The anatomopathological findings of AD include deposits of neuritic plaque (amyloid) and neurofibrillary tangles (Tau).
Revista Española de Medicina Nuclear e Imagen Molecular (English Edition)
Continuing EducationAmyloid PET in neurodegenerative diseases with dementiaPET amiloide en enfermedades neurodegenerativas que cursan con demencia☆
Introduction
Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive impairment of the memory and cognitive function. This disease is found is approximately 50–75% of all the cases of dementia followed by Lewy body dementia (LBD), frontotemporal lobe degeneration (FTLD) and vascular dementia. The incidence of AD in Europe is 11.8 per 1000 persons-year with a prevalence of 5.05%. The incidence increases with age and affects approximately 2.5% of individuals less than 65 years of age, reaching up to 22.53% among people 85 years old.1 The appearance of most cases is sporatic, although 5% of cases are associated with a genetic mutation producing a dominant autosomic form of the disease. The anatomopathological findings of AD regarding both the sporatic and genetic origin of the disease are neuritic plaque deposits of amyloid-beta (Aβ) protein and neurofibrillary tangles of the Tau protein.2 Aβ plaque deposits are most frequently found in the frontal cortex, the cingulate gyrus, the precuneus and the lateral region of the temporal and parietal cortex. They are relatively infrequent in the primary sensorimotor cortex, the occipital cortex and the mesial temporal area, contrary to the neurofibrillary tangles of the Tau protein which are present in the mesial area of the temporal lobe, including the hippocampus.
At present, AD is considered to be a continuum of clinical and biological phenomena which initiate with a preclinical phase already presenting the physiopathological processes. This is followed by an early symptomatic or prodromic phase also known as mild cognitive impairment (MCI) and a phase of dementia which represents the final stage of the disease. A model has been proposed to explain the sequence of events in which the Aβ are the first physiopathological processes to be altered, later followed by alteration of biomarkers of neuronal lesion.3 The action of α-secretase or β-secretase (BACE-1) and γ-secretase produces the excision of the precursor amyloid protein leading to the formation and aggregation of Aβ peptides (the predominant forms being Aβ40 and Aβ42). Although it has been demonstrated that the aggregates of Aβ are directly toxic for neuron cell culture, the mechanism by which the neurotoxic effects take place remains to be clarified.4 The first consequence of this extracellular physiopathological process in AD is synaptic dysfunction which, together with the formation of intracellular neurofibrillary tangles, result in neuronal loss. At present, AD is considered as a continuum of clinical and biological phenomena which initiates with a preclinical phase followed by an early symptomatic phase (prodromic or MCI) and the phase of dementia.
In the last decades the diagnosis of AD has been exclusively based on diagnostic criteria such as those defined by the Working Group of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association.5 According to these criteria, the clinical diagnosis of AD can only be “probable AD” since definitive diagnosis requires postmortem histological confirmation and can only be assigned when the disease has advanced and fulfills the criteria of dementia. In the last revision of clinical criteria of AD published in 2011,6 the essential clinical criterion for the diagnosis of AD continued to be cognitive decline, although biomarkers which increase the probability of diagnosis have been incorporated, differentiating between biomarkers of Aβ deposition (increased fibrillar amyloid load observed by positron emission tomography (PET) or a reduction in Aβ1-42 in cerebrospinal fluid (CSF) and biomarkers of neuronal degeneration (elevation of total Tau [T-Tau] or phosphorylated Tau [P-Tau] in CSF, a reduction of temporo-parietal metabolism in PET with 18F-FDG, and temporal and parietal atrophy observed by magnetic resonance imaging [MRI]). Likewise, the International Working Group (IWG-2) and the US National Institute on Aging-Alzheimer's Association (NIA-AA)7 define phenotypes and include biomarkers in the diagnostic approach to AD. These biomarkers include a reduction of Aβ1-42 and an increase of the Tau protein in CSF and an increase of fibrillar amyloid load observed by PET or biomarkers of disease progression (hippocampal atrophy observed in MRI and cortical hypometabolism in 18F-FDG PET). Physiopathological or diagnostic biomarkers (increased fibrillar amyloid load observed by PET or a reduction of Aβ1-42 and an elevation of P-Tau in CSF) and biomarkers of neurodegeneration or topographic findings (reduction of temporo-parietal metabolism in 18F-FDG PET and medial temporal atrophy observed in MRI) have recently been included as clinical criteria of AD.
The current treatment of AD is symptomatic with cholinesterase (donepezil, galantamine, rivastigmine) or glumate inhibitors (memantine). The benefits of early diagnosis are well established and have not only medical and therapeutic implications but also ethical, personal and social relevance, making early diagnosis a necessity in a disease such as AD which is accompanied by great discapacity and dependence.8 The use of specific biomarkers such as amyloid PET may help to achieve a more accurate and early diagnosis, especially in patients with the initial symptoms.
Section snippets
Indications
The Spanish Society of Nuclear Medicine and Molecular Imaging together with the Spanish Society of Neurology have recently proposed a series of recommendations as guidelines for the adequate use of biomarkers of PET imaging, which include amyloid PET.8 These guidelines recommend the use of amyloid PET in patients with clinically and objectively well characterized cognitive decline in whom a neurodegenerative origin is suspected after having ruled out other causes of dementia and the origin is
Amyloid PET radiotracers
The use of amyloid PET radiotracers provides quantitative in vivo measurement of cortical amyloid load. These radiotracers have affinity for fibrillar Aβ but are not specific and also bind to different forms of extracellular Aβ (diffuse and dense plaque). The ideal characteristics of a amyloid PET radiotracer are: high affinity and specificity for extracellular amyloid of the cerebral cortex, low molecular weight and lipophilia which allows passage through the blood brain barrier, stable
Interpretation of amyloid PET
The interpretation of these studies is made by structured visual evaluation based on concrete, detailed instructions for each of the 3 approved radiotracers (Table 2). There are small differences in the criteria of interpretation for each radiotracer since each has been validated according to specific studies. Therefore, nuclear physicians interpreting these studies should receive specific accredited training for each radiotracer in on site or online courses. Despite the different nuances of
Amyloid PET in Alzheimer's disease (Fig. 2)
The addition of biomarkers of PET imaging to the new criteria of the NIA-AA has increased the diagnostic certainty in patients with dementia. In patients with AD, cerebral uptake of amyloid PET reflects the density of cortical Aβ plaque, histologically demonstrated with not only 11C-PIB but also with the other fluorinated radiopharmaceuticals with a postmortem histological concordance greater than 95%.11, 17, 18, 19 Different studies have visually and quantitatively shown elevated cortical
Cerebral PET with 18F-FDG
The use of PET-FDG has been widely studied in cognitive decline. Analysis of regional hypometabolism of glucose in the cerebral cortex was one of the first applications of PET techniques to help achieve the clinical diagnosis of neurodegenerative diseases. An alteration of regional cerebral metabolism is associated with different diseases which present characteristic lesion patterns or synaptic dysfunction (neurodegenerataion) based on the localization of the areas affected. Hypometabolism of
Future
Both the NIA-AA and the IWG-2 have added biomarkers to the diagnostic process of AD. Although these biomarkers are well defined, their use in the diagnostic algorithm of dementias is not completely established. In advanced AD it seems that biomarkers of topography and of neurodegeneration such as PET with 18F-FDG and MRI play a more important role in the evaluation of disease severity and evolution. On the other hand, in the diagnosis of early onset AD or MCI, the use of biomarkers of amyloid
Conclusions
Amyloid PET is a useful and available technique which provide in vivo information of amyloid deposition. The scientific societies have developed specific recommendations for their correct use in clinical practice: persistent or progressive cognitive decline (initial AD, prodromic AD and MCI), atypical cognitive decline, early onset cognitive decline and to differentiate between AD and other neurodegenerative diseases with dementia.8
Depending on the radiotracer used, PET provides information
Conflict of interests
The authors have no conflicts of interest to declare.
Acknowledgments
The authors thank the Departments of Nuclear Medicine of the Hospital Universitario 12 de Octubre in Madrid, the Hospital de la Santa Creu i Sant Pau in Barcelona, the Hospital Vithas-Nisa 9 de Octubre in Valencia abnd the Hospital Universitario Marqués de Valdecilla in Santander for the contributions of images.
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Please cite this article as: Camacho V, Gómez-Grande A, Sopena P, García-Solís D, Gómez Río M, Lorenzo C, et al. PET amiloide en enfermedades neurodegenerativas que cursan con demencia. Rev Esp Med Nucl Imagen Mol. 2018;37:397–406.