and severity, as well as the extent of spongiform burden at autopsy. In addition, patients with sporadic CJD show reduced white matter integrity in multiple white matter pathways.¹³² A resting-state fMRI study showed increased connectivity in the default-mode network.¹³³ Arterial spin labeling studies of cerebral perfusion in CJD have also shown hypoperfusion in the cortex, thalamus, and cerebellum.¹³⁴

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FIGURE 9-9. Structural axial imaging in prion diseases. Diffusion-weighted images (DWI) in patients with sporadic Creutzfeldt-Jakob disease are shown. In the first patient (A), hyperintense signal on DWI is observed in the caudate and putamen (A, thick arrows), whereas the other two patients (B, C) show widespread hyperintensities in the cortex, which can often be asymmetric, including in the temporal, parietal, and frontal lobes, referred to as ribboning (B, C, thin arrows).Modified with permission from Bertleson JA and Ajtai B, Neurol Clin.130 © 2014 Elsevier Inc.

Patients with Gerstmann-Strӓussler-Scheinker disease and some with familial CJD showed mixed results with structural MRI measures, with some showing no atrophy and others with generalized cerebral and cerebellar atrophy. However, similar to CJD, hyperintensities on T2-weighted scans are commonly observed in the basal ganglia in Gerstmann-Strӓussler-Scheinker disease.¹³⁵ Patients with familial CJD also show reduced white matter integrity in multiple white matter pathways, including the corticospinal tract, internal capsule, external capsule, fornix, and posterior thalamic radiations.¹³⁵ Finally, patients with fatal familial insomnia may or may not show mild cerebral atrophy but often have restricted diffusion in the thalamus.¹³⁵

Metabolic and Molecular Imaging Findings in Creutzfeldt-Jakob Disease and Related Prion Disorders

FDG-PET studies in all forms of CJD show widespread and often asymmetric hypometabolism in the cortex and cerebellum, with relative sparing of the basal ganglia and thalamus.¹³⁶ SPECT and PET studies of cerebral perfusion have also shown cortical hypoperfusion in patients with CJD. The reduced glucose metabolism on FDG-PET in patients with CJD was associated with astrocytosis and reduced perfusion. Patients with familial CJD show reduced metabolism in the postcentral gyri, temporal lobe, and superior parietal lobule before the onset of clinical symptoms.¹³⁷ Amyloid and tau PET scans show minimal binding in patients with CJD, suggesting that these tracers are not sensitive to the prion protein deposits.^136,138 In a study with [¹¹C]PK11195, a tracer for neuroinflammatory response, patients with CJD demonstrated upregulated neuroinflammation in the cortex, thalamus, basal ganglia, and cerebellum.¹³⁹

SPECT and FDG-PET studies in patients with Gerstmann-Strӓussler-Scheinker disease demonstrate hypoperfusion and hypometabolism throughout the cerebral cortex, especially in the frontal lobe and cerebellum.¹⁴⁰ Like in CJD, amyloid PET scans in patients with Gerstmann-Strӓussler-Scheinker disease show no specific binding¹⁴¹; however, some variants of Gerstmann-Strӓussler-Scheinker disease, including the PRNP F198S variant, show tau deposition that is immunochemically identical to that in AD at autopsy. A 2018 study with [¹⁸F]flortaucipir showed specific binding in the striatum, thalamus, anterior cingulate cortex, and insula of two patients with Gerstmann-Strӓussler-Scheinker disease due to the F198S mutation.¹⁴² Finally, hypometabolism on FDG was observed in the thalamus and cingulate of patients with fatal familial insomnia with relative sparing of the occipital lobes. No amyloid or tau PET scans have been reported in fatal familial insomnia.¹³⁵

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of diseases presenting with or without motor symptoms, such as late-onset AD, atypical AD, CJD, and FTLD, can be improved by using structural MRI and PET techniques. Patterns of atrophy often differ between neurodegenerative disorders and can be used to support a clinical diagnosis. Traditional AD shows the most severe atrophy and tau deposition in bilateral medial temporal lobe and lateral temporal and posterior cortical regions (ie, parietal and secondary visual areas).

Atypical AD cases, such as posterior cortical atrophy and logopenic variant PPA, show more extensive atrophy and tau deposition in other brain regions, specifically posterior brain regions (including the occipital lobe, which is spared in traditional AD) in posterior cortical atrophy and asymmetric (left more than right) temporoparietal atrophy and tau deposition in logopenic variant PPA. Amyloid PET is not useful for differentiating these cases but can assist with differentiating AD syndromes from FTLD, where most patients have negative amyloid scans. In addition, patients with behavioral variant FTLD show more atrophy in the frontal lobe and less in the parietal lobe than do patients with AD; they also show more hypometabolism on FDG-PET, which can be clinically ordered to differentiate these conditions.

Semantic dementia can be distinguished from other neurodegenerative conditions by the highly asymmetric and focal atrophy and hypometabolic pattern in the anterior temporal lobe (left more than right), whereas progressive nonfluent aphasia shows asymmetric (left more than right) atrophy and hypometabolism in the inferior frontal lobe (ie, the Broca area). These focal findings on MRI and FDG-PET, along with a negative amyloid PET scan, provide excellent diagnostic sensitivity for semantic dementia and progressive nonfluent aphasia relative to other FTLD and AD syndromes. Tau PET is less helpful in FTLD because the underlying pathology could be tau (and thus, show binding), TDP-43, or another proteinopathy. Finally, patients with vascular cognitive impairment present with more vascular abnormalities clinically and neuroradiologically, including white matter lesions, than seen in patients with FTLD and AD. Furthermore, FDG-PET hypometabolism in vascular cognitive impairment is seen only in patchy areas that correspond to areas of hypoperfusion, and widespread amyloid deposition is not seen in vascular cognitive impairment in the absence of co-occurring CAA.

Although DLB and PDD have a higher frequency of extrapyramidal symptoms than AD, these disorders can be difficult to distinguish clinically at times. However, patients with DLB have less extensive cortical atrophy than patients with AD and have relative preservation of the medial temporal lobe, which can help in the differential diagnosis between DLB and AD. In addition, patients with DLB show more atrophy of the midbrain and basal ganglia but less frontal lobe atrophy than patients with AD (or FTLD syndromes). Patients with DLB show more hypometabolism in the primary visual cortex relative to patients with AD, which can also be used to distinguish these conditions. Finally, the use of dopaminergic-specific SPECT and PET tracers will distinguish DLB and PDD disorders from AD, as well as FTLD syndromes.

For the neurodegenerative conditions that have extensive motor, extrapyramidal, and cognitive symptoms (FTLD-ALS, CBD, PSP, DLB and PDD, prion diseases), differential diagnosis can be quite challenging because of the overlapping symptoms and areas of pathology. Patients with FTD-ALS show atrophy and reduced perfusion and metabolism in the frontal (including the primary motor area) and temporal lobes, whereas patients with DLB and PDD show greater posterior cortical hypometabolism and atrophy in the parietal and occipital lobes. In addition, patients with DLB and PDD will show decreased dopaminergic neurotransmission in the striatum on PET or SPECT relative to patients with FTLD-ALS. Amyloid and tau PET are likely not helpful for distinguishing FTLD-ALS, DLB, and PDD. However, tau PET tracers could be useful in the differential diagnosis of CBD and PSP, because these conditions show focal signal in disease-related areas, especially the second-generation tau tracers. In addition, PSP shows a characteristic atrophy pattern of the midbrain (noted earlier as the hummingbird sign on a sagittal view and the Mickey Mouse sign on an axial view) that can assist with the differential diagnosis. Finally, sporadic and variant prion diseases can be distinguished from most other dementias by the areas of restricted diffusion seen in the basal ganglia and thalamus on DWI techniques, including the hockey stick sign in the pulvinar of the thalamus in variant CJD. In summary, the combination of both MRI and metabolic and molecular imaging techniques to understand pathology in various neurodegenerative conditions can aid with differential diagnoses in cases with overlapping symptomatology.

CONCLUSION

MRI and molecular imaging techniques provide important information about atrophy patterns and pathologic proteins in multiple types of neurodegenerative conditions, including slower-progressing dementias such as typical and atypical AD, FTLD, and DLB and PDD, as well as rapidly progressing dementias such as CJD and other prion protein disorders. Future studies with novel tracers for important pathologic proteins such as TDP-43, α-synuclein, and others will improve differential diagnoses and the understanding of the clinical course of patients with these devastating diseases.

KEY POINTS

• Alzheimer disease (AD) neuroimaging biomarkers become abnormal in a characteristic order where first amyloid deposition is detected on CSF or positron emission tomography (PET), then tau deposition is detected on CSF or PET, followed by changes in atrophy on MRI, and finally cognitive impairment.
• A research framework for diagnosing AD by classifying patients based on their amyloid status (positive versus negative), tau status (positive versus negative), and neurodegeneration (positive versus negative), as well as cognitive status, has been proposed and widely adopted.
• AD exists on a continuum of cognitive impairment, from cognitively normal individuals with AD pathophysiology (ie, preclinical AD), to mild impairment (mild cognitive impairment [MCI]), and ultimately clinical dementia (clinical AD dementia) with pathology defined by the amyloid, tau, neurodegeneration (A/T/N) framework.
• Patients with AD show widespread degeneration on structural MRI both subcortically, including in the hippocampus, amygdala, basal ganglia, and basal forebrain, and cortically, with the greatest changes in the medial and lateral temporal lobes.
• Structural MRI in patients with MCI shows focal atrophy in the medial and lateral temporal lobes, most especially in the entorhinal cortex and hippocampus, which is intermediate between cognitively normal patients and patients with clinical AD dementia, which can predict future progression to dementia.
• Patients with preclinical AD with normal cognition but positive AD biomarkers or at least one apolipoprotein E ε4 allele (APOE ε4) also show subtle changes in MRI measures of brain structure and function.
• Metabolic imaging with fludeoxyglucose (FDG)-PET shows bilateral hypometabolism in patients with clinical AD, as well as intermediate changes in patients with MCI. Patients with preclinical AD may also show altered metabolism, including either increased or decreased metabolism in several brain regions.
• Amyloid and tau PET imaging allow for visualization of AD pathology across clinical stages, with most clinically diagnosed AD dementia cases showing extensive amyloid and tau binding. The majority of patients with MCI show amyloid binding with some tau binding, and patients with preclinical AD show cortical amyloid binding and minimal tau signal.
• One major area of advancement in the field of AD is the development of blood-based tests that detect amyloid and tau in the plasma. These biomarkers provide excellent prediction of clinical status as well as cerebral amyloid and tau deposition, especially with the plasma phosphorylated tau assays.
• Tau deposition in AD typically follows a staging system originally defined in the pathologic literature (ie, Braak staging). The findings to date suggest that tau may spread through connected networks in the brain that can be measured using functional imaging (eg, functional resting-state imaging) or structural diffusion imaging.
• Although most patients with clinical AD present with memory impairment as the primary symptom, heterogeneity of both clinical symptoms and brain atrophy patterns are observed most commonly in patients with early-onset AD (ie, before the age of 65 years).
• Three subtypes of AD include logopenic aphasia, posterior cortical atrophy, and cerebral amyloid angiopathy, which often occur at younger ages and have distinct clinical and neuroimaging signatures on MRI and tau PET but not on amyloid PET (which is broadly positive across all forms).
• Heterogeneity also occurs in late-onset AD, which is linked to different patterns of brain atrophy and FDG hypometabolic patterns. Some of the subtype definitions map to genetic markers (ie, APOE ε4), higher rates of clinical progression, and more severe cognitive impairment.
• Patients with vascular cognitive impairment most commonly show white matter hyperintensities throughout the white matter of the brain, as well as subcortical infarcts, lacunes, prominent perivascular spaces, and cerebral microhemorrhages on MRI. Although these pathologies can be seen in normal aging, the pathology in vascular cognitive impairment or subcortical ischemic vascular dementia is much more severe and widespread.
• FDG-PET imaging has demonstrated that patients with vascular cognitive impairment have multifocal hypometabolism, which often presents in an asymmetric or scattered pattern or both. This hypometabolism can be cortical or subcortical or both and found near arteries or watershed regions of the brain.
• The majority of dementia cases that come to autopsy have more than one pathologic finding, most commonly AD pathology and small vessel disease, especially in older patients. In life, AD often presents as mixed dementia, reflecting the presence of AD pathophysiology and one or more other suspected pathologies.
• Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLB) are diseases along the same continuum with the distinguishing factor being the sequence of onset of motor versus cognitive symptoms.
• Patients with DLB and PDD show widespread cortical atrophy on structural MRI, particularly in the posterior cortical regions and relative sparing of the medial temporal lobe compared with patients with AD.
• MRI in patients with multiple system atrophy shows atrophy of the cerebellum, pons, thalamus, substantia nigra, and the parietal and occipital lobes. One characteristic (but nonspecific) sign of multiple system atrophy can be found using T2-weighted imaging, which shows a cruciform hyperintensity in the pons known as the hot cross buns sign.
• FDG-PET studies in PDD and DLB show hypometabolism in the cortex, including the primary visual cortex, with relative sparing of the hippocampus, most distinctively showing the cingulate island sign, which is a relative preservation of metabolism in the posterior cingulate relative to the surrounding parietal and occipital lobes.
• Unique to DLB and PDD, PET and single-photon emission computed tomography (SPECT) measures of dopaminergic neurotransmission are excellent biomarkers for differential diagnosis, with tracers targeting the dopamine transporter and dopamine receptors (ie, D2 receptors) showing reduced binding in the striatum and cortex.
• Frontotemporal lobar degeneration (FTLD) disorders can be classified into two forms by symptoms: (1) behavioral variant FTLD, in which patients show behavioral disturbances among other symptoms; and (2) primary progressive aphasias, which feature language impairments of multiple types.
• FTLD syndromes can feature extrapyramidal or motor symptoms with the FTLD and parkinsonism spectrum consisting of corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), as well as FTLD with motor neuron disease (or FTLD-amyotrophic lateral sclerosis).
• Patients with behavioral variant FTLD generally show frontal and temporal lobe atrophy, as well as atrophy in the basal ganglia, thalamus, and other deep gray matter structures, but can vary by underlying pathology (ie, tau versus transactive response DNA-binding protein 43 [TDP-43]).
• Patients with semantic dementia show focal MRI atrophy of the anterior and inferior temporal lobe, with an asymmetric (left more than right) pattern in most cases.
• Patients with progressive nonfluent aphasia show asymmetric perisylvian and anterior insular atrophy with the dominant language hemisphere most affected (usually the left hemisphere in right-handed individuals), as well as in the frontal and temporal lobe (eg, Broca area).
• Patients with CBD show asymmetric atrophy of the frontal and parietal lobes without sparing of the primary motor and sensory cortices, as well as the basal ganglia contralateral to the side most affected with rigidity and apraxia.
• Structural MRI studies in patients with PSP show significant midbrain atrophy, particularly in comparison with the neighboring pons, which is more severe than that seen in CBD. This atrophy pattern has been described as the hummingbird sign on sagittal view and the Mickey Mouse sign or morning glory sign on axial view.
• Patients with FTLD-ALS show atrophy in the frontal and temporal lobes, as well as the anterior cingulate, occipital lobe, and precentral gyrus, which is more severe in patients with FTLD-ALS than in patients with ALS and no FTLD symptoms.
• Patients with behavioral variant FTLD show symmetric frontal hypometabolism on FDG-PET, as well as hypometabolism in the anterior cingulate, parietal lobe, and temporal lobe in later stages.
• FDG-PET studies in semantic dementia have identified reduced metabolism in the left anterior temporal lobe but less significant frontal lobe hypometabolism than in other forms of FTLD.
• Patients with progressive nonfluent aphasia show asymmetric (usually left more than right) frontal cortical hypometabolism in the language-dominant hemisphere, including in the Broca area.
• FDG-PET studies in CBD show asymmetric hypometabolism in the posterior frontal lobes, sensorimotor cortex, and subcortical regions.
• FDG-PET studies in PSP show notable hypometabolism of the prefrontal cortex, caudate, pallidum, thalamus, mesencephalon, and subthalamic nucleus.
• Patients with FTLD-ALS show hypometabolism in the frontal lobe, superior temporal lobe, parietal lobe, occipital lobe, and insula, which is more severe in FTLD-ALS than in ALS without FTLD.
• Amyloid PET scans have shown minimal binding in any subtype of FTLD unless comorbid AD pathology exists.
• Tau PET scans have shown less binding in FTLD relative to that seen in AD, potentially because of less sensitivity of the tracers to non-AD tau conformations. However, the tau PET studies generally show higher tau deposition in regions that mirror the location of atrophy across the FTLD spectrum.
• The primary imaging biomarkers for prion disorders are MRI based, the most sensitive type being diffusion-weighted imaging (DWI). All forms of CJD can show restricted diffusion in the basal ganglia, cerebellum, and diffuse regions of the cortex (“ribboning”), most commonly affecting the frontal and parietal lobes.
• Familial prion protein forms, such as Gerstmann-Sträussler-Scheinker disease and familial CJD, show mixed results with structural MRI measures, with some patients showing no atrophy and others with generalized cerebral and cerebellar atrophy. Patients with fatal familial insomnia may show mild cerebral atrophy and often have restricted diffusion in the thalamus.
• FDG-PET studies in all forms of CJD show widespread and often asymmetric hypometabolism in the cortex and cerebellum, with relative sparing of the basal ganglia and thalamus, whereas familial forms of prion protein disease show cerebral, cerebellar, and subcortical hypometabolism.
• Amyloid and tau PET scans generally show minimal binding in prion protein diseases.
• The differential diagnosis of diseases presenting with or without motor symptoms, such as late-onset AD, atypical AD, CJD, and FTLD, can be improved by using structural MRI and PET techniques.
• Patterns of atrophy and hypometabolism often differ between neurodegenerative disorders and can be used to support a clinical diagnosis, whereas amyloid and tau PET, along with dopaminergic PET or SPECT, can provide support for or rule out a probable diagnosis.