Senan Nagaratnam
Historical Perspective
In 1895 the German physicist Wilhelm Conrad Röntgen acci- dently noticed a glow on a nearby fluorescent screen when test- ing whether cathode rays could pass through glass. He called this glow X-rays, because of their unknown nature [1, 2].
Weeks later he took an image of his wife’s hand. Röntgen was awarded the Nobel Prize in Physics in 1901. Today X-ray tech- nology is widely used. After a lull, a new wave of advanced technology began with the advent of the CT scanner. In 1972 the British engineer Godfrey Hounsfield and South African- born physicist Allan Cormack invented computed tomography (CT) imaging, also known as computed axial tomography (CAT) scanning [3]. Over the next quarter of a century, CT advanced in terms of speed, patient comfort and resolution [3].
In the mid-1980s, the power slip ring was developed which has brought about a new dawn in CT spiral or helical scanning [4].
In 1882, Nikola Tesla in Budapest discovered the rotating magnetic field, a fundamental discovery in physics, and the strength of a magnetic field is now measured in Tesla or Gauss units [5]. In 1937, Isidor I. Rabi observed the quantum phenomenon dubbed nuclear magnetic resonance and received the Nobel Prize [5]. Today imaging has contributed in a number of ways in the study involving all fields of medi- cine, and currently there are an array of imaging modalities that are available for research and clinical use.
Ageing and Age-Related Changes
Current demographic data predicts an increase in the elderly population worldwide. Life expectancy has increased dra- matically, and the 90 years and older age group represent the fastest-growing segment of the population growing at a faster rate than the 85–89-year-olds [6]. In the United States, it contributes to 2% of the US population [7].
Numerous structural and physiological changes occur with ageing [8]. The kidney decreases in size primarily due to loss of cortical mass [9] which is due to glomerular scle- rosis [10]. With ageing there is reduction of renal blood flow, impaired autoregulation and reduction in glomerular filtra- tion rate (GFR) [11, 12]. Renal function declines with age, but the independent effects of age, sex and race have not been studied [13], and the decline has been variously attrib- uted to the effects of hypertension, atherosclerosis or other co-morbidities such as cardiovascular disease [14, 15]. The glomerular filtration rate progressively declines at an aver- age rate of 8 ml/min/1.73m2 per decade [16]. One third of the people over the age of 65 years have an estimated glomerular filtration rate (eGFR) below 60 ml/min/1.73m2 [17, 18].
With ageing a wide variety of changes occur in structure and function of the brain [19]. The brain shrinks in size with age, and the shrinkage is selective [20]. The frontal, prefron- tal, basal ganglia, cerebellum, corpus callosum and the ven- tricles are the areas most susceptible to changes. MRI has revealed changes in the volume of the amygdala hippocam- pus and temporal horns of healthy individuals which remains relatively stable till the age of 60 years and thereafter under- goes atrophy with age [21]. In a study of the oldest old age- ing without dementia characterised by imaging, the investigators found the brains to be smaller and with cerebro- vascular lesions as the individuals aged [22]. Brain loss occurred in the hippocampus and its surrounding structures and the other areas involved were the primary sensory cortex and posterior regions [22].
Neuroimaging in the Elderly
Disability increases rapidly with age and in the oldest old [23] with the highest rates of dementia [24]. About half of the oldest old will have dementia [25]. Sarcopenia, lung function, sedentary life style and chronic degenerative conditions such as arthritis and arteriosclerosis contribute to disability in the oldest old [26].
S. Nagaratnam
Alfred Medical Imaging, Sydney, NSW, Australia
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On the other hand, there is a population of very elderly who are living independently in the community who have scored well on scales that measure well-being and quality of life (QoL) [27]. The clinician is often in doubt as to what to do in terms of whether, in this group of patients, additional diagnostic procedures are helpful [28]. This patient population is less prone to the long-term effects of radiation burden or contrast-induced nephropathy [29], and the use of advanced imaging techniques is justifiable.
Age alone should not be a determining factor of whether or not to provide procedures to the elderly for diagnostic pur- poses [30].
Currently, screening for diagnosis and monitoring of dis- ease are largely possible due to the availability of modalities such as CT, MRI, positron emission tomography (PET), combined PET-CT and ultrasound, but they come with a risk [31]. In older patients with obstructive coronary artery dis- ease, the use of dipyridamole-thallium imaging has been shown to be a safe non-invasive procedure and similar to that seen in younger patients [32]. Apart from potential risk of cancer following exposure of patients to ionising radia- tion, hypersensitivity reactions, risks related to use of IV contrast agents [31] and thyrotoxicosis [33] are other adverse effects. The risk of developing cancer to ionising radiation in the oldest old is insignificant for it takes several years for cancer to occur after radiation exposure. Asthma increases the risk of bronchospasm, and beta-blockers may worsen bronchospasm and have been associated with hyper- sensitivity [33].
Contrast-induced nephropathy (CIN) is commonly defined as acute renal failure occurring within 48 h of exposure to IV contrast but not to any other causes [34].
There are many risk factors, such as nephrotoxic drugs, advancing age and route of administration, among others, which may contribute to CIN, but the only two confirmed independent risk factors are pre-existing impairment of renal function and renal impairment associated with diabe- tes mellitus [35]. Patient-dependent risk factors for devel- opment of CIN are congestive heart failure, age over 70 years, elevated creatinine levels and nephrotoxic drugs [36]. However a more comprehensive pre-procedural assessment may be justifiable, especially in a high-risk hospital population undergoing interventional radiology procedures [35].
Prevention of CIN
Hydration and avoidance of nephrotoxic drugs are used to decrease the incidence of CIN [35]. Some of the strategies used are shown in Box 10.1.
Radiographic contrast agents have been classified as iodin- ated contrast media and non-iodinated contrast media, and the former is further classified as non-ionic and ionic [33]. The non-ionic agents are selectively used where osmolality may affect the examination quality as in cardiac CT coronary angi- ography and lower-limb angiography [33]. The non-iodinated contrast agents are generally used in ultrasound and MRI [33].
Nearly 4% of diabetic patients with normal renal function may develop CIN with non-ionic contrast material [37].
Intravenous administration of iodinated contrast media to patients on metformin can result in lactic acidosis [38, 39].
Patients on metformin with an eGFR of less than 60 ml/min should stop taking the metformin at the time of contrast administration [40]. The European Society of Urogenital Radiology recommends that in patients with eGFR less than 45 ml/min, metformin should be stopped 48 h before CT [41]. It has been reported that 8% of the patients with diabe- tes on metformin and baseline serum creatinine levels
<1.5 mg/dl acquire a risk of lactic acidosis with non-ionic contrast [37]. Others have recommended that there is no jus- tification to withhold the metformin before the procedure but to withhold it after the administration of the contrast material for 48 h and if the renal function is normal to restart the met- formin [38]. The Royal College of Radiologists advice is that metformin should not be used in the 48 h before and after intravenous contrast medium [39]. According to McCartney et al. [39], it is safe to give IV contrast medium to patients on metformin with normal renal function.
Geriatric Imaging in Clinical Practice and Research
Geriatric chest imaging With ageing changes occur in both the chest wall and lungs with multiple changes in structure and function [42] giving rise to changes in pulmonary mechanics, respiratory muscle strength [43] and ventilation control. It is important to have a clear understanding of the changes in respiratory structure and function associated with ageing as these changes may affect, for instance, in the interpretation of
Box 10.1 Strategies Used to Prevent CIN Hydrate the patient
Avoid contrast in high risk patents Cease nephrotoxins early
Look for imaging alternatives Use the lowest dose
Avoid repetitive dosing within one study Information sources: [35, 37]
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imaging findings. Table 10.1 shows the changes with ageing and age-related imaging changes in relation to the chest. It may be difficult to differentiate normal, age- related X-ray findings and that due to disease and often impossible to distin- guish between them on imaging tests alone [44].
Geriatric brain imaging Over one half of the oldest old will have dementia [52, 53], and this group has the highest rate of dementia in the population [23]. The diagnosis of dementia is a clinical one. The diagnosis of dementia in the
oldest old can be challenging especially in the early stages of the disease [54]. The main subtypes of dementia include Alzheimer’s disease (AD), frontotemporal dementia (FTD), diffuse Lewy body dementia (DLBD) and vascular dementia (VD). AD is the most common neurodegenerative disease characterised by progressive loss of memory and other cog- nitive functions, by inability to perform basal activities of daily living and in the later stages by behavioural and psychi- atric symptoms. The hallmarks of AD are the extracellular accumulation of amyloid beta (Abeta) peptides forming the core of the senile plaques and intracellular neurofibrillary tangles [55] which spreads in stages from the entorhinal cor- tex to the neocortex [56]. The Abeta deposits involve the neocortex, while the intracellular accumulation mainly affects the hippocampus [57]. Figure 10.1 shows atrophy of the hippocampi and medial temporal lobes. The earliest sites involved affected by atrophy are the medial temporal lobes (Fig. 10.2) [58], followed by atrophy in the medial parietal regions, posterior cingulate and precuneus (Fig. 10.3) and, in the later stages of the disease, the association areas of the frontal and lateral temporal lobes [59] (Fig. 10.4).
Prominent involvement of the frontal and temporal lobes give rise to frontotemporal dementia (FTD). Frontotemporal lobar degeneration is a syndrome that embraces various pathologi- cal substrates including Pick’s disease, corticobasal degener- ation, FTLD with microtubule-associated protein tau gene mutation and FTLD-U with progranulin gene mutation among others [60]. It has three patterns of presentation, fron- tal variant with gradual change in behaviour and the temporal
Table 10.1 Aging-related chest imaging findings and likely misinter- pretation as age-related diseases
Anatomical structure Imaging findings I. Thoracic cage
Intervertebral cartilages, costo-vertebral joints
Calcification Solitary pulmonary nodules Parietal muscles Loss of muscle
mass (atrophy)
Increase in pulmonary transparency on X-ray
Intercostal muscles Spine-kyphosis,
degenerative changes
‘barrel-shaped chest’
COPD II. Diaphragm
Loss of muscle mass dyskinesis
‘hump’ (bulging) Hemi- diaphragm III. Lung parenchyma
Enlargement of distal air-spaces,
Hyperinflation on X’ray
Emphysema Interstitial changes. Sub-pleural
reticular pattern
Interstitial lung disease Thickening of interloper
septa,
Moderate basal fibrosis
Laminar atelectasis Bronchial thickening and
dilatation
Parenchymal changes
Sub-pleural thickening Reduction in calibre and
number of the vessels Cardiovascular I. Cardiac
Loss of myocytes and increase in remaining, left ventricular wall thickens,left atrium hypertrophies
Cardiac enlargement
Left ventricular size of dysfunction
Fibrous tissue of skeleton- sclerotic and calcify
Mitral annular and aortic valve calcify
Valve insufficiency II. Vascular
Reduction of elastic connective tissue
Enlargement and tortuosity of aorta
widened mediatinum Information sources: Mereu et al. [45]; Grossman and Nau [46]; Sharma and Goodwin [47]; Hochhegger et al. [44]; Copley [48]; Caskey [49];
Carmeli et al. [50]; Booth et al. [51]
Fig. 10.1 Alzheimer’s disease. Coronal T2: Atrophy of the hippo- campi and medial temporal lobes. (Reproduced with kind permission from Dr. Lisa Tarlinton and courtesy of Nepean Hospital)
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variant with gradual progressive language dysfunction (semantic dementia and progressive non-fluent aphasia) [59].
Dementia with Lewy bodies also known as cortical Lewy body dementia or diffuse Lewy body dementia is a neurode- generative disorder associated with abnormal structures (Lewy bodies) which are formed by aggregates of insoluble a-synuclein [59]. It is the second most common form of
degenerative dementia [61]. It is characterised by fluctuating cognitive impairment, parkinsonism and recurrent visual hallucinations [61]. It could present like Alzheimer’s disease or Parkinson’s disease or a combination of the two [62].
There are three phases of dementia in Parkinson’s disease, namely, that of Alzheimer’s disease, that of cortical Lewy bodies and cell loss in the nucleus basalis and remaining cells showing tangles [62].
Vascular dementia (VaD) now termed vascular cognitive impairment includes a wide spectrum of cognitive decline ranging from mild deficits in one or more cognitive domains referred to as vascular mild cognitive impairment (vaMCI) to a broad dementia-like syndrome [63]. It includes vascular cognitive impairment with no dementia and mixed Alzheimer’s disease and cerebrovascular disease [64].
The detection of pre-dementia Alzheimer’s disease (AD) is crucial, to begin early and improved management [65] for symptoms which appear long after the onset of degeneration.
About half of the demented oldest old do not appear to have significant pathology to account for their cognitive loss, while a similar proportion of non-demented oldest old have high degree of AD and other pathologies while preserving their cognition [66]. Kawas and Corrado [66] hypothesised that AD, vascular and other pathologies represent preclinical disease in non-demented oldest old (i.e. significant pathol- ogy but without actual dementia). Thus there seem to be notable differences in this group, and better appreciation of the pathology is crucial. Although clinical-based testing is helpful, rarely does it allow the clinician to make a firm diag- nosis [65] and in distinguishing between the subtypes.
Fig. 10.2 Alzheimer’s disease. Sagittal MRI. Atrophy of the medial temporal lobe. (Reproduced with kind permission from Dr. Lisa Tarlinton and courtesy of Nepean Hospital)
Fig. 10.3 Alzheimer’s disease. MRI T1 Sagittal. Showing atrophy of precuneus (and posterior cingulate to a less degree). (Reproduced with kind permission from Dr. Lisa Tarlinton and courtesy of Nepean Hospital)
Fig. 10.4 Alzheimer’s disease. Sagittal MRI T1. Lateral parietal lobe and posterior temporal lobe (lateral parieto-temporal association cor- tex) atrophy. (Reproduced, with kind permission, from Dr. Lisa Tarlinton and courtesy of Nepean Hospital)
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Therapeutic regimens vary depending on the type of demen- tia, and hence accurate diagnosis is vital [54].
Imaging biomarkers are emerging as valuable tools [54]
for clinical and preclinical studies, to interpret their patho- physiology [65] and their usefulness in subtype management [67]. The brains of the very elderly usually have mixed pathologies associated with dementia, the commonest being Alzheimer’s disease, and other pathologies include Lewy bodies, hippocampal sclerosis, white matter disease and infarction [68]. Neuroimaging techniques are increasingly used as additional markers to detect AD onset and predict conversion of mild cognitive impairment (MCI) to AD [69, 70], and a variety of neuroimaging biomarkers have been put forward to identify the patterns of the pathology in AD and MCI [69]. Magnetic resonance imaging and positron emission tomography (Figs. 10.5, 10.6, 10.7, 10.8 and 10.9) play an important role in the diagnosis of primary neurode- generative disorders [71] and have been used to demonstrate structural, functional and metabolic changes and have been shown to provide useful disease markers [70]. Basically structural and molecular imaging in patients with dementia have a supportive role rather than diagnostic [72]. Functional connectivity MRI, diffusion tensor imaging and magnetic resonance spectroscopy and molecular imaging techniques such as 18F-fluoro-deoxy-glucose positron emission tomog- raphy (PET), amyloid PET and tau PET are now available for clinical use [72]. Measurement of the regional cerebral glucose metabolism (rCMR glc) using PE7 and 18F-fluoro- deoxy- glucose (FDG) has become the accepted technique for dementia research [73]. FDG-PET provides diagnostic specificity [74] and has been used to categorise the dementia subtypes such as Alzheimer’s diseases; frontotemporal, dif-
fuse Lewy body, vascular dementias [75]; and posterior cor- tical atrophy [76].
The pathological hallmark of AD is amyloid beta pep- tide 42 (Aβ42) [70], and amyloid load may identify increased risk of developing AD [77]. Amyloid load deter- mined by florbetapir F18 positron emission tomography in non-demented old correlated with poorer cognition and faster cognitive decline in this group [77], and high amy- loid on florbetapir PET can identify oldest old individuals
Fig. 10.5 Alzheimer’s disease. Coronal PET: Hypometabolism in the hippocampi and medial temporal lobes. (Reproduced with kind permis- sion from Dr. Lisa Tarlinton and courtesy of Nepean Hospital)
Fig. 10.6 Alzheimer’s disease. Sagittal PET. Hypometabolism in medial temporal lobe. (Reproduced with kind permission from Dr. Lisa Tarlinton and courtesy of Nepean Hospital)
Fig. 10.7 Alzheimer’s disease. Sagittal PET. Hypometabolism in lat- eral parietal lobe and posterior temporal lobe (lateral parieto-temporal association cortex). (Reproduced with kind permission from Dr. Lisa Tarlinton and courtesy of Nepean Hospital)
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at high risk of cognitive decline [78]. MR imaging-derived hippocampal atrophy and white matter hyperintensities are regarded as biomarkers in AD and cerebrovascular disease [79]. Cortical thickness can be quantified allowing
early diagnosis and rate of progression from mild cogni- tive impairment to dementia [80]. Individuals with Lewy body dementia show as array of impaired indicators of dopaminergic function which helps to distinguish them from healthy elderly and those with Alzheimer’s disease [81]. Abnormal FP-CIT SPECT [79] and dopamine trans- porter imaging with iodine-123-b-carbo-methoxy- 3-b-(4- iodophenyl tropane) fluoropropyl SPECT support the diagnosis of dementia with Lewy bodies in clinical prac- tice [72]. In healthy individuals, the i-123 ioflupane images show comma-shaped structure bilaterally in the region of the corpus striatum [82] (Fig. 10.10). In Parkinson’s disease the usual pattern is the unilateral dis- appearance of the ‘comma’ beginning with the tail [82].
Majority of the patients with DLB show a similar pattern, but the change is often symmetrical [82]. Perfusion SPECT [67, 79] and molecular imaging with FDG-PET showing defects in the frontal and/or anterior temporal atrophy are characteristic of frontotemporal dementias (Fig. 10.10). The diffusion tensor magnetic resonance imaging categorises the microstructural soundness of the white matter [83] and could be used to detect white matter changes and is a useful tool to detect early MCI/
Alzheimer’s disease [84–86].
Procedure Utilisation in the Oldest Old
In a study of utilisation patterns, the oldest old consumed 3.9% of the studies carried out in nuclear medicine although they comprised 1.3% of the state population [87].
The average number of procedures per person during the year was 1.56 in the oldest old compared to 1.57 in younger persons [87]. In a study of oldest old seen in a radiology department over a period of 7 years, the overall activity had increased by 22% over that period, and the activity in the 90 years old age group had increased by 51% with 12.3% more CT in this age group [88]. Digital X-ray fluo- roscopy, ultrasound and MRI have made considerable advancement in their ability to image the chest and abdo- men. Some of the imaging procedures, such as magnetic resonance imaging, require patient cooperation and toler- ance [30]. The oldest old are associated with decreased physical activity and a higher number of chronic diseases such as osteoarthritis, osteoporosis and cardiovascular dis- eases, including hypertension and stroke [89], and physi- cians will hesitate to use MRI in the elderly because of the discomfort it may cause [30]. In a study of feasibility and discomfort of MRI procedures in subjects >90 years, Wollman et al. [30] reported that very long sessions of MRI are attainable even in the oldest old and are not asso- ciated with any serious discomfort. The key points are summarised in Box 10.2.
Fig. 10.8 Frontotemporal dementia-sagittal PET. Subtle but definite reduced metabolism in the frontal and anterior temporal lobes 1 year before the MRI show changes. (Reproduced with kind permission from Dr. Lisa Tarlinton and courtesy of Nepean Hospital)
Fig. 10.9 Frontotemporal dementia. Axial PET. Shows subtle but defi- nite reduced metabolism in the frontal and temporal lobes. Changes are more prominent in the left than in the right. The changes of FTD in both PET and MRI are often asymmetrical. (Reproduced with kind permis- sion from Dr. Lisa Tarlinton and courtesy of Nepean Hospital)
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