Alzheimer's disease (AD) is the most common cause of dementia and its prevalence is expected to increase in the coming years. Therefore, accurate diagnosis is crucial for patients. The emerging imaging techniques have provided important information for the clinical practice and management of the disease. Computed tomography, magnetic resonance imaging, positron emission tomography, single-photon emission computed tomography and in vivo amyloid imaging are currently available for clinical use.
Keywords: Alzheimer disease, amyloid, imaging technics
| Aetiology and Epidemiology|| |
Alzheimer disease (AD) was first described in 1907 by Alois Alzheimer. From its original status as a rare disease, AD has become one of the most common diseases in the aging population, ranking as the fourth most common cause of death. AD is a progressive neurodegenerative disorder characterised by the gradual onset of dementia. The pathologic hallmarks of the disease are amyloid-β (Aβ) plaques, neurofibrillary tangles (NFTs) and reactive.
| Epidemiological Risk Factors|| |
Epidemiological risk factors have been identified, including:
- Old age
- Family history of dementia
- Female gender
- Apo-lipoprotein E ε4 allele carrier status
- Mutations of amyloid precursor protein
- Down's syndrome
- Socio-economic factors such as:
- Fewer years of formal education
- Lower income
- Lower occupational status
- Smaller social network/family support.
| Anatomy|| |
Traditionally, AD has been clinically characterised predominantly by memory deficits, at least in initial stages. It has become increasingly evident that in addition to the typical presentation, a number of atypical clinical patterns exist, which are nonetheless pathologically AD.
Typical Alzheimer disease
The typical patient with AD will present with:
- Antegrade episodic memory deficits. Over time (often years), the disease progresses, with eventual involvement of attentional and executive processes, semantic memory, praxis, and visuoperceptual abilities. Neuropsychiatric symptoms are also common and eventually affect almost all patients. These include apathy, depression, anxiety, aggression/agitation, and psychosis (delusions and hallucinations).
Atypical Alzheimer disease
These entities are characterised by slowly progressive focal cortical atrophy, with symptoms and signs matched to the affected area. Examples include:
- Posterior cortical atrophy
- A frontal variant of AD
- A minority of cases with predominant semantic dementia.
| Radiological Features|| |
Although computed tomography (CT) can demonstrate the characteristic patterns of cortical atrophy, magnetic resonance imaging (MRI) is more sensitive to these changes and better able to exclude other causes of dementia (e.g. multi-infarct dementia) and as such is the favoured modality [Figure 1].
|Figure 1: Non-contrast axial and coronal computed tomography of the brain revealed marked volume loss is seen involving both hippocampi and parahippocampal gyri, especially anteriorly, with relative sparing of the rest of the temporal lobe|
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Structural magnetic resonance imaging
Progressive cerebral atrophy is a characteristic feature of neurodegeneration that can be visualised in life with MRI [best with T1-weighted volumetric sequences; [Figure 2]. The major contributors to atrophy are thought to be dendritic and neuronal losses. Studies of regional (e.g., hippocampal) MRI volumes have shown these are closely related to neuronal counts at autopsy.
|Figure 2: Coronal non-contrast T1 and T2 reveal that the sulci and ventricles are mildly more prominent than expected. The mesiotemporal structures, including the temporal horns of the lateral ventricles, are slightly more prominent, with bilateral hippocampi reduced volume|
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Other structures within the limbic lobe such as the posterior cingulate are also affected early on. These losses then spread to involve the temporal neocortex and then all neocortical association areas usually in a symmetrical fashion. This sequence of progression of atrophy on MRI most closely fits histopathological studies that have derived stages for the spread of NFTs.
Limitations of structural magnetic resonance imaging in Alzheimer disease
Structural MRI lacks molecular specificity. It cannot directly detect the histopathological hallmarks of AD (amyloid plaques or NFTs) and as such it is downstream from the molecular pathology. Cerebral atrophy is a nonspecific result of neuronal damage and whereas certain patterns of loss are characteristic of different diseases, they are not entirely specific. Atrophy patterns overlap with other diseases and unusual forms of AD have atypical patterns of atrophy too.
Functional magnetic resonance imaging
Functional MRI (fMRI) is being increasingly used to probe the functional integrity of brain networks supporting memory and other cognitive domains in aging and early AD. fMRI is a non-invasive imaging technique which provides an indirect measure of neuronal activity, inferred from measuring changes in blood oxygen level-dependent MR signal which is considered to reflect the integrated synaptic activity of neurons via MRI signal changes because of changes in blood flow, blood volume, and the blood oxyhaemoglobin/deoxyhaemoglobin ratio [Figure 3].
|Figure 3: Increased functional magnetic resonance imaging activity in neocortical (a) and medial temporal (b) brain areas during processing of repeated face-name stimuli in patients with Alzheimer's disease (in red) relative to healthy older control subjects (in yellow). a: Crosshair is located in the right (R) prefrontal cortex, MNI coordinate: 40, 8, 50; b: Crosshair is located in the left (L) anterior hippocampus, MNI coordinate: -24, -4, -28|
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Limitations of functional magnetic resonance imaging in Alzheimer's disease
There are multiple challenges in performing longitudinal fMRI studies in patients with neurodegenerative dementias. It is likely that fMRI will remain quite problematic in examining patients with more severe cognitive impairment, as these techniques are very sensitive to head motion. If the patients are not able to adequately perform the cognitive task, one of the major advantages of task fMRI activation studies is lost. Resting state fMRI may be more feasible in more severely impaired patients.
Fluorodeoxyglucose positron emission tomography in Alzheimer's disease
Brain fluorodeoxyglucose (FDG) PET primarily indicates synaptic activity. Because the brain relies almost exclusively on glucose as its source of energy, the glucose analogue FDG is a suitable indicator of brain metabolism and when labelled with Fluorine-18 (half-life 110 min) is conveniently detected with PET. The brain's energy budget is overwhelmingly devoted to the maintenance of intrinsic, resting (task-independent) activity, which in cortex is largely maintained by glutamaturgic synaptic signalling. FDG uptake strongly correlates at autopsy with levels of the synaptic vesicle protein synaptophysin.
18F-FDG PET typically shows bilateral temporoparietal, precuneus and posterior cingulate hypometabolism which is usually symmetric. Uptake may be asymmetric in the early stages. The anterior cingulate, visual cortex (eyes should be kept open while scanning to avoid the pitfall of hypometabolism in the visual cortex), basal ganglia, thalami, occipital lobes and cerebellum are usually spared. Frontal lobes may be involved in late stage [Figure 4].
|Figure 4: Transaxial fused F-18 fluorodeoxyglucose positron emission tomography/computed tomography images in a case of mild cognitive impairment with mini mental state examination of 25 showing hypometabolism in the left parietal cortices (arrow). (b) Coronal fused fluorodeoxyglucose-positron emission tomography/computed tomography image showing hypometabolism in the left precuneus (arrow) and in the left parietal cortex. (c) Transaxial fused fluorodeoxyglucose-positron emission tomography/computed tomography images showing hypometabolism in the left mesial temporal cortices|
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Limitations of fluorodeoxyglucose positron emission tomography in Alzheimer's disease
FDG PET is relatively expensive and like all PET techniques, has more limited availability, although its use in oncology has dramatically increased availability in the USA over the past decade. It requires intravenous access and involves exposure to radioactivity, although at levels well below significant known risk. Brain FDG retention is a non-specific indicator of metabolism that can be deranged for a variety of reasons (e.g., ischemia or inflammation) and may in certain individuals be irrelevant or only indirectly related to any AD-related process.
Amyloid positron emission tomography in Alzheimer's disease
11C-Pittsburgh compound B, as well as newer compounds such as 18F-florbetapir, 18F-flutemetamol, and 18F-florbetaben, are PET tracers that bind preferentially to beta-amyloid fibrils and thus may be able to improve the specificity of antemortem diagnosis, although there is considerable overlap with normal controls. With increased cerebral Aβ deposition, increased activity is demonstrated in the cortex. It is particularly useful in excluding AD as the cause of dementia, as a negative amyloid PET scan renders the diagnosis unlikely.
Amyloid PET scanning makes amyloid plaques ‘light up’ on a brain PET scan [Figure 5], enabling, for the first time, accurate detection of plaques in living people. Before amyloid PET, these plaques could only be detected by examining the brain at autopsy.
|Figure 5: Axial, sagittal and coronal images of positron emission tomography amyloid scan show comparison between the normal and positive subjects|
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Limitations of amyloid positron emission tomography in Alzheimer's disease
Major deterrents to the widespread use of amyloid PET remain cost and availability.
Cost remains an issue, especially where CSF measurement of Aβ42 can provide very similar information when the question is simply the presence or absence of brain Aβ deposition. Being an early event in the pathogenesis of AD, amyloid PET is not a good surrogate marker of progression during the clinical stage of the disease.
This role is filled much better by structural MRI and FDG PET.
Treatment and prognosis
There is no cure for this disease; some drugs have been developed trying to improve symptoms or, at least, temporarily slow down their progression.
Treatment options include:
- Cholinesterase inhibitors
- Partial N-methyl-D-aspartate (NMDA) receptor antagonists.
- Creating a safe and supportive environment
- High-calorie, healthy shakes and smoothie
- Partial NMDA receptor antagonists.
- Alternative medicine
- Omega-3 fatty acids
- Vitamin E.
- Medications for behavioural symptoms
- Antiparkinsonian (movement symptoms)
- Anticonvulsants/sedatives (behavioural).
Neuropathology of Alzheimer's disease
The two primary cardinal lesions associated with AD are the NFT and the senile plaque [Figure 6]. The NFT consists of abnormal accumulations of abnormally phosphorylated tau within the perikaryal cytoplasm of certain neurons. The senile plaque consists of a central core of Aβ, a 4-kD peptide, surrounded by abnormally configured neuronal processes or neurites. Other neuropathological lesions are encountered in cases of AD, but the disease is defined and recognised by these two cardinal lesions.
|Figure 6: Photomicrograph of the temporal cortex of a patient with Alzheimer's disease (modified Bielschowsky stain; ×40). Numerous senile (neuritic) plaques (black arrow) and neurofibrillary tangles (red arrow) are shown|
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| Conclusion|| |
Imaging is playing and has played an essential role in the study of AD over the past four decades.
Initially, CT and then MRI used to rule out other causes of dementia. Recently, emerging imaging modalities including structural and functional MRI and PET studies of cerebral metabolism with FDG and amyloid tracers such as Pittsburgh Compound-B (PiB) have shown characteristic changes in the brains of patients with AD that can help rule in the AD pathophysiological process in earlier stages.
No single imaging modality can serve all purposes as each has unique strengths and weaknesses that set a challenge for the future to find an imaging biomarker that is efficient, available and economic for diagnosis, as well as staging of the disease, and most importantly, development of effective disease-modifying therapies.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Miller-Thomas MM, Sipe AL, Benzinger TL, McConathy J, Connolly S, Schwetye KE, et al.
Multimodality review of amyloid-related diseases of the central nervous system. Radiographics 2016;36:1147-63.
Whalley LJ. Spatial distribution and secular trends in the epidemiology of Alzheimer's disease. Neuroimaging Clin N Am 2012;22:1-10, vii.
Norfray JF, Provenzale JM. Alzheimer's disease: Neuropathologic findings and recent advances in imaging. AJR Am J Roentgenol 2004;182:3-13.
Galton CJ, Patterson K, Xuereb JH, Hodges JR. Atypical and typical presentations of Alzheimer's disease: A clinical, neuropsychological, neuroimaging and pathological study of 13 cases. Brain 2000;123(Pt 3):484-98.
Jalbert JJ, Daiello LA, Lapane KL. Dementia of the Alzheimer type. Epidemiol Rev 2008;30:15-34.
Bobinski M, de Leon MJ, Wegiel J, Desanti S, Convit A, Saint Louis LA, et al.
The histological validation of post mortem magnetic resonance imaging-determined hippocampal volume in Alzheimer's disease. Neuroscience 2000;95:721-5.
Braak H, Braak E. Neuropathological staging of Alzheimer-related changes. Acta Neuropathol 1991;82:239-59.
Johnson KA, Fox NC, Sperling RA, Klunk WE. Brain imaging in Alzheimer disease. Cold Spring Harb Perspect Med 2012;2:a006213.
Ogawa S, Lee TM, Nayak AS, Glynn P. Oxygenation-sensitive contrast in magnetic resonance image of rodent brain at high magnetic fields. Magn Reson Med 1990;14:68-78.
Logothetis NK, Pauls J, Augath M, Trinath T, Oeltermann A. Neurophysiological investigation of the basis of the fMRI signal. Nature 2001;412:150-7.
Sibson NR, Dhankhar A, Mason GF, Behar KL, Rothman DL, Shulman RG, et al. In vivo
13C NMR measurements of cerebral glutamine synthesis as evidence for glutamate-glutamine cycling. Proc Natl Acad Sci U S A 1997;94:2699-704.
Rocher AB, Chapon F, Blaizot X, Baron JC, Chavoix C. Resting-state brain glucose utilization as measured by PET is directly related to regional synaptophysin levels: A study in baboons. Neuroimage 2003;20:1894-8.
Tripathi M, Tripathi M, Sharma R, Jaimini A, Md'souza M, Saw S, et al.
Functional neuroimaging using F-18 FDG PET/CT in amnestic mild cognitive impairment: A preliminary study. Indian J Nucl Med 2013;28:129-33.
] [Full text]
Yeo JM, Waddell B, Khan Z, Pal S. A systematic review and meta-analysis of (18) F-labeled amyloid imaging in Alzheimer's disease. Alzheimers Dement (Amst) 2015;1:5-13.
Kadir A, Almkvist O, Forsberg A, Wall A, Engler H, Långström B, et al.
Dynamic changes in PET amyloid and FDG imaging at different stages of Alzheimer's disease. Neurobiol Aging 2012;33:198.e1-14.
Jack CR Jr., Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, et al.
Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol 2010;9:119-28.
Perl DP. Neuropathology of Alzheimer's disease. Mt Sinai J Med 2010;77:32-42.
Thumbay Clinics, 4184 Ajman
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]