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Paper text:
amyloid pet can identify fibrillar amyloid- ( a ) deposition , a core aspect of alzheimer s disease ( ad ) pathology , in vivo .
however , cost , availability , and paucity of evidence that it changes management are factors that limit its clinical use . proposed  appropriate use  criteria suggest that amyloid pet may be used in unexplained mild cognitive impairment , young - onset dementia , and atypical dementia syndromes [ 2 , 3 ] .
csf measures of amyloid and tau provide an alternate means of substantiating a molecular diagnosis of ad , with broadly similar diagnostic performance to amyloid pet when either is used in isolation . in many clinical centers ,
while previous studies assessing the use of amyloid pet in the clinical setting have found it to provide added diagnostic value , patients included in these studies have often had incomplete prior investigative work - up , in some cases without mri , neuropsychometry , and/or csf [ 69 ] .
few studies have assessed the utility of amyloid pet in circumstances where it may prove most useful , i.e. , in cases fulfilling good use criteria in whom a csf has been performed and an equivocal / uncertain result is obtained and there remains clinical equipoise as to whether the patient has ad pathology or not . in this study
, we aimed to determine in a real life clinical setting whether amyloid pet can provide added diagnostic value beyond csf measurements alone ; and in what specific clinical circumstances the addition of amyloid pet is likely to provide the most benefit .
twenty patients with a range of different dementia syndromes were recruited from a specialist cognitive disorders service ( supplementary table  1 ) .
ten had memory - led syndromes ; the remainder had a range of other presentations including posterior cortical atrophy ( n  =  5 ) , primary progressive aphasia ( ppa ) ( n  =  4 ) , and behavioral change ( with the patient becoming impulsive and socially disinhibited ) ( n  =  1 ) . as part of their routine clinical evaluation , each patient had been seen by an experienced cognitive neurologist , and been investigated with neuropsychological testing , mr brain imaging and lumbar puncture , with samples analyzed for a42 , total tau , and p - tau ( innotest elisas , fujirebio , ghent belgium ) . at the time of testing , the normal clinical ranges for csf measures in use were : a42 > 450  ng / l , tau : a42 ratio < 1 , p - tau < 68  ng / l . tau and a42 cut - points were those in use clinically at our center at the time of the study , and were based on reference ranges of healthy controls and ability to distinguish clinically diagnosed ad from ftd ; the p - tau cut - point was that determined by the kit manufacturer .
as part of a research study , each patient subsequently had an f18 florbetapir pet scan on a siemens 3 t pet / mr unit , with a 50-min dynamic acquisition commencing immediately after intravenous injection of 370 mbq of florbetapir .
a single static pet image , reconstructed from the last 10  min of the pet acquisition , was used for analysis .
three nuclear medicine physicians , blinded to the diagnosis , visually rated the images as positive / negative according to standard criteria . with the benefit of the psychology , mri , and csf results , but
prior to the pet scan , the treating clinician was asked to give their diagnosis and degree of diagnostic certainty ( on a percentage scale ) .
the clinician was subsequently provided with the pet scan result , which with their consent was also shared with the patient , and asked again to give the diagnosis / diagnostic certainty .
the patients had a meansd age of 65.57.6 , and age of symptom onset of 59.26.2 .
csf examination preceded scanning , with a median delay of 145 days ( range 32427 ) . across all subjects ,
csf a42 ranged between 3431127  ng / l , tau / a42 ratio 0.242.54 , and p - tau 24227  ng / l . prior to the amyloid pet ,
13 patients had a diagnosis of ad , and seven of non - ad dementia .
based on the visual pet results , 18 patients were amyloid positive and 2 patients amyloid negative , with no disagreement between the three readers for any scan .
the amyloid pet result led to a change in diagnosis in 7/20 patients ( 5 non - amnestic , 2 amnestic ) ( table  1 ) .
six patients diagnoses changed from non - ad to ad ; and 1 from ad to non - ad .
the pet scan result led to an increase in diagnostic certainty in 18/20 patients ( to a mean 8414% ) .
management was changed in 8/20 patients : an acetylcholinesterase inhibitor was started / stopped ( n  =  4 ) ; memantine was started ( n  =  1 ) ; immune suppression was stopped ( n  =  1 ) ; and ad genetic testing was requested ( n  =  2 ) . of the seven individuals in whom the pet led to a change in diagnosis , all had young - onset dementia ( age - at - onset < 65 y ) , and five had non - amnestic syndromes , particularly primary progressive aphasia ( n  =  4 ) ( table  1 , supplementary table  1 ) .
clinically , the ppa cases had each been felt to be most consistent with progressive non - fluent aphasia ( pnfa ) , although three of the four cases did not fulfill one of the canonical ppa syndromes , having some features additionally consistent with a logopenic aphasia ( e.g. , anomia and word finding pauses ) .
the seven cases in whom the pet scan altered the diagnosis had a rather lower pre - pet diagnostic certainty than the rest of the group ( 55% versus 76% ) . also , the csf results for these cases were generally close to the pre - determined csf diagnostic cut - points , particularly for the tau : a42 ratio ( table  1 , fig .  1 ) .
providing molecular evidence to support / refute a diagnosis of ad will become ever more important as we move toward an era of disease - modifying therapies . in many centers ,
csf measurements remain the first - line molecular biomarker of choice . here , we show that in certain situations , amyloid pet provides added diagnostic value above and beyond csf measurements , leading not only to increased diagnostic certainty but also to changes in management .
we found that amyloid pet had most benefit in two particular scenarios , ( 1 ) in patients with young onset , atypical clinical syndromes ; and ( 2 ) in those where there was diagnostic uncertainty despite otherwise comprehensive investigation .
these findings are consistent with  appropriate use  criteria , but also extend on the previous guidelines by assessing the use of amyloid pet in patients who have already had csf amyloid and tau measurements ; which in most clinical centers is likely to be the situation where amyloid pet may most commonly be used .
atypical ( i.e. , non - amnestic ) syndromes may be underpinned by a variety of different underlying pathologies and this is particularly the case for ppa , where a tauopathy , tdp-43 proteinopathy , and ad are all possibilities .
although consensus clinical diagnostic criteria describe three major forms ( pnfa , logopenic aphasia , and semantic dementia ) , in many cases patients do not easily fulfill any one criteria [ 10 , 11 ] .
additionally , while there is good clinico - pathological correspondence in some of the ppa syndromes , notably semantic dementia and logopenic aphasia ( tdp43 and ad , respectively ) , in nosyndrome is this perfect ; and in non - fluent aphasia and undetermined aphasias ascribing a particular pathology is notoriously difficult [ 12 , 13 ] .
while previous studies have found relatively high concordance between csf measures and amyloid pet [ 14 , 15 ] , atypical ad syndromes may have less clear - cut csf profiles than would normally be seen in typical ad .
this subtle variability between the csf profiles of different ad syndromes , combined with the high proportion of atypical cases in our cohort , may have contributed in some cases to diagnostic uncertainty and the discrepancy between the csf and pet results .
cases where there was most diagnostic uncertainty were often those where the csf levels were equivocal , lying close to or even outside diagnostic cut - points .
no csf cut - point is perfect , and it is possible that the csf cut - points in clinical use at the time of this study were overly conservative .
csf values can vary substantially if not taken , handled , and stored appropriately ; and establishing csf cut - points is difficult , as evidenced by the wide differences in normal ranges used at different clinical centers , leading us and others to propose the adoption of diagnostic grey - zones , and to suggest that comparing csf and amyloid pet results may be useful in refining csf cut - point use .
this study reinforces that it is just such equivocal cases with atypical phenotypes and borderline csf results that addition of an amyloid brain scan may be most useful , and that so doing can alter clinical management .
given the known incidence of cerebral amyloid deposition within the asymptomatic aging population , it is always necessary to consider whether a positive amyloid pet scan reflects the primary cause of a patient s symptoms , or if it is merely reflective of a second coincident pathology .
however , particularly considering the patients relatively young ages of symptom onset , the possibility of dual pathology was felt to be unlikely , again in keeping with the inclusion of young - onset dementia as an  appropriate use  criterion for amyloid pet .
however , as a load is thought to plateau prior to the onset of ad symptoms , this delay is unlikely to have had a significant effect on the relative diagnostic utility of the two tests , and also reflects what is likely to happen in real life clinical practice . and , without pathological confirmation , we can not know whether any diagnostic or management changes following the amyloid pet were correct or not .
this study demonstrates that amyloid pet scanning has clinical utility is some cases in addition to csf examination , and provides evidence to support its use particularly in young - onset , atypical dementias , where csf results are borderline and diagnostic uncertainty remains .
demographic and clinical information on the study participants : clinical presentation refers to the most prominent symptom at initial presentation .
family history is considered positive if at least one first order relative had a diagnosis of dementia , with  young onset  classed as an onset of symptoms before the age of 65 . those with a family history of young onset dementia were tested for known autosomal dominant mutations of neurodegenerative dementias , but none were found .
the addenbrook 's cognitive examination ( ace ) iii gives a score out of 100 , incorporating a range of cognitive domains including attention , memory , verbal fluency , language , and visuospatial skills .
those seven participants for whom the pet scan led to a change in diagnosis are indicated by an .
further information on these seven individuals can be found in table 1 of the main paper .
cerebrospinal fluid ( csf ) measures of amyloid and tau are the first - line alzheimer s disease biomarkers in many clinical centers . 
 we assessed if and when the addition of amyloid pet following csf measurements provides added diagnostic value . 
 twenty patients from a cognitive clinic , who had undergone detailed assessment including csf measures , went on to have amyloid pet . 
 the treating neurologist s working diagnosis , and degree of diagnostic certainty , was assessed both before and after the pet . 
 amyloid pet changed the diagnosis in 7/20 cases . 
 amyloid pet can provide added diagnostic value , particularly in young - onset , atypical dementias , where csf results are borderline and diagnostic uncertainty remains .