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Journal of Alzheimer’s Disease 42 (2014) 885–892 DOI 10.3233/JAD-132729 IOS Press
Management Impact of FDG-PET in Dementia: Results from a Tertiary Center Memory Clinic Alby Eliasa , Michael Woodwardb and Christopher C. Rowea,∗ a Department of Nuclear Medicine and Centre for PET, Austin Health, The University of Melbourne, VIC, Australia b Department
of Aged Care, Austin Health, Melbourne, VIC, Australia
Accepted 25 April 2014
Abstract. Background: 2-[18F]fluoro-2-Deoxy-D-glucose (FDG) positron emission tomography (PET) may assist the diagnosis of dementia but it is an expensive investigation. Objective: To obtain management impact data for FDG-PET in dementia. Methods: This was a prospective study of 194 consecutive patients referred from a memory clinic for FDG-PET at the discretion of the dementia specialists. Diagnosis and management plans formulated at a multidisciplinary patient review meeting were compared before and after the release of PET findings. Results: FDG-PET had moderate to high impact on the diagnosis and management in 85 (44%) participants. Diagnosis changed from probable neurodegenerative disease in 27 patients to a non-degenerative diagnosis and vice versa in 12 patients. PET changed the type of dementia in another 29 (15%) participants and prescription of cholinesterase inhibitors in 33 patients (17%). Number of uncertain diagnoses reduced from 58 to 35 (p < 0.001, χ2 = 15.12), differential diagnoses reduced from 127 to 55 (p = 0.003) and very probable diagnoses increased from 5 to 42 (p ≤ 0.001, χ2 = 1.01). Mini-Mental State Examination score was higher in those where PET had high diagnostic impact (26.3 ± 3.1 versus 23.9 ± 5.1, p ≤ 0.05). The degree of impact correlated with the pre-scan level of diagnostic uncertainty (ρ = −0.258, p < 0.001). Discussion: The management impact was higher in those with greater diagnostic uncertainty and in those with less severe cognitive impairment. The findings suggest that FDG-PET is a useful adjunct for the management of suspected dementing disorders in appropriately selected patients. Keywords: Alzheimer’s disease, diagnostic impact, FDG-PET, memory clinic
INTRODUCTION Alzheimer’s disease (AD) is the most common form of dementia and with the aging of the population in developed countries, its incidence and cost to society will increase substantially [1, 2]. Longitudinal studies have recently shown that the disease process begins 20–30 years before dementia while impairment of memory function, regional cerebral hypometabolism, ∗ Correspondence
to: Christopher Rowe, Director of Nuclear Medicine, Austin Hospital, The University of Melbourne, 145 Studley Road PO Box 5555 Heidelberg, VIC 3084, Australia. Tel.: +61 3 9496 5183; Fax: +61 3 9496 5663; E-mail: christopher. [email protected].
and brain atrophy in an individual is detectable approximately 5 years before dementia [3, 4]. The accuracy of conventional diagnostic criteria for probable AD is limited with sensitivity of 81% and specificity of 70% compared to neuropathological diagnosis [5–7] and the criteria require the presence of dementia [5]. It has been proposed that earlier and more accurate diagnosis provides medical, social and economic benefits [8–10]. Revised diagnostic criteria for AD that use biomarkers to give an earlier and more accurate diagnosis have recently been proposed [11–14]. One of the well validated biomarkers for AD is the characteristic pattern of parieto-temporal and posterior cingulate gyrus hypometabolism seen
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in 2-[18F]fluoro-2-Deoxy-D-glucose (FDG) positron emission tomography (PET) [15, 16]. Other patterns of hypometabolism assist detection of other dementias including the clinical variants of frontal temporal lobar degeneration (FTLD) and dementia with Lewy bodies (DLB) (Fig. 1) [17–22]. A recent literature summary concluded that the sensitivity and specificity of FDG-PET varied from 84 to 97% and 58 to 86% respectively [23]. Addition of FDG-PET to clinical assessment has been shown to improve diagnostic accuracy compared to eventual neuropathological diagnosis [24, 25]. FDG-PET for dementia has also performed well in cost-benefit analyses [10, 26]. Appropriate use criteria (AUC) have an important role in achieving the greatest patient benefit from diagnostic services while exercising responsible cost containment. AUC for FDG-PET in dementia have been produced by the American College of Radiology [27] based on a literature review of diagnostic accuracy. Ideally, AUC should be based on management impact and patient outcome data but there is limited such information available for FDG-PET in dementia. In the present prospective study, we report our findings on the management impact of FDG-PET in patients referred for this investigation after initial assessment by a dementia specialist and examine factors that may influence the degree of management impact.
METHODS A prospective study was conducted from November 2003 to November 2007 at a multidisciplinary memory disorders clinic at Austin Health, Melbourne, Australia. Each patient was assessed by a geriatrician or neurologist with expertise in dementia evaluation and management. FDG-PET was ordered at the discretion of the treating specialist upon completion of the initial clinical evaluation. The clinical evaluation and results of investigations including MRI and neuropsychology assessment were then discussed at a multidisciplinary team meeting consisting of geriatricians, a neurologist, a neuropsychologist, and other clinical staff. The neuropsychology assessment was tailored to the patient and usually included tests of episodic memory, working memory, visuospatial, language, and executive function. The neuropsychologist gave a descriptive report based on their clinical assessment and testing results. Visual rating of MRI for medial temporal atrophy and vascular disease was performed. A provisional diagnosis and management plan was then formulated and documented. The FDG-PET findings were then
released and the diagnosis and management plan was revised by the multidisciplinary team. Management impact of FDG-PET was then classified as follows: Nil = discrepancy between FDG-PET findings and multidisciplinary team diagnosis but the FDG-PET did not change diagnosis or management; Low = PET result concordant with multidisciplinary team diagnosis but did not change diagnosis or management; Moderate = PET changed the type of dementia or changed the prescription of cholinesterase inhibitors; High = PET changed the diagnosis of dementia to a non-neurodegenerative condition or vice versa. The non-neurodegenerative category included psychiatric disorders, sleep apnea, vasculitis, thyroid disease, and no disease. Vascular dementia was grouped with the neurodegenerative diagnoses. Both pre- and post-FDGPET scan diagnoses were rated at one of three levels of certainty by the multidisciplinary team: possible, probable and very probable. There were no specific criteria for these diagnostic confidence ratings. Image acquisition Subjects were scanned on a Phillips AllegroTM PET scanner (resolution 5 mm FWHM) in 3D mode. Subjects fasted for 4 hours before injection of 250–300 MBq of 18 F-FDG and remained in a quiet, darkened room with eyes open for 30 minutes. Acquisition was commenced 30–45 minutes post injection. A post-injection transmission scan for attenuation correction was performed. Acquisition time was 20 minutes. Reconstruction was performed with a RAMLA algorithm. Images were displayed on a workstation in the readers preferred color scale and as a stereotactic surface display (SSP) of Z-score difference compared to a normal elderly control database of activity in each cortical voxel using the freely available program, Neurostat 3D-SSP. Examples of the SSP display are shown in Fig. 1. Image analysis FDG-PET diagnosis was made by visual inspection of images and Neurostat 3D-SSP by an experienced nuclear medicine physician with access to the request form and therefore to some clinical details. Interpretation criteria followed published findings on the patterns of hypometabolism most associated with various neurodegenerative diseases. These patterns were: 1) AD: metabolic reduction in parieto-temporal regions and posterior cingulate gyrus [15, 16]; 2) DLB: parietal and occipital hypometabolism with sparing of posterior
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Fig. 1. Stereotactic surface display of the distribution of hypometabolism typically associated with a range of dementias. The Z-score color scale illustrates the severity of hypometabolism in the patient’s FDG-PET scan relative to a normal elderly FDG-PET database. The pattern of hypometabolism indicates the type of dementia.
cingulate gyrus [17, 18]; 3) FTLD: hypometabolism in frontal and anterior temporal regions in the behavioral variant [19], in the anterior temporal lobe in semantic dementia [20] and in the left dorsolateral and dorsomedial prefrontal cortex in progressive non-fluent aphasia [21]; 4) Corticobasal degeneration: asymmetric dorsal frontal and anterior parietal metabolic reduction with or without ipsilateral striatum and thalamus hypometabolism, greatest on the side of the brain contralateral to the most affected limbs [22]; 5) Vascular dementia: focal cortical, subcortical or cerebellar metabolic defects with corresponding areas of infarction on MRI [28]. Mixed vascular-AD was diagnosed when the FDGPET showed temporoparietal and posterior cingulate gyrus hypometabolism with focal cortical, subcortical, or cerebellar defects and there was a history of progressive cognitive decline following a stroke, or MRI showed extensive white matter hyperintensity with subcortical or cortical infarction. Statistical tests Results were expressed as mean ± S.D. Spearman’s correlation was applied for two ordinal variables: level
of confidence (possible, probable, and very probable diagnosis) and degree of impact. The difference in diagnostic certainty in two paired samples, i.e., before and after the release of scan findings was tested using McNamer’s test of the frequency distribution of a dichotomous variable between two paired samples. Independent t-test was used to examine if there was any difference in the Mini-Mental State Examination (MMSE) score between the groups with and without a disparity between pre-scan and post scan diagnosis. RESULTS Over the four year period of study, 194 patients were referred for FDG-PET from a total of approximately 800 new patient consultations. The mean age of those referred for FDG-PET was 73 ± 10.01 years, the level of cognitive impairment was generally mild to moderate with a MMSE score of 24 ± 4.91, and 62% were male. A pre-scan diagnosis of dementia was present in 161 (82.9%) patients compared to findings supportive of a neurodegenerative disease on FDG-PET in 146 (75.2%) (Fig. 2). Some patients received a differential diagnosis of more than one dementia type either pre or post FDG-PET scan.
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Fig. 2. Frequency distribution of diagnosis before and after FDGPET. AD, Alzheimer’s disease; FTD, fontotemporal dementia; VD, vascular dementia; DLB, dementia with Lewy bodies. Number of subjects (ordinate) and diagnosis (abscissa). Some patients had more than one type of dementia diagnosis. Other dementia category included: corticobasal degeneration (n = 3), traumatic brain injury (n = 3), Parkinson’s dementia complex (n = 2), encephalitis (n = 2), dementia pugulistica, thyroid disease, obstructive hydrocephalus, drug related (n = 1 each).
In only two patients was the PET report ignored when it was inconsistent with the pre-scan diagnosis and therefore impact was rated as nil. Impact was low in 107 (55.2%), moderate in 46 (23.7%), and high in 39 (20%) patients. Overall in 85 (44%) patients, FDG-PET produced significant impact (score of 3 or 4) by changing the diagnosis or treatment or both. In 27 patients (14% of the cohort) the pre-scan diagnosis of dementia changed to a non-neurodegenerative condition post PET. In 12 (6.1%) patients the opposite occurred, where a pre-scan diagnosis of non-dementia such as depression or anxiety disorder became a diagnosis of a neurodegenerative disorder, such as AD, post-scan. In these latter cases, most fit criteria for mild cognitive impairment at the time of their initial assessment. The mean MMSE score in the group where PET had high impact was 26.3 (SD ± 3.1) and significantly higher than the MMSE of 23.9 (SD ± 5.1) in the remaining patients (p = 0.03, 95% CI: 0.20–4.7). The diagnostic confidence or the degree of certainty was also significantly improved after the scan (Fig. 3). The number of subjects with possible diagnosis decreased from 58 to 35 (χ2 = 15.1, p < 0.001) whereas those with very probable diagnosis increased from 5 to 42 (χ2 = 1.019, p < 0.001). Of the five patients with a prescan diagnosis classified as very probable (3 AD, 1 DLB, 1 FTD), FDG-PET changed the diagnosis in only one and that was from DLB to cortico-basal degeneration. Twenty-seven patients were classified as having mild cognitive impairment at the time of assessment
Fig. 3. Frequency distribution of diagnostic certainty. The first three grey bars show the pre FDG-PET diagnostic confidence (possible, probable, or very probable); the first 3 black bars show the post FDGPET diagnostic confidence. The fourth grey and black bars show the number of patients with multiple differential diagnoses before and after the FDG-PET scan. Diagnostic confidence was greater and differential diagnoses decreased post FDG-PET. The Y-axis is the number of subjects. D, diagnosis, V Probable D, very probable diagnosis.
Table 1 Patient characteristics Male:Female Age MMSE
120 : 74 73 (±10.01); range 46–91 24.42 (±4.91); range 5–30
and FDG-PET showed evidence of neurodegenerative disease in 10 of these patients. The level of pre-scan diagnostic confidence (possible, probable, very probable) inversely correlated with the degree of management impact (Spearman’s rho = −0.258, p < 0.001). The improved diagnostic certainty was also reflected in the lower number of patients with multiple differential diagnoses after the scan compared to pre-scan. 127 patients had a differential diagnosis of more than one dementia type before the scan and this figure fell to 55 post scan (p = 0.003). Though total number of patients to be prescribed cholinesterase inhibitors (ChEIs) did not differ pre and post scan (74 versus 79; p = 0.48), the medication plan for 14 patients changed to not prescribing ChEIs while for 19 patients ChEIs was added to their management after the scan following a change in diagnoses and/or the level of diagnostic confidence. Therefore treatment was changed in 33 (17%) patients. DISCUSSION Many studies of FDG-PET in dementia have looked at its advantages as a diagnostic tool. However, with growing concern over the rising cost of diagnostic
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procedures, data that can guide development or refinement of appropriate use criteria is increasingly important. To the best of our knowledge this is the first prospective study that examined the management impact of FDG-PET alone in a pragmatic setting where the investigation was ordered at the discretion of the memory specialist. In this setting, the study found that FDG-PET had significant impact both in terms of dementia diagnosis and its treatment. The degree of management impact increased with level of diagnostic uncertainty and was greatest in those with milder degrees of cognitive impairment or dementia. Our findings are remarkably concordant with those reported from a retrospective management impact study of 94 Canadian patients who also had FDGPET after routine evaluation in a memory clinic [29]. The authors concluded that FDG-PET changed diagnosis in 29% of patients, led to earlier initiation of ChEI treatment, reduced uncertain diagnosis from 39% to 16% but contributed little to patients with typical clinical features of AD or frontotemporal dementia. Similarly, our prospective study found that FDG-PET changed diagnosis in 35%. It altered the use of ChEI medication in 17%, reduced uncertain diagnosis (i.e., possible diagnosis) from 30% to 18% while increasing diagnostic confidence to the very probable level from 3% to 22% of patients and that management impact was less in those with high pre-scan diagnostic confidence and in those with more advanced dementia. Of crucial importance is that in our study, FDG-PET changed a pre-scan diagnosis of dementia to a nonneurodegenerative diagnosis or vice versa in 20% of patients after a multidisciplinary specialist Memory Disorders clinic assessment. In a recent report from a quaternary referral center for patients with early onset dementia in the Netherlands, the impact of combined FDG-PET and amyloid PET imaging was reported on 154 patients [30]. The authors found that the diagnosis of dementia was changed in 23% of cases, and that this occurred more often when pre-PET diagnostic confidence was lower. Importantly, no change in diagnosis occurred in the 27 patients where pre PET diagnostic confidence was >90%. The impact of FDG-PET alone could not be determined from this study. These results suggest that the use of FDG-PET in patients with uncertain dementia diagnosis will deliver benefits to the patient. Appropriate initiation of treatment for AD with ChEIs has been shown to delay the cognitive decline and maintain functional level for 9–12 months [31, 32]. It is estimated that the cost of FDG-PET is less than one month of lost productivity and independence of a patient who does
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not receive timely diagnosis and treatment [10]. Conversely, avoidance of side effects from inappropriate medication use due to a wrong diagnosis of AD is also important. Gastrointestinal side effects are common and serious cardiac complications, though rare, can arise with ChEIs [32–34]. So a trial and error approach to their use when diagnosis is uncertain may not be justified. Accurate subtyping of dementia is of clinical importance to ensure appropriate use of medication and provide accurate prognostic information to the patient and their family. ChEI medications may exacerbate the behavioral features of FTLD and it is recommended they be avoided in this condition [35]. Antipsychotic medication is frequently used for the behavioral problems associated with dementia, but may have catastrophic effects in DLB and should be avoided in this condition [36]. Sensitivity and specificity of clinical diagnosis of DLB against pathological diagnosis remains a challenge [37, 38] with low sensitivity a particular problem. FDG-PET has good diagnostic accuracy for DLB [17]. In our study, FDG-PET changed the diagnosis of DLB in 23 patients with 18 patients with a pre-scan diagnosis reduced to 6 and 11 others given a post-scan diagnosis of DLB. Improved diagnostic confidence post PET should reduce further investigation, saving the patient and family from the inconvenience of more testing and saving the cost of more investigations. Prompt and accurate diagnosis can assist patients and their families to prepare for the major life decisions required as dementia progresses, when their cognitive functions are relatively preserved allowing the patient to have input into their future care plans. Delay in diagnosis of dementia is of concern to the general community and reducing this delay has been identified as an important goal [39]. Appropriate use criteria (AUC) have emerged as important tools to contain health care costs for diagnostic technology while maximizing patient benefit. Ideally, these AUC are based on management impact and patient outcome data. When this data is lacking, AUC are derived from evidence of diagnostic accuracy and expert opinion as to how improved diagnosis will most benefit patients. AUC for FDG-PET in dementia have been produced by the American College of Radiology [27] based on accuracy data. Our data indicates that AUC for FDG-PET in dementia should discourage use of this technology in patients with typical presentation for AD where a clinical diagnosis can be made with high confidence, and in those with more severe dementia. This study confirms that FDG-PET substantially alters management in patients where diagnostic
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uncertainty persists after expert evaluation and that the use of FDG-PET in this circumstance is appropriate. This recommendation is consistent with the recently published AUC for amyloid PET imaging for dementia from the joint Society of Nuclear Medicine and Alzheimer’s Association taskforce [40] that state that use of amyloid PET is most appropriate for patients with uncertain diagnosis after evaluation by a dementia specialist. The relative merits of amyloid PET and FDG-PET for the evaluation of dementia are beyond the scope of this study. Both provide unique information that may assist patient diagnosis and management impact studies are needed to define their relative role in patient evaluation. The study was designed to reflect clinical practice. The investigator who read the PET scan was not blind to the initial diagnosis or clinical history but this is usually the case when patients are referred for FDG-PET. A limitation of the study is the absence of confirmation of the PET diagnosis by neuropathological examination and the absence of clinical follow-up data. Consequently the benefits of the alterations in management by FDG-PET can only be inferred and are not proven. Although the study has implications for a patient referred from a specialist memory disorder clinic, its utility in other settings such as non-specialist evaluation is not clear from this study. While it is quite possible that change in diagnosis, diagnostic confidence and management would be greater in a nonspecialist setting, it is unknown if this would be more or less cost effective than initial specialist evaluation. In the absence of this data, expert opinion based appropriate use criteria recommend that PET follow evaluation of the patient by a memory disorder specialist as done in this study [27, 39].
The Victorian Government Department of Health and Human Services. Income from FDG-PET scans supports this Department. Authors’ disclosures available online (http:// www.j-alz.com/disclosures/view.php?id=2303).
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CONCLUSION FDG-PET has a moderate to high management impact in nearly half of the patients referred from a memory disorder clinic at the discretion of the treating specialist. The impact is greater in those patients whose dementia is at an early stage and where diagnosis is uncertain. These findings can be applied to refine the appropriate use criteria for FDG-PET in dementia. ACKNOWLEDGMENTS We thank the medical, nursing, and allied health staff of the Austin Health Memory Disorders Clinic for their assistance with this study. Funding Source:
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Journal of Alzheimer’s Disease 42 (2014) 885–892 DOI 10.3233/JAD-132729 IOS Press
Management Impact of FDG-PET in Dementia: Results from a Tertiary Center Memory Clinic Alby Eliasa , Michael Woodwardb and Christopher C. Rowea,∗ a Department of Nuclear Medicine and Centre for PET, Austin Health, The University of Melbourne, VIC, Australia b Department
of Aged Care, Austin Health, Melbourne, VIC, Australia
Accepted 25 April 2014
Abstract. Background: 2-[18F]fluoro-2-Deoxy-D-glucose (FDG) positron emission tomography (PET) may assist the diagnosis of dementia but it is an expensive investigation. Objective: To obtain management impact data for FDG-PET in dementia. Methods: This was a prospective study of 194 consecutive patients referred from a memory clinic for FDG-PET at the discretion of the dementia specialists. Diagnosis and management plans formulated at a multidisciplinary patient review meeting were compared before and after the release of PET findings. Results: FDG-PET had moderate to high impact on the diagnosis and management in 85 (44%) participants. Diagnosis changed from probable neurodegenerative disease in 27 patients to a non-degenerative diagnosis and vice versa in 12 patients. PET changed the type of dementia in another 29 (15%) participants and prescription of cholinesterase inhibitors in 33 patients (17%). Number of uncertain diagnoses reduced from 58 to 35 (p < 0.001, χ2 = 15.12), differential diagnoses reduced from 127 to 55 (p = 0.003) and very probable diagnoses increased from 5 to 42 (p ≤ 0.001, χ2 = 1.01). Mini-Mental State Examination score was higher in those where PET had high diagnostic impact (26.3 ± 3.1 versus 23.9 ± 5.1, p ≤ 0.05). The degree of impact correlated with the pre-scan level of diagnostic uncertainty (ρ = −0.258, p < 0.001). Discussion: The management impact was higher in those with greater diagnostic uncertainty and in those with less severe cognitive impairment. The findings suggest that FDG-PET is a useful adjunct for the management of suspected dementing disorders in appropriately selected patients. Keywords: Alzheimer’s disease, diagnostic impact, FDG-PET, memory clinic
INTRODUCTION Alzheimer’s disease (AD) is the most common form of dementia and with the aging of the population in developed countries, its incidence and cost to society will increase substantially [1, 2]. Longitudinal studies have recently shown that the disease process begins 20–30 years before dementia while impairment of memory function, regional cerebral hypometabolism, ∗ Correspondence
to: Christopher Rowe, Director of Nuclear Medicine, Austin Hospital, The University of Melbourne, 145 Studley Road PO Box 5555 Heidelberg, VIC 3084, Australia. Tel.: +61 3 9496 5183; Fax: +61 3 9496 5663; E-mail: christopher. [email protected].
and brain atrophy in an individual is detectable approximately 5 years before dementia [3, 4]. The accuracy of conventional diagnostic criteria for probable AD is limited with sensitivity of 81% and specificity of 70% compared to neuropathological diagnosis [5–7] and the criteria require the presence of dementia [5]. It has been proposed that earlier and more accurate diagnosis provides medical, social and economic benefits [8–10]. Revised diagnostic criteria for AD that use biomarkers to give an earlier and more accurate diagnosis have recently been proposed [11–14]. One of the well validated biomarkers for AD is the characteristic pattern of parieto-temporal and posterior cingulate gyrus hypometabolism seen
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in 2-[18F]fluoro-2-Deoxy-D-glucose (FDG) positron emission tomography (PET) [15, 16]. Other patterns of hypometabolism assist detection of other dementias including the clinical variants of frontal temporal lobar degeneration (FTLD) and dementia with Lewy bodies (DLB) (Fig. 1) [17–22]. A recent literature summary concluded that the sensitivity and specificity of FDG-PET varied from 84 to 97% and 58 to 86% respectively [23]. Addition of FDG-PET to clinical assessment has been shown to improve diagnostic accuracy compared to eventual neuropathological diagnosis [24, 25]. FDG-PET for dementia has also performed well in cost-benefit analyses [10, 26]. Appropriate use criteria (AUC) have an important role in achieving the greatest patient benefit from diagnostic services while exercising responsible cost containment. AUC for FDG-PET in dementia have been produced by the American College of Radiology [27] based on a literature review of diagnostic accuracy. Ideally, AUC should be based on management impact and patient outcome data but there is limited such information available for FDG-PET in dementia. In the present prospective study, we report our findings on the management impact of FDG-PET in patients referred for this investigation after initial assessment by a dementia specialist and examine factors that may influence the degree of management impact.
METHODS A prospective study was conducted from November 2003 to November 2007 at a multidisciplinary memory disorders clinic at Austin Health, Melbourne, Australia. Each patient was assessed by a geriatrician or neurologist with expertise in dementia evaluation and management. FDG-PET was ordered at the discretion of the treating specialist upon completion of the initial clinical evaluation. The clinical evaluation and results of investigations including MRI and neuropsychology assessment were then discussed at a multidisciplinary team meeting consisting of geriatricians, a neurologist, a neuropsychologist, and other clinical staff. The neuropsychology assessment was tailored to the patient and usually included tests of episodic memory, working memory, visuospatial, language, and executive function. The neuropsychologist gave a descriptive report based on their clinical assessment and testing results. Visual rating of MRI for medial temporal atrophy and vascular disease was performed. A provisional diagnosis and management plan was then formulated and documented. The FDG-PET findings were then
released and the diagnosis and management plan was revised by the multidisciplinary team. Management impact of FDG-PET was then classified as follows: Nil = discrepancy between FDG-PET findings and multidisciplinary team diagnosis but the FDG-PET did not change diagnosis or management; Low = PET result concordant with multidisciplinary team diagnosis but did not change diagnosis or management; Moderate = PET changed the type of dementia or changed the prescription of cholinesterase inhibitors; High = PET changed the diagnosis of dementia to a non-neurodegenerative condition or vice versa. The non-neurodegenerative category included psychiatric disorders, sleep apnea, vasculitis, thyroid disease, and no disease. Vascular dementia was grouped with the neurodegenerative diagnoses. Both pre- and post-FDGPET scan diagnoses were rated at one of three levels of certainty by the multidisciplinary team: possible, probable and very probable. There were no specific criteria for these diagnostic confidence ratings. Image acquisition Subjects were scanned on a Phillips AllegroTM PET scanner (resolution 5 mm FWHM) in 3D mode. Subjects fasted for 4 hours before injection of 250–300 MBq of 18 F-FDG and remained in a quiet, darkened room with eyes open for 30 minutes. Acquisition was commenced 30–45 minutes post injection. A post-injection transmission scan for attenuation correction was performed. Acquisition time was 20 minutes. Reconstruction was performed with a RAMLA algorithm. Images were displayed on a workstation in the readers preferred color scale and as a stereotactic surface display (SSP) of Z-score difference compared to a normal elderly control database of activity in each cortical voxel using the freely available program, Neurostat 3D-SSP. Examples of the SSP display are shown in Fig. 1. Image analysis FDG-PET diagnosis was made by visual inspection of images and Neurostat 3D-SSP by an experienced nuclear medicine physician with access to the request form and therefore to some clinical details. Interpretation criteria followed published findings on the patterns of hypometabolism most associated with various neurodegenerative diseases. These patterns were: 1) AD: metabolic reduction in parieto-temporal regions and posterior cingulate gyrus [15, 16]; 2) DLB: parietal and occipital hypometabolism with sparing of posterior
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Fig. 1. Stereotactic surface display of the distribution of hypometabolism typically associated with a range of dementias. The Z-score color scale illustrates the severity of hypometabolism in the patient’s FDG-PET scan relative to a normal elderly FDG-PET database. The pattern of hypometabolism indicates the type of dementia.
cingulate gyrus [17, 18]; 3) FTLD: hypometabolism in frontal and anterior temporal regions in the behavioral variant [19], in the anterior temporal lobe in semantic dementia [20] and in the left dorsolateral and dorsomedial prefrontal cortex in progressive non-fluent aphasia [21]; 4) Corticobasal degeneration: asymmetric dorsal frontal and anterior parietal metabolic reduction with or without ipsilateral striatum and thalamus hypometabolism, greatest on the side of the brain contralateral to the most affected limbs [22]; 5) Vascular dementia: focal cortical, subcortical or cerebellar metabolic defects with corresponding areas of infarction on MRI [28]. Mixed vascular-AD was diagnosed when the FDGPET showed temporoparietal and posterior cingulate gyrus hypometabolism with focal cortical, subcortical, or cerebellar defects and there was a history of progressive cognitive decline following a stroke, or MRI showed extensive white matter hyperintensity with subcortical or cortical infarction. Statistical tests Results were expressed as mean ± S.D. Spearman’s correlation was applied for two ordinal variables: level
of confidence (possible, probable, and very probable diagnosis) and degree of impact. The difference in diagnostic certainty in two paired samples, i.e., before and after the release of scan findings was tested using McNamer’s test of the frequency distribution of a dichotomous variable between two paired samples. Independent t-test was used to examine if there was any difference in the Mini-Mental State Examination (MMSE) score between the groups with and without a disparity between pre-scan and post scan diagnosis. RESULTS Over the four year period of study, 194 patients were referred for FDG-PET from a total of approximately 800 new patient consultations. The mean age of those referred for FDG-PET was 73 ± 10.01 years, the level of cognitive impairment was generally mild to moderate with a MMSE score of 24 ± 4.91, and 62% were male. A pre-scan diagnosis of dementia was present in 161 (82.9%) patients compared to findings supportive of a neurodegenerative disease on FDG-PET in 146 (75.2%) (Fig. 2). Some patients received a differential diagnosis of more than one dementia type either pre or post FDG-PET scan.
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Fig. 2. Frequency distribution of diagnosis before and after FDGPET. AD, Alzheimer’s disease; FTD, fontotemporal dementia; VD, vascular dementia; DLB, dementia with Lewy bodies. Number of subjects (ordinate) and diagnosis (abscissa). Some patients had more than one type of dementia diagnosis. Other dementia category included: corticobasal degeneration (n = 3), traumatic brain injury (n = 3), Parkinson’s dementia complex (n = 2), encephalitis (n = 2), dementia pugulistica, thyroid disease, obstructive hydrocephalus, drug related (n = 1 each).
In only two patients was the PET report ignored when it was inconsistent with the pre-scan diagnosis and therefore impact was rated as nil. Impact was low in 107 (55.2%), moderate in 46 (23.7%), and high in 39 (20%) patients. Overall in 85 (44%) patients, FDG-PET produced significant impact (score of 3 or 4) by changing the diagnosis or treatment or both. In 27 patients (14% of the cohort) the pre-scan diagnosis of dementia changed to a non-neurodegenerative condition post PET. In 12 (6.1%) patients the opposite occurred, where a pre-scan diagnosis of non-dementia such as depression or anxiety disorder became a diagnosis of a neurodegenerative disorder, such as AD, post-scan. In these latter cases, most fit criteria for mild cognitive impairment at the time of their initial assessment. The mean MMSE score in the group where PET had high impact was 26.3 (SD ± 3.1) and significantly higher than the MMSE of 23.9 (SD ± 5.1) in the remaining patients (p = 0.03, 95% CI: 0.20–4.7). The diagnostic confidence or the degree of certainty was also significantly improved after the scan (Fig. 3). The number of subjects with possible diagnosis decreased from 58 to 35 (χ2 = 15.1, p < 0.001) whereas those with very probable diagnosis increased from 5 to 42 (χ2 = 1.019, p < 0.001). Of the five patients with a prescan diagnosis classified as very probable (3 AD, 1 DLB, 1 FTD), FDG-PET changed the diagnosis in only one and that was from DLB to cortico-basal degeneration. Twenty-seven patients were classified as having mild cognitive impairment at the time of assessment
Fig. 3. Frequency distribution of diagnostic certainty. The first three grey bars show the pre FDG-PET diagnostic confidence (possible, probable, or very probable); the first 3 black bars show the post FDGPET diagnostic confidence. The fourth grey and black bars show the number of patients with multiple differential diagnoses before and after the FDG-PET scan. Diagnostic confidence was greater and differential diagnoses decreased post FDG-PET. The Y-axis is the number of subjects. D, diagnosis, V Probable D, very probable diagnosis.
Table 1 Patient characteristics Male:Female Age MMSE
120 : 74 73 (±10.01); range 46–91 24.42 (±4.91); range 5–30
and FDG-PET showed evidence of neurodegenerative disease in 10 of these patients. The level of pre-scan diagnostic confidence (possible, probable, very probable) inversely correlated with the degree of management impact (Spearman’s rho = −0.258, p < 0.001). The improved diagnostic certainty was also reflected in the lower number of patients with multiple differential diagnoses after the scan compared to pre-scan. 127 patients had a differential diagnosis of more than one dementia type before the scan and this figure fell to 55 post scan (p = 0.003). Though total number of patients to be prescribed cholinesterase inhibitors (ChEIs) did not differ pre and post scan (74 versus 79; p = 0.48), the medication plan for 14 patients changed to not prescribing ChEIs while for 19 patients ChEIs was added to their management after the scan following a change in diagnoses and/or the level of diagnostic confidence. Therefore treatment was changed in 33 (17%) patients. DISCUSSION Many studies of FDG-PET in dementia have looked at its advantages as a diagnostic tool. However, with growing concern over the rising cost of diagnostic
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procedures, data that can guide development or refinement of appropriate use criteria is increasingly important. To the best of our knowledge this is the first prospective study that examined the management impact of FDG-PET alone in a pragmatic setting where the investigation was ordered at the discretion of the memory specialist. In this setting, the study found that FDG-PET had significant impact both in terms of dementia diagnosis and its treatment. The degree of management impact increased with level of diagnostic uncertainty and was greatest in those with milder degrees of cognitive impairment or dementia. Our findings are remarkably concordant with those reported from a retrospective management impact study of 94 Canadian patients who also had FDGPET after routine evaluation in a memory clinic [29]. The authors concluded that FDG-PET changed diagnosis in 29% of patients, led to earlier initiation of ChEI treatment, reduced uncertain diagnosis from 39% to 16% but contributed little to patients with typical clinical features of AD or frontotemporal dementia. Similarly, our prospective study found that FDG-PET changed diagnosis in 35%. It altered the use of ChEI medication in 17%, reduced uncertain diagnosis (i.e., possible diagnosis) from 30% to 18% while increasing diagnostic confidence to the very probable level from 3% to 22% of patients and that management impact was less in those with high pre-scan diagnostic confidence and in those with more advanced dementia. Of crucial importance is that in our study, FDG-PET changed a pre-scan diagnosis of dementia to a nonneurodegenerative diagnosis or vice versa in 20% of patients after a multidisciplinary specialist Memory Disorders clinic assessment. In a recent report from a quaternary referral center for patients with early onset dementia in the Netherlands, the impact of combined FDG-PET and amyloid PET imaging was reported on 154 patients [30]. The authors found that the diagnosis of dementia was changed in 23% of cases, and that this occurred more often when pre-PET diagnostic confidence was lower. Importantly, no change in diagnosis occurred in the 27 patients where pre PET diagnostic confidence was >90%. The impact of FDG-PET alone could not be determined from this study. These results suggest that the use of FDG-PET in patients with uncertain dementia diagnosis will deliver benefits to the patient. Appropriate initiation of treatment for AD with ChEIs has been shown to delay the cognitive decline and maintain functional level for 9–12 months [31, 32]. It is estimated that the cost of FDG-PET is less than one month of lost productivity and independence of a patient who does
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not receive timely diagnosis and treatment [10]. Conversely, avoidance of side effects from inappropriate medication use due to a wrong diagnosis of AD is also important. Gastrointestinal side effects are common and serious cardiac complications, though rare, can arise with ChEIs [32–34]. So a trial and error approach to their use when diagnosis is uncertain may not be justified. Accurate subtyping of dementia is of clinical importance to ensure appropriate use of medication and provide accurate prognostic information to the patient and their family. ChEI medications may exacerbate the behavioral features of FTLD and it is recommended they be avoided in this condition [35]. Antipsychotic medication is frequently used for the behavioral problems associated with dementia, but may have catastrophic effects in DLB and should be avoided in this condition [36]. Sensitivity and specificity of clinical diagnosis of DLB against pathological diagnosis remains a challenge [37, 38] with low sensitivity a particular problem. FDG-PET has good diagnostic accuracy for DLB [17]. In our study, FDG-PET changed the diagnosis of DLB in 23 patients with 18 patients with a pre-scan diagnosis reduced to 6 and 11 others given a post-scan diagnosis of DLB. Improved diagnostic confidence post PET should reduce further investigation, saving the patient and family from the inconvenience of more testing and saving the cost of more investigations. Prompt and accurate diagnosis can assist patients and their families to prepare for the major life decisions required as dementia progresses, when their cognitive functions are relatively preserved allowing the patient to have input into their future care plans. Delay in diagnosis of dementia is of concern to the general community and reducing this delay has been identified as an important goal [39]. Appropriate use criteria (AUC) have emerged as important tools to contain health care costs for diagnostic technology while maximizing patient benefit. Ideally, these AUC are based on management impact and patient outcome data. When this data is lacking, AUC are derived from evidence of diagnostic accuracy and expert opinion as to how improved diagnosis will most benefit patients. AUC for FDG-PET in dementia have been produced by the American College of Radiology [27] based on accuracy data. Our data indicates that AUC for FDG-PET in dementia should discourage use of this technology in patients with typical presentation for AD where a clinical diagnosis can be made with high confidence, and in those with more severe dementia. This study confirms that FDG-PET substantially alters management in patients where diagnostic
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uncertainty persists after expert evaluation and that the use of FDG-PET in this circumstance is appropriate. This recommendation is consistent with the recently published AUC for amyloid PET imaging for dementia from the joint Society of Nuclear Medicine and Alzheimer’s Association taskforce [40] that state that use of amyloid PET is most appropriate for patients with uncertain diagnosis after evaluation by a dementia specialist. The relative merits of amyloid PET and FDG-PET for the evaluation of dementia are beyond the scope of this study. Both provide unique information that may assist patient diagnosis and management impact studies are needed to define their relative role in patient evaluation. The study was designed to reflect clinical practice. The investigator who read the PET scan was not blind to the initial diagnosis or clinical history but this is usually the case when patients are referred for FDG-PET. A limitation of the study is the absence of confirmation of the PET diagnosis by neuropathological examination and the absence of clinical follow-up data. Consequently the benefits of the alterations in management by FDG-PET can only be inferred and are not proven. Although the study has implications for a patient referred from a specialist memory disorder clinic, its utility in other settings such as non-specialist evaluation is not clear from this study. While it is quite possible that change in diagnosis, diagnostic confidence and management would be greater in a nonspecialist setting, it is unknown if this would be more or less cost effective than initial specialist evaluation. In the absence of this data, expert opinion based appropriate use criteria recommend that PET follow evaluation of the patient by a memory disorder specialist as done in this study [27, 39].
The Victorian Government Department of Health and Human Services. Income from FDG-PET scans supports this Department. Authors’ disclosures available online (http:// www.j-alz.com/disclosures/view.php?id=2303).
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CONCLUSION FDG-PET has a moderate to high management impact in nearly half of the patients referred from a memory disorder clinic at the discretion of the treating specialist. The impact is greater in those patients whose dementia is at an early stage and where diagnosis is uncertain. These findings can be applied to refine the appropriate use criteria for FDG-PET in dementia. ACKNOWLEDGMENTS We thank the medical, nursing, and allied health staff of the Austin Health Memory Disorders Clinic for their assistance with this study. Funding Source:
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