Recommendations from the Italian Interdisciplinary Working Group (AIMN, AIP, SINDEM) for the utilization of amyloid imaging in clinical practice

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1 DOI /s NEWS AND VIEWS Recommendations from the Italian Interdisciplinary Working Group (AIMN, AIP, SINDEM) for the utilization of amyloid imaging in clinical practice Ugo Paolo Guerra Flavio Mariano Nobili Alessandro Padovani Daniela Perani Alberto Pupi Sandro Sorbi Marco Trabucchi Ó Springer-Verlag Italia 2015 Abstract Positron emission tomography (PET) of brain amyloid is a technology that has been approved by Food and Drug Administration and European Medical Agency, but its clinical utility in medical practice requires careful definition. To provide guidance to italian dementia care practitioners, patients, and caregivers, a group of experts from Associazione Italiana di Medicina Nucleare (AIMN), Associazione Italiana di Psicogeriatria (AIP) and Società Italiana per lo Studio delle Demenze (SINDEM) convened the Italian Interdisciplinary Working Group on Amyloid Imaging. The Working Group considered a range of clinical scenarios in which amyloid PET should be recommended. Peer-reviewed, published Authors are listed in alphabetical order as they contributed equally to this work. Italian Interdisciplinary Working Group, AIMN Italian Association of Nuclear Medicine, AIP Italian Association of Psychogeriatrics, SINDEM Italian Neurological Society for the Study of Dementia. U. P. Guerra Nuclear Medicine, Fondazione Poliambulanza, Istituto Ospedaliero, Brescia, Italy F. M. Nobili Clinical Neurology, Department of Neuroscience (DINOGMI), University of Genoa, IRCCS AOU San Martino-Ist, Genoa, Italy A. Padovani (&) Neurology Unit, Department Clinical and Experimental Sciences, University of Brescia, Piazza Ospedale 1, Brescia, Italy alessandro.padovani@unibs.it D. Perani Nuclear Medicine Unit San Raffaele Hospital and Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, Milan, Italy literature was searched to ascertain available evidence relevant to these recommendations. Although empirical evidence of impact on clinical outcomes is not yet available, a set of specific recommended use criteria were agreed to define the types of patients and clinical circumstances in which amyloid PET could be used. Both correct and incorrect uses were considered and formulated. Because both dementia care and amyloid-pet technology are in active development, these recommendations will require periodic reassessment. Keywords Alzheimer disease Neuroimaging Amyloid imaging Positron emission tomography Clinical practice Introduction In a recent publication, [1] a group of Italian neurologists, members of the Italian Society for the study of dementia (SINDEM), has discussed the new terminology proposed A. Pupi Nuclear Medicine, Dipartimento di Scienze Biomediche, Sperimentali e Cliniche Mario Serio, University of Florence, Florence, Italy S. Sorbi NEUROFARBA (Department of Neuroscience, Psychology, Drug Research and Child Health), University of Florence, Florence, Italy M. Trabucchi University of Tor Vergata, Rome, Italy M. Trabucchi Geriatric Research Group, Brescia, Italy

2 by Dubois and colleagues for Alzheimer Disease (AD) and the respective diagnostic criteria for the different stages of the disease [2]. In the latter article the working group members stated that PET for the investigation of amyloid deposition (Amyloid PET) might be used in clinical practice, jointly with the other biomarkers, for patients with atypical dementia or in clinical trials. The Amyloid-PET use should be restricted to a selected number of dementia centers with established experience. After the publication of that paper, there have been several key events in the path to the utilization of Amyloid PET. First, the Amyloid Imaging Task Force (AIT) has first defined [3] and then amended [4] a list of recommendations for which Amyloid PET is considered as appropriate for MCI patients showing a persistent or progressive deterioration not otherwise explained; for those that fulfill clinical criteria for possible AD because of an atypical syndrome or of an onset with mixed etiology; and lastly for cases with progressive dementia atypical for the early age at onset (\65 years). In addition, starting from April 2012 to date, Food and Drug Administration and the European Medical Agency have examined and approved three radiopharmaceuticals for Amyloid PET, florbetapir (Amyvid TM ), flutemetamol (Vizamyl TM ), florbetaben (Neuraceq TM ). In July 2013, the Centers of Medicare and Medicaid Services (CMS) performed an evaluation of the available evidence in scientific literature to decide whether Amyloid PET can be useful to patients with AD symptoms. The result of this evaluation was that the present evidence is not sufficient per se to conclude that Amyloid PET (a) brings significant improvement to the prognosis of patients showing signs and symptoms of AD; (b) provides to clinicians data useful to significantly improve patients state of health. However, the CMS report states that florbetapir is able to detect in human the burden of cerebral amyloid plaques. Hence the report, taking into account the available literature suggests that the use of Amyloid PET can be promising in two scenarios: (a) to exclude AD in specific cases with difficult differential diagnosis, like in AD vs. Frontotemporal Dementia (FTD); and (b) to enrich populations for clinical trials aiming at improved treatments or prevention strategies for AD, allowing to recruit patients not only relying on clinical and epidemiological criteria but also on biological markers. In addition, in October 2013, the marketing authorisation for florbetapir (28th October 2013, Italian Law gazette) commercially known as Amyvid Ò has been released. This radiopharmaceutical is appropriate to detect, with positron emission tomography (PET), the b-amyloid neurites plaque density images in the brain of adult patients with cognitive deterioration evaluated for Alzhemeir s Disease (AD) or other causes. Following these premises, a group of experts on behalf of three scientific associations, i.e., the Italian Society for the Study of Dementia (SINDEM), the Italian Association of Psychogeriatrics (AIP) and the Italian Association of Nuclear Medicine (AIMN) met up to discuss the key questions mentioned above to jointly provide a set of recommendations on whether and when Amyloid PET should be considered as useful for clinical practice. The experts are aware that (a) these recommendations are provided in a moment in which some questions about Amyloid- PET use, particularly regarding the procedures of quantification or semi-quantification of amyloid burden, are unsolved, (b) the meaning of brain amyloid burdening (marker or cause of disease?) is still unclear, and (c) the needs and modalities for the training in reading and interpretation of Amyloid-PET images, also expected in the AIC document, as well as (d) the possible interpretation divergences associated with the use of different radiopharmaceuticals need to be discussed. Despite these limitations, the importance of the topic and the risk that an inappropriate use of Amyloid PET might reduce its value led to the provision of these recommendations. Preamble The recommendations drawn-up by this working group are extensively based on available international scientific literature and recommendations [3 10]. It is mandatory to say that the meaning of a result obtained by PET techniques with amyloid radiopharmaceuticals (Amyloid PET) is not a diagnostic test for AD but rather an index of cerebral amyloidosis. The positivity to the exam therefore means that a significant burden of brain amyloid has been detected, represented by the amyloid of neurites plaques, diffuse plaques and of perivascular amyloid (amyloid angiopathy). In addition, even in a patient with cognitive disturbances, the positivity to amyloid-pet exam does not mean per se that the cognitive disturbances are the result of the amyloidosis pathological process. The expert physicians must consider that a positive amyloid-pet exam is rather common in elderly individuals ([75 years) and that this might be not correlated with the symptoms exhibited by the patient. In contrast, a negative amyloid PET is much more significant in excluding that the symptoms might be due to AD (or to a Dementia with Lewy Bodies-DLB, if suspected) as also expressed in the FDA- and EMA-approved indications, which state: a negative scan indicating sparse to no amyloid plaques is inconsistent with a neuropathological diagnosis of AD. The authors agree that the scientific scenario is rapidly evolving and that these recommendations may be revised in the near future. Importantly, the IWG-2 research criteria [11] emphasized the need to investigate the presence of amyloidosis

3 biomarkers, e.g., using Amyloid PET in the case of both typical (with amnestic deficits) or atypical AD (variants). According to IWG2, MRI and FDG-PET rather than diagnostic markers, would be markers of disease progression. These research criteria, even if in need to be validated in large and ecological populations of patients, are useful to characterize the rapid disease progression. A somehow divergent approach, with respect to the IWG-2 criteria, comes from the Mayo Clinic research group [12]. The authors, studying about 1000 healthy subjects, showed that significant part of them presented AD-like pathological signatures reveled with MRI and/or FDG-PET, in absence of amyloidosis. Therefore, they suggest that in some cases neurodegenerative-like signs can precede amyloidosis in the progression toward AD. A further issue related to the utilization of different fluorinated tracers needs to be here underlined. Different amyloid tracers could bind to identical sites on amyloidbeta fibrils, offering the same ability to detect the regional amyloid-beta burden in the brains. From competition postmortem studies, it has been shown that PIB, AV-45 (florbetapir) and AV-1 (florbetaben) share similar binding to nanomolar high affinity sites, thus supporting these amyloid ligands for the use in a comparable and reliable manner to assess brain amyloid density [13]. In vivo comparison among the fluorinated amyloid tracers offered by commercial companies exists in separate populations showing more consistencies than differences [14]. Only one paper describes the use of two fluorinated amyloid tracers in the same population [15]. They found discrepancies among cortical gray and subcortical white matter uptake. However, thresholds for amyloid positivity were highly consistent when values were converted between tracers (semiquantification). Thus, given the possibility that different fluorinated tracers will be available in Italy, there is a need for the recommendation of a quantitative rather than qualitative visual assessment of amyloid-pet burden. Recommendations for a clinical utilization of amyloid PET Before considering the exam and performing it, the presence of all three following conditions is necessary: 1. The patient must have a cognitive impairment objectively confirmed by means of a standardized neuropsychological battery. Normative reference values for these tests must be based on the Italian population. 2. The cause of the cognitive impairment remains uncertain despite an extensive clinical evaluation performed by an expert in dementias and related Cognitive Disorders (such as those working in Alzheimer Assessment Unit UVA ). AD must be one of the possible causes in the differential diagnosis. 3. The expert believes that knowing whether cerebral amyloidosis is present or not, could increase the diagnostic accuracy. This information may substantially modify the patient clinical/therapeutic management, consisting not only in pharmacological approaches, but also in a globally considered planning of non-pharmacological supports. When all the above conditions are met, Amyloid PET is recommended in the following cases: 1. Subjects affected by a persistent or progressive (for at least 6 months) Mild Cognitive Impairment (MCI), defined according to the NIA-AA criteria [16], when the expert s diagnosis based on morphological* and/or functional** neuroimaging is still uncertain. 2. MCI subjects (a) when the clinical onset is either atypical or uncertain without a clear diagnosis, (b) when the etiology may be mixed due to a concomitant cerebrovascular disease or (c) when there are potentially misleading clinical conditions, i.e., pharmacological effects or not properly controlled systemic diseases (e.g., diabetes). In these rare but important cases, there is the risk of waiting for the progression of clinical syndrome to obtain the diagnosis and prognosis. This is a poor strategy because it could preclude the adoption of effective therapeutic approaches, which instead need to be provided correctly and rapidly. Crucially, a negative amyloid PET can exclude that the MCI condition is due to AD pathology (or DLB, if clinically suspected). 3. Patients with a diagnosis of possible AD, defined according to the NIA-AA criteria [17] when the final diagnosis is still uncertain after the diagnostic procedures involving morphological* and possibly functional** neuroimaging. This uncertainty should be due to an unclear clinical picture, that is (a) atypical presentation; (b) unusual progress (e.g., sudden onset or occasional and/or fluctuating manifestation of symptoms); (c) the presence of confounding comorbidities that can alter/mislead the interpretation of clinical and functional neuroimaging data (e.g., cerebrovascular diseases, a severe hyperglycaemia, other concomitant neurologic diseases, treatment- resistant depression, drugs altering the cognitive functions and the activities of daily living, and in the case of a pronounced cerebral atrophy, both deep and superficial). In this category of peculiar possible AD cases the amyloid PET could be performed before functional neuroimaging and, above all, with the aim of excluding AD diagnosis. In fact, the role of functional neuroimaging by FDG-PET in patients with possible AD is of

4 value when structural neuroimaging is poorly informative (e.g., absence of MTLA) to document a typical temporal-parietal hypometabolism; on the other hand, there is evidence that its diagnostic usefulness is less obvious when structural neuroimaging shows specific brain abnormalities such as MTLA, Colibri sign, putaminal hyperintensities, ischemic/hemorrhagic infarcts, fronto-parietal asymmetric atrophy, pulvinar hyperintensities, as these are typically associated with specific diseases (respectively, AD, Progressive Supranuclear Palsy, Multi System Atrophy, Vascular Dementia, Cortico-Basal Degeneration, Creutzfeldt Jakob Disease). 4. Patients with cognitive decline or progressive dementia and an early age at onset (B65 years old) when the expert s diagnosis is still unclear at the end of the diagnostic procedure involving morphological* and functional** neuroimaging. 5. Patients affected by focal syndromes (e.g., progressive aphasia, agnosia and apraxia; cortico-basal syndrome) when the expert s diagnosis is still unclear after structural * and functional** neuroimaging and with the aim to exclude AD pathology. *Structural neuroimaging The reference structural neuroimaging technique for patients with cognitive impairments is the Magnetic Resonance Imaging (MRI) with standard acquisitions (possibly T1-weighted volumetric 3D acquisitions), whose aim is to exclude cerebrovascular pathology, space-occupying or demyelinating processes and encephalitis. It is recommended to evaluate both the medial temporal lobe (MTL) atrophy and the vascular damage by means of visual-analog scales (such as the Scheltens scale for MTL atrophy [18] and the Wahlund s scale for vascular lesions [19]. The use of quantification methods, which will be increasingly adopted in the future, is desirable even if, by now, only few research centers can apply them. Computerized Tomography (CT) is indicated in some specific circumstances (e.g., claustrophobia or MRI-related contraindications). **Functional neuroimaging The reference functional neuroimaging for patients with cognitive impairments is PET with 18F-Fluorodeoxyglucose (FDG-PET). SPECT imaging with perfusion tracers (either 99m Tc-HMPAO or 99m Tc-ECD) is appropriate if there is no access to FDG-PET or in the case of uncontrolled diabetes that may affect the FDG-PET. As regards FDG-PET, it is advisable to use semi-quantification methods that will be presumably commonly adopted in the future in all the Nuclear Medicine Centers. SPECT with the marker for dopamine transporter (DAT) is recommended in the differential diagnosis between AD and DLB/PD, as well as between AD and other degenerative Parkinsonisms causing cognitive deterioration (e.g., the Progressive Supranuclear Palsy and the Cortico-basal syndrome). Methods for semi-quantifications are advisable also for DAT SPECT. Moreover, also FDG-PET patterns widely described by scientific literature may support the differential diagnosis with respect to atypical Parkinsonisms. Recommendations against a clinical utilization of amyloid PET Given that the incidence of positivity to amyloid PET increases with age, starting from the 7th decade of life, this method progressively loses its accuracy (e.g.: the likelihood of positivity after 80 years old in cognitively intact individuals is [25 %) [3, 20]. The use of amyloid PET is not recommended in the following conditions: 1. Patients who met the criteria for probable AD [17] and with a typical age at onset, probable DLB [21], probable PDD and amyloid angiopathy (given that positivity of amyloid PET does not discriminate the specific pathology). 2. For the definition of the severity and for the follow-up of the cognitive impairment. 3. For asymptomatic individuals, even in the presence of a familiarity for dementia and/or with one or two of the e4 alleles of the apolipoprotein E (ApoE). 4. For patients reporting deficits not confirmed by the objective neuropsychological evaluation. 5. As an alternative to the genetic testing in suspected carriers of dominant autosomal gene mutations causing AD. 6. For non-medical use (legal and insurance purposes, screening for employment). The role for nuclear medicine centers On the national territory, excluding few centers involved in research protocols, the experience in carrying out and reporting amyloid PET is virtually absent. Although for Italian legislation the nuclear medicine physicians working at the operative units of nuclear medicine are qualified to read and analyze PET data (of any kind), the current level of expertise among these clinicians will be enhanced through ongoing educational programs organized by Scientific Society (e.g. AIMN, European Association of

5 Nuclear Medicine) or Pharmaceutical Industry commercializing radiotracers. It is common wisdom that a dichotomous classification (positive/negative exam) is inadequate for a thorough interpretation and reporting procedure. The amyloid accumulation period can last for up to 15 years and during this period the positivity level gradually increases [22, 23]. Therefore, a quantification or semi-quantification of the PET exam providing information about the level of positivity is advisable and should be strongly encouraged. Quantification in terms of deviations of normal values or semiquantitatively assessing changes in follow-up studies is considered so far very helpful in assisting visual interpretation and should be used to provide additional information to conventional image interpretation. It is likely that in the next future the measurement would be performed through adequate and innovative quantification tools, adapted to validated and standardized criteria. For these reasons, AIMN (with reference to the study group of Neurology) will draw up the procedural recommendations regarding the correct use of PET-CT or PET-MRI scanner acquisition and reconstruction procedures together with the quantitative and semi-quantitative analysis of the data. The role of dementia centers The Dementia Centers, following the North American and European tradition of centralizing specialist knowledge in a local outpatient service, were created as supportive practices providing help to people affected by dementia and other amnestic disorders. Their role is to produce early assessments and interventions, i.e., therapeutic and administrative support, and counseling. In Italy over 13 years ago, services for dementia care have been developed within the Cronos Project, a national plan promoted by the Ministry of Health to create 500 Alzheimer Assessment Units (UVA). In the last years, several Italian regions promoted a reconfiguration of dementia health and social networks. They proposed the identification of high-level structures mainly centered on initial diagnosis, management and treatment, and the identification of Dementia Centers specialized on a second level diagnosis, necessary for a more in-depth analysis of unclear and atypical cases, genetic variants or rare diseases, or to perform clinical experimental trials. The II Level Dementia Centers should coordinate and authorize the information about the Amyloid-PET exam, developing a network both with the I Level centers and with the Nuclear Medicine Units, to rationalize and uniform diagnostic-therapeutic strategies, and to allow a correct use of diagnostic tools. Clinical training in neurology, psychiatry, or geriatric medicine organized by Scientific Societies (e.g., AIP, SINDEM) or Pharmaceutical Industry commercializing radiotracers, should be required, although for Italian jurisdiction the specialist working in the UVA or in Dementia Centers is already authorized to define a diagnostic-therapeutic profile (of any kind). Creation of a national register The working group strongly recommend the creation of a national register, that is a data base including both clinical and imaging data (possibly coordinated by the Ministry of Health) in which patients following consensus criteria can be inserted as a guarantee of a standardized and appropriate diagnostic classification. All the members of the Working Group agree on the need to identify regional Reference Centers in which the II Level Centers and Nuclear Medicine Units could work in synergy for the requests management and data collection. Data considered mandatory for the Register are: Age and data of first symptoms; Physician/centre; Description of clinical history (mild cognitive impairment or MCI, dementia); MMSE score; Presence of comorbidities; Prescription drug information and indication about the administration of psychoactive drugs (if necessary); Structural Imaging data (e.g., from MRI or CT); Functional Imaging data (e.g,. from FDG-PET, DATscan); Lab test results (blood count, chemical profile, BI2 and thyroid hormone); A motivated description about the diagnostic uncertainty notwithstanding a complete clinical assessment and the treatment of concomitant pathologies; Amyloid-PET Imaging results; Treatment and assistance plan based on Amyloid-PET results. The reference centers should be responsible to update patients medical records and to encourage the inclusion of clinical information on the national register. Conclusions Amyloid-PET imaging is an important technology for the direct view in living human brains of one of the main pathologic lesions of Alzheimer s disease, i.e., b-amyloid deposition. Parallel progress has improved our understanding of b- amyloid as an important and therapeutically targetable component of AD pathology. In fact, b-amyloid is not the unique causal event in AD, as other pathological alterations were

6 found in AD and many otherwise normal elderly people show elevated levels of b-amyloid, as do patients with clinical syndromes other than AD dementia (e.g., DLB). This is also the case of Cerebral Amyloid Angiopathy as it results from deposition of b-amyloid in the media and adventitia of small arteries and capillaries of the leptomeninges and cerebral cortex and is a major cause of lobar intracerebral hemorrhage and cognitive impairment in the elderly. Advanced CAA is present in approximately onefourth of brains with AD, and half of CAA cases meet pathologic criteria for AD [24]. There are few studies addressing the role of Amyloid PET in CAA, all of them using 11C PIB tracer. Global PiB retention in the nondemented CAA subjects was significantly increased relative to healthy control subjects, although lower in CAA than in AD subjects and the occipital-to-global PiB ratio was found to be significantly greater in CAA than AD, thus suggesting a possible specific marker [25, 26]. Noteworthy, a negative PiB scan rules out CAA with excellent sensitivity, which has clinical implications for prognostication and selection of candidates for drug trials. Amyloid-PET imaging might help diagnose cerebral amyloid angiopathy (CAA) in patients with lobar intracerebral hemorrhage [27, 28]. However, a recent paper showed no significant difference in whole cortex or regional DVRs between CAA patients and agematched healthy controls [29]. In patients with symptomatic l-ich, [11] C-PiB-PET has low specificity for CAA due to the frequent occurrence of high [11] C-PiB uptake in the healthy elderly reflecting either incidental amyloid load or incipient Alzheimer s disease, which might also be present in suspected CAA. All these aspects should be considered in the evaluation of elderly subjects presenting CAA. For all the above reasons, amyloid PET cannot be considered as an exam for the identification of Alzheimer s disease, but as a good biomarker for cerebral amyloidosis and, possibly, depending on the amyloid burden, also a risk predictor for Alzheimer dementia [30]. Amyloid PET could not be considered as the unique method allowing the identification of AD-related pathologies. Consistent evidence supports the important role of cerebrospinal fluid quantifications of A-beta 42, total-tau and phospho-tau despite the huge analytical variability in such measures among centers and the lack of universal cut-off values that still need to be defined. The authors agree that several aspects of Amyloid PET still need to be clarified (e.g., modalities of acquisition and quantification of detected alterations, and differences between radiotracers). For all these reasons, the recommendations here reported may change over time. 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