Abstract
There is currently a huge variation in clinical practice as to whether patients being assessed for dementia undergo neuroimaging. With an ageing population it is likely that there will be greater pressures on psychogeriatric services, so accurate assessment, diagnosis, and prompt treatment will be required. This chapter will examine the evidence for the use of different neuroimaging techniques in the diagnosis of mild cognitive impairment (MCI) and dementia.
Introduction
There is currently a huge variation in clinical practice as to whether patients being assessed for dementia undergo neuroimaging. With an ageing population it is likely that there will be greater pressures on psychogeriatric services, so accurate assessment, diagnosis, and prompt treatment will be required. This chapter will examine the evidence for the use of different neuroimaging techniques in the diagnosis of mild cognitive impairment (MCI) and dementia.
The UK has an ageing population. In the 25 years to 2016, the number of UK residents aged 65 years and over rose from 9.1 million (15.8% of the population) to 11.8 million (18% of the population). By 2066, there are predicted to be a further 8.6 million UK residents aged 65 years and over.1 The total number of those 65 years and over will then be 20.4 million or 26% of the total population. The fastest increase will be seen in those 85 years and over.1 In mid-2016, there were 1.6 million people aged 85 years and over (2% of the total population); by 2066 there will be 5.1 million people aged 85 years and over (7% of the total UK population). Meanwhile, the population aged 16–64 years is projected to increase by only 5% by 2066.1 Dementia is one of the most common conditions in the elderly and it is estimated that in 2013, approximately 815,000 people were affected in the UK.2 This number is expected to double over the next 30 years, which will increase financial pressures on clinical budgets, so there is a significant emphasis on early assessment, diagnosis, and prompt initiation of treatment.
NICE recommends an initial approach to improving the rate of diagnosis of dementia.3 A significant number (up to 32%) of people living with dementia may not have a formal diagnosis of dementia. It suggests that the diagnosis of dementia should be timely, personalized, and accurate, and that it is vital to rule out reversible causes of cognitive decline, and to distinguish dementia from delirium. Referral to a specialist dementia diagnostic service is then recommended if reversible causes of cognitive decline have been excluded and dementia is still suspected. The role of structural imaging, such as computed tomography (CT) and magnetic resonance imaging (MRI), is to rule out reversible causes of cognitive decline, such as normal pressure hydrocephalus, subdural haemorrhage, and brain tumour; and to assist with subtype diagnosis, unless dementia is well established and the subtype diagnosis is clear.
Further imaging tests are only recommended if those would help to diagnose a dementia subtype and knowing more about the dementia subtype would change management. In the setting of an uncertain diagnosis of Alzheimer’s disease (AD) or frontotemporal dementia (FTD) and high clinical suspicion, positron emission tomography (PET) using the tracer fluorine-18 (F-18) fluorodeoxyglucose (FDG), therefore known as 18F-FDG PET, or perfusion single-photon emission computed tomography (SPECT) are to be considered, along with cerebrospinal fluid (CSF) for tau or amyloid proteins for AD. If dementia with Lewy bodies (DLB) is suspected, but the diagnosis is uncertain,123 I-FP-CIT SPECT scanning is recommended. The full name for the compound is ioflupane (123I)-N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenyl)nortropane. More simply, the scan is known as a DaTSCAN. Table 13.1 outlines the basic details of CT, MRI, SPECT, and PET in terms of indications, benefits, risks, adverse effects, costs, and tolerability in the elderly.
| CT | MRI | SPECT | PET | |
|---|---|---|---|---|
| Scan details | X-rays producing cross-sectional images | Magnetic field alters the axes of spinning protons, which is detected by scanner | Uses a gamma camera to detect gamma-emitting radioisotopes. Can involve a CT scan at same time | Uses a gamma camera to detect a positron-emitting radioisotope. CT scan can be performed during same session |
| Benefits | Quick, painless, quiet, readily available, well-established | Non-invasive, painless, no exposure to ionising radiation, post-scan modification of images |
| Allows assessment of biological activity such as glucose activity. Non-invasive |
| Cost | Least expensive | Slightly more expensive than CT | Relatively inexpensive compared with PET | Most expensive, particularly if CT used in combination |
| Invasiveness | Standard CT non-invasive. Contrast media can cause allergic reactions | Standard MRI non-invasive. Contrast media can cause allergic reactions | Intravenous injection, with rare possibility of allergy | Potential allergies to radioisotopes (these are short-lived isotopes) |
| Risks | Radiation exposure Radiologist experience in interpretation | Contraindicated with some metal implants | Radiation exposure. Allergic reaction to radioisotope | Exposure to ionising radiation – substantial if concomitant CT |
| Tolerability in elderly patients | Generally well tolerated | Can be less well tolerated, as longer to perform, claustrophobic, and noisy | Can be less well tolerated because of the invasiveness and claustrophobia | Generally well tolerated |
There has been a greater clinical emphasis on functional neuroimaging, such as technetium-99m hexamethyl propylene amine oxime (Tc-99m HMPAO) SPECT PET scanning with 18F FDG and DaTSCANs. Single-photon emission CT uses radio-labelled tracers such as Tc-99m HMPAO to measure cerebral perfusion to show areas where blood flow is reduced. This procedure takes about 30 minutes to perform and can help in the differential diagnosis of dementia. DaTSCANs use a tracer that binds to the presynaptic dopamine transporter and is useful in the investigation of DLB and Parkinson’s disease (PD), in which there is decreased uptake in the transporters of the tracer 123I ioflupane.
Alzheimer’s Disease
In the clinical diagnosis of AD, NICE recommends that clinicians use the updated version of the NINCDS–ADRDA diagnostic criteria, sometimes known as the McKhann criteria.4 The McKhann criteria have a sensitivity of 81% (i.e. will correctly detect patients who have AD); however, they only have a specificity of 70%, as patients with other forms of dementia often fulfil the criteria.5 The updated criteria were published in 2011 and are shown in Box 13.1.6 The criteria also cover possible AD dementia and probable or possible AD dementia with evidence of the AD pathophysiological process (these are not shown in Box 13.1).
Core clinical criteria for dementia
Cognitive or behavioural (neuropsychiatric) symptoms that:
1 interfere with the ability to function at work or at usual activities;
2 represent a decline from previous levels of functioning and performing; and
3 are not explained by delirium or major psychiatric disorder.
4 Cognitive impairment is detected and diagnosed through a combination of
(i) history-taking from the patient and a knowledgeable informant, and
(ii) an objective cognitive assessment.
5. The cognitive or behavioural impairment involves a minimum of two of the following domains:
a. Impaired ability to acquire and remember new information
b. Impaired reasoning and handling of complex tasks, poor judgement
c. Impaired visuospatial abilities
d. Impaired language functions (speaking, reading, writing)
e. Changes in personality, behaviour, or comportment
Probable AD dementia
1. Meets core clinical criteria for dementia and has the following characteristics:
A. Insidious onset
B. Clear-cut history of worsening of cognition by report or observation
C. The initial and most prominent cognitive deficits are evident on history and examination in one of the following categories:
a. Amnestic presentation
b. Non-amnestic presentations
D. The diagnosis of probable AD dementia should not be applied when there is evidence of
(a) substantial concomitant cerebrovascular disease;
(b) core features of dementia with Lewy bodies other than dementia itself;
(c) prominent features of behavioural variant FTD;
(d) prominent features of semantic variant primary progressive aphasia or nonfluent/agrammatic variant primary progressive aphasia; or
(e) evidence for another concurrent, active neurological disease, or a non-neurological medical comorbidity, or use of medication that could have a substantial effect on cognition.
Computed Tomography
CT is a well-established, widely available, quick, and relatively inexpensive tool. However, it is associated with radiation exposure, which can limit the use of serial scanning. It is most commonly used to exclude potentially reversible causes of cognitive impairment, but it can have some diagnostic value in AD. Normal ageing (without cognitive impairment) is associated with general brain atrophy. Therefore, neuroimaging studies of brain volume show very little discrimination between normal ageing, cognitive impairment, and dementia.7 However, there are several studies that show atrophy of specific brain regions on CT and MRI: notably, the hippocampus and entorhinal cortices in the medial temporal lobes are associated with cognitive impairment in AD.8 The sensitivity and specificity of using CT alone in detecting medial temporal lobe atrophy are 94% and 93%, respectively.9
Magnetic Resonance Imaging
MRI is becoming more widely used as a diagnostic tool in the investigation of dementia. Studies have shown that patients with AD have a greater reduction in the volume of entorhinal cortices (37%) and hippocampus (27%) compared with normal elderly adults and patients with MCI (combined data: entorhinal cortices 11%, hippocampus 13%), and that these findings correlate well with neuropsychological testing.10 Although these changes are seen in up to two-thirds of cases of AD, they are often absent on CT scans of patients with clinical diagnoses of the disease and are seen in about 5–10% of normal elderly individuals.9 In patients over 80 years old, these changes are much less specific, and it may be more difficult to differentiate between normal ageing and AD.9
Serial MRI has been used to assess the progression of changes in MRI findings; however, this has tended to be in clinical trial settings, with very little diagnostic applicability. In AD, brain atrophy progresses at a rate of about 2% per year, in contrast to 0.1–0.5% per year in controls who are cognitively intact,9 but it remains to be seen whether this could be used diagnostically. Some studies suggest that serial MRI, in combination with other markers such as CSF biomarkers and pattern classification, may be useful in differentiating patients with MCI from patients with AD by assessing the rate of neurodegeneration.10
Functional Neuroimaging
Functional neuroimaging – SPECT, PET, proton or 1hydrogen magnetic resonance spectroscopy (1H-MRS), and magnetic resonance volumetry (MRV) – can be as effective as post-mortem pathological examination in differentiating elderly patients with normal cognition from patients with AD .11
Single-Photon Emission Computed Tomography
SPECT findings in AD centre on the detection of hypoperfusion of the temporal and parietal brain regions (Figure 13.1).11
A comparison of clinical diagnosis, SPECT findings, and post-mortem examination showed that SPECT increased the diagnostic certainty in patients who were clinically diagnosed with AD from 84% to 92%.12 This study found that a negative SPECT in these patients reduced the diagnostic certainty to 70%.
Positron Emission Tomography
PET imaging uses PiB to detect amyloid deposition in AD, which can be seen early in the disease process. As the disease progresses, amyloid deposits are less of a burden than neurodegeneration,13 so PET imaging may be more useful in detecting cases of AD in the early stages. Pittsburgh Compound-B PET imaging is sensitive in detecting deposition of amyloid in AD, but it is less specific, as 10–30% of cognitively intact elderly people have PiB-PET-detected amyloid deposition.13
The evidence has gradually built that (18)F-FDG PET is significantly superior to perfusion (HMPAO) SPECT in the differential diagnosis of degenerative dementia.14 Moreover, patients seemed no more stressed by the process of undergoing PET or SPECT than they did by a home visit from a researcher and they showed no preference for one type of scan over the other, although carers seemed slightly to prefer SPECT, presumably because they were able to remain with the patient through the procedure.15 (18)F-fluorodeoxyglucose ((18)FDG) PET detects glucose metabolism, and studies suggest that bilateral hypometabolism of the corpus callosum, temporoparietal, and frontal association areas may be associated with AD.16 Investigations using FDG PET can detect hypometabolism up to 1 year before subjective complaints of memory impairment in patients who later develop AD.16
Future Imaging Techniques
Future imaging techniques may centre on the use of more detailed MRI such as functional MRI (fMRI), spin-labelled MRI, magnetic resonance microscopy, and magnetization transfer MRI. fMRI measures cerebral blood flow in relation to functional activity in the brain and early studies show that inferior prefrontal and left temporal activation is associated with better scoring on cognitive testing.9 However, fMRI is still in the early stages of trial for this use and is not a routine investigation. Advances in radioligands and tracers used in SPECT and PET scanning, such as monoclonal antibodies to β-amyloid and flumazenil, are likely to allow for further development in diagnostic validity. The development of new biomarkers increases the possibility of greater understanding of pathophysiological changes. In recent years this has included, for instance, the development of ligands that allow tau deposition to be visualized in the brain using PET scanning.17
The complicating factor is that amyloid is found in the brains of normal older people. None the less, amyloid-PET scans are already proving useful. In one study, the progression from amnestic mild cognitive impairment (aMCI) to probable AD was 2.5 times more likely within three years if the person’s PET scan was β-amyloid-positive in comparison with those whose scans were negative.18 When additional biomarkers (see Chapter 12), namely hippocampal volume loss and cognitive status, were added to the result of the amyloid-PET scan, the risk of progression increased to 8.5 times the risk in amyloid-negative participants. Meanwhile, there is evidence emerging that amyloid-positivity on a PET scan is helpful in changing the management of patients where the diagnosis is challenging. 19
Vascular Dementia
To some extent vascular dementia (VaD) may be preventable, as early detection of potentially modifiable vascular risk factors can allow for intervention to minimize subsequent cardiac and cerebrovascular disease (for further discussion of VaD, see also Chapter 2). For the clinical diagnosis of VaD, NICE recommends the National Institute of Neurological Disorders and Stroke and Association Internationale pour le Recherche et l’Enseignement en Neurosciences (NINDS–AIREN) criteria (Box 13.2),3 which are widely used across the globe.20 However, although the criteria have a high specificity at 0.80, they have a relatively low sensitivity at 0.58 in diagnosing VaD.21
Dementia:
Memory impairment
Deficits in two other cognitive domains
Neurological signs of cerebrovascular diseasea on neuroimaging:
Multiple large vessel infarcts/single strategically placed infarct
Multiple basal ganglia and white matter lacunes
Bilateral thalamic lesions or extensive periventricular white matter lesions
A relationship between the first two disorders: onset of dementia within 3 months of a stroke or stepwise deterioration of cognitive deficits
Clinical features consistent with VaD:
Early gait disturbance
Frequent and unprovoked falls
Urinary symptoms not explained by urological disease
Pseudobulbar palsy
Personality change, apathy, and abulia
Importantly, O’Brien demonstrated that it was not possible to differentiate those with and without dementia using the diagnostic criteria and imaging results alone in older patients who had had a stroke.9 Therefore, structural neuroimaging can only be used to support a clinical diagnosis.
Periventricular White Matter Lesions
Periventricular white matter lesions are an important component of the diagnostic criteria for VaD (Box 13.2). However, these lesions are present in other forms of dementia, depression, and even in normal ageing. It is felt that bilateral or left-sided white matter lesions may be important predictors of dementia and cognitive impairment.8 Structural neuroimaging (CT/MRI) provides information about the volume, location, and severity of vascular lesions and is an important tool for excluding other causes of cognitive impairment. MRI is more sensitive than CT in detecting ischaemic lesions.9 It has been suggested that the presence of periventricular white matter changes can help differentiate VaD from AD, as both conditions are associated with cortical atrophy and ventricular enlargement on imaging.8
Functional Neuroimaging
Technetium-99m HMPAO SPECT findings in VaD reveal considerably reduced cerebral blood flow to certain brain areas compared with Alzheimer’s dementia; a typical SPECT scan is shown in Figure 13.2. These brain regions include frontal lobes and the basal ganglia. Other studies have demonstrated reduced cerebral blood flow in bilateral thalami, anterior cingulate gyri, superior temporal gyri, caudate, and the left parahippocampal gyrus in patients with VaD compared with controls.22 However, SPECT is not routinely recommended in the investigation of dementia owing to a lower diagnostic accuracy than that of clinical guidelines; sensitivity is reported to be as low as 43%.22
Figure 13.2 Tc-99m HMPAO single-photon emission computed tomography findings in a patient with cognitive impairment. The scan shows patchy perfusion defects in temporal and parietal lobes bilaterally, with reduction in perfusion to the occipital lobes (right > left). These findings are in keeping with vascular dementia
PET imaging in VaD shows hypometabolism of cortical and subcortical brain areas. One PET study of patients with AD and VaD found deficits in metabolism in thalamus, caudate, and frontal lobe which were strongly associated with VaD.23
Dementia with Lewy Bodies
DLB shares clinical symptoms with AD and PD (Box 13.3).
Mrs Y, aged 78, was referred to a memory clinic with a 7-month history of deteriorating memory. She lived alone and her family had become concerned as she appeared less able to care for herself. She was more forgetful: misplacing things, forgetting appointments and meals. She had started to leave sweets around the house, and when asked about this she said that children often visited her during the day. She also spoke about seeing children playing in her garden. On further questioning, it emerged that Mrs Y had no grandchildren and her family thought it unlikely that any children visited her. Her confusion appeared to fluctuate, and some days it was better than others. Her sleep pattern had become quite disturbed and she frequently complained of nightmares. The family were concerned that she was having falls and appeared to be slow in her movements, having been a very sprightly woman before. There was no family history of dementia and no medical history.
Physical examination revealed bilateral cogwheel rigidity and bradykinesia. Her gait was unsteady. MMSE was 21/30 (losing 6 points on orientation and 3 points on recall). Addenbrooke’s Cognitive Examination score was 69/100 (she lost 6 points on orientation and concentration, 15 points on memory, 5 points on language, and 5 points on visuospatial skills). She was referred for a DaTSCAN, which revealed low dopamine transporter uptake in the brain’s basal ganglia.
Related posts:
Chapter 3 – Young-Onset Dementias
Chapter 7 – Drug Misuse in Older People
Chapter 12 – Biomarkers and the Diagnosis of Preclinical Alzheimer’s Disease
Chapter 15 – What Can Person-Centred Care in Dementia Learn from the Recovery Movement?
Chapter 22 – Deprivation of Liberty
Chapter 19 – Reducing the Healthcare Burden of Delirium
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