Dement Geriatr Cogn Disord 2015;39:186–193 DOI: 10.1159/000369551 Received: October 13, 2014 Accepted: November 4, 2014 Published online: January 6, 2015
© 2015 S. Karger AG, Basel 1420–8008/14/0394–0186$39.50/0 www.karger.com/dem
Original Research Article
The Diagnostic Utility of 99mTc-HMPAO SPECT Imaging: A Retrospective Case Series from a Tertiary Referral Early-Onset Cognitive Disorders Clinic Amanda Swan a Shuna Colville b
Briony Waddell c Guy Holloway b, d Zubair Khan e Suvankar Pal b, c
Thomas Bak b
a College of Medicine and Veterinary Medicine, and b Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, c Division of Clinical Neurosciences, Western General Hospital, and Departments of d Old Age Psychiatry and e Nuclear Medicine, NHS Lothian, Edinburgh, UK
Key Words Early-onset dementia · SPECT imaging · Alzheimer’s disease · Structural imaging modalities Abstract Background/Aims: Patients with early-onset dementia (EOD) often present atypically, making an accurate diagnosis difficult. Single-photon emission-computed tomography (SPECT) provides an indirect measure of cerebral metabolic activity and can help to differentiate between dementia subtypes. This study aims to investigate the clinical utility of SPECT imaging in the diagnosis of early-onset Alzheimer’s disease. Methods: All patients attending a tertiary referral clinic specialising in EOD between April 2012 and October 2013 were included in the study. Statistical analysis of SPECT patterns with clinical diagnoses, Addenbrooke’s Cognitive Examination version 3 scores, and magnetic resonance imaging (MRI) atrophy was undertaken. Results: The results demonstrated a highly significant association between SPECT hypoperfusion patterns and clinical diagnoses. SPECT changes were demonstrated more frequently than MRI atrophy. Conclusions: The results suggest that SPECT imaging may be a useful adjunct to clinical evaluation and a more sensitive biomarker than standard structural imaging. © 2015 S. Karger AG, Basel
Introduction
Dr. Suvankar Pal Consultant Neurologist and NHS Scotland Research Fellow Anne Rowling Regenerative Neurology Clinic 49 Little France Crescent, Edinburgh EH16 4SB (UK) E-Mail suvankar.pal @ ed.ac.uk
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Early-onset dementia (EOD), defined as functionally impairing and progressive cognitive symptoms arising in adults aged 65 years or younger, incurs substantial personal, familial, caregiver, and societal burden [1]. The most common cause is early-onset Alzheimer’s disease
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(AD) [2]. Other aetiologies include frontotemporal dementia (FTD), vascular dementia (VaD), and dementia with Lewy bodies (DLB) as well as rarer degenerative syndromes such as progressive supranuclear palsy and corticobasal syndrome [3]. These disorders are diagnostically challenging, untreatable, progressive, and uniformly fatal [4]. There is substantial heterogeneity in the clinical presentation and imaging findings between dementia subtypes [5]. Furthermore, individuals with early-onset AD often present atypically with progressive deficits in visuospatial function or language, often more marked than typical amnestic presentations seen in older adults [6]. A timely diagnosis obviates prolonged uncertainty, unnecessary investigations, delays in the initiation of symptomatic treatments, and incorrect recruitment of poorly characterised patients into clinical trials [7, 8]. A definitive diagnosis may be achieved by histopathological examination of invasive brain biopsy or postmortem tissue, or by molecular genetic testing in a minority with an inherited dementia [9]. Clinical diagnostic criteria recently used for AD often fail to robustly differentiate accurately between AD and non-AD pathology, with up to 40% of the patients diagnosed with non-AD dementias identified as having pathology consistent with AD at postmortem in some series. Single-photon emission-computed tomography (SPECT) brain imaging provides a measure of the cerebral blood flow. 99mTc-hexamethylpropyleneamine oxime (99mTc-HMPAO, CeretecTM) is a small lipophilic compound which distributes in the brain to reflect the regional cerebral blood flow [10]. Specific regional and volumetric hypoperfusion patterns have been described for different types of dementia [11–13]. Brain perfusion is related to metabolic activity, and, therefore, SPECT offers an opportunity to examine cerebral activity [13, 14]. This functional imaging modality introduces an added dimension to structural neuroimaging techniques, such as computed tomography (CT) and magnetic resonance image (MRI), currently used in the routine clinical evaluation of patients with cognitive impairment. SPECT perfusion patterns may also act as a reliable biomarker predating atrophy identified using structural imaging modalities [15, 16], with characteristic patterns of hypoperfusion that differ between different dementia subtypes. Previous studies of SPECT imaging in dementia have included older adults and predominantly focused on discriminating AD patients from cognitively intact individuals [17]. Studies investigating the diagnostic utility of SPECT in differentiating AD from non-AD dementias in younger adults are limited, tending to be based on small numbers of patients, with evaluation of cognitive symptoms limited to Mini-Mental State Examination (MMSE) scores [18]. There is also little data on the additional diagnostic utility of SPECT compared to conventionally available structural neuroimaging techniques such as MRI. Aims The primary aim of this study was to investigate the diagnostic utility of 99mTc-HMPAO SPECT imaging in a tertiary referral cognitive disorders clinic specialising in the diagnosis of EOD. Specifically, our study aimed to determine the correlation between different dementia syndromes and hypoperfusion patterns on SPECT imaging and to investigate whether SPECT imaging provided additional clinical diagnostic support beyond that of routinely employed structural imaging.
Data Collection Consecutive patients attending the Anne Rowling Regenerative Neurology Cognitive Disorders Clinic at the University of Edinburgh over an 18-month period between April 2012 and October 2013 were retrospectively screened. The clinical phenotypic information and investigation results were extracted from the Edinburgh Cognitive Diagnosis Audit Research and Treatment (ECOG-DART) register.
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Methods
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Consecutive patients, in whom 99mTc- HMPAO SPECT imaging was undertaken as part of their diagnostic workup, were included for analysis. Patients were excluded if SPECT imaging was not performed, which was the case in patients where: (1) a clinical diagnosis of subjective memory symptoms was soundly made [with Addenbrooke’s Cognitive Examination (ACE) scores >90/100]; (2) a clear diagnosis of static cognitive impairment secondary to trauma or hypoxic brain injury was made; (3) cognitive impairment was thought to be secondary to significant alcohol excess or the effect of sedating drugs (psychotropics/analgesics); (4) features were consistent with extrapyramidal degenerative syndromes and 123I-FP-CIT (DaT) imaging was more appropriate than SPECT (e.g. Lewy body dementia, progressive supranuclear palsy, or multiple system atrophy); (5) clinical findings were consistent with HIV-associated cognitive impairment; (6) cognitive impairment was associated with systemic conditions such as epilepsy/anticonvulsant treatment/transient epileptic amnesia, hypoglycaemia/diabetes, hepatic failure, or systemic vasculitis; (7) features were consistent with genetic causes of cognitive impairment and in the presence of diagnostic genotyping (such as Huntington’s disease); (8) cognitive impairment occurred at an older age (>65 years), and where (9) further investigations were declined. Ethical approval for investigating the patients’ symptoms, cognitive profiles, clinical test results, and phenotypes was gained from the Scotland A Research Ethics Committee. Clinical Assessment The initial patient assessment was performed by a neurologist and an old-age psychiatrist and included a structured history and a neurological examination as well as the ACE version 3 (ACE-3). Clinical diagnoses were reached following this assessment using established diagnostic criteria including the NINCDS-ADRDA [19] and DSM-IV criteria for AD, the Lund-Manchester criteria for FTD [20, 21], the NINDS-AIREN criteria for VaD [22], and the McKeith International Consensus Consortium Criteria for DLB [23]. Imaging Analysis and Interpretation MRI structural imaging and 99mTc-HMPAO SPECT imaging were performed within 6 weeks of the initial assessment. One nuclear medicine physician and one nuclear medicine physicist assessed SPECT hypoperfusion by visual inspection blinded to clinical diagnosis. This method closely reflects routine clinical practice. 99m
Tc-HMPAO SPECT Images were acquired using a gamma camera GE Discovery NM/CT 670. The patients were placed in a darkened, quiet room for 20 min before 500 MBq of 99mTc-HMPAO was injected. The imaging was performed 2 h later with the patients lying in a supine position. The acquisition parameters were as follows: H-mode, zoom –1.5, matrix 128 × 128, 360° rotation, 3° increments, and 120 × 20 s frame time. Data were then reconstructed with OSEM reconstruction using 5 iterations and 10 subsets applying a Chang attenuation correction (threshold 5, coefficient 0.11). The images were visually inspected and reported by nuclear medicine physicians with expertise in dementia. The visual inspection involved an initial interpretation of the structural imaging, the evaluation of visually processed orthogonal images, followed by a comparison with normal healthy libraries. Hypoperfusion patterns were reported as ‘anterior’ (frontotemporal), ‘posterior’ (temporoparietal and occipital), or ‘mixed’.
Statistical Analyses Statistical analysis was conducted using SPSS (19.0). The correlation between SPECT imaging and clinical dementia diagnosis was analysed using Fisher’s exact test. The χ2 test was used to investigate for an association between the clinical diagnosis and the different patterns of hypoperfusion. One-way analysis of variance (ANOVA) with post hoc Bonferroni correction was used to determine differences in the ACE-3 total scores and sub-scores across the hypoperfusion groups. The McNemar test was employed to investigate for statistically significant differences between structural imaging and SPECT scan results. Independent t tests were used to determine differences between ACE-3 scores and structural imaging results. Acceptable levels of significance were set at p < 0.05.
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Structural Imaging The structural imaging of the brain was performed with MRI (sagittal T1 FLAIR volume, axial T2, sagittal cube FLAIR, coronal 3D volume, and T2 hippocampal sections) or CT if MRI was contraindicated. Radiologists with expertise in dementia imaging reviewed all images. The scans were graded as ‘normal’ or ‘abnormal’ (global atrophy, focal atrophy, or vascular change) and correlated with SPECT imaging findings.
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Results
Patient Characteristics A total of 224 patients were screened, of whom 104 (46.4%) met the inclusion criteria; 48 patients were male (46.2%) and 56 female (53.8%). The mean age was 61 years. One hundred patients were clinically diagnosed with dementia: 51 had AD diagnoses and 49 had non-AD diagnoses including behavioural variant FTD, primary progressive aphasia, mixed dementia (VaD and AD dementia syndromes), and VaD. The mean disease duration was 18 months (range 6 months to 4 years). The mean ACE-3 score of the AD group was 64.02 ± 17.38 (range 17–82) in the AD group and 70.59 ± 15.67 (range 9–82) in the non-AD group. 99mTc-HMPAO
SPECT Analysis Of the 104 SPECT scans conducted, 4 demonstrated normal perfusion. These patients met the clinical diagnostic criteria for dementia (mean ACE-3 score = 75.75 ± 15.92). The concordance of the presence of hypoperfusion on SPECT with a clinical diagnosis of dementia was 96.2%. 99mTc-HMPAO
SPECT Hypoperfusion Patterns Forty-two (40.4%) SPECT scans demonstrated posterior hypoperfusion, 19 (18.3%) anterior hypoperfusion, and 39 (37.5%) a mixed hypoperfusion pattern. The χ2 test found a highly significant association between hypoperfusion pattern and clinical diagnosis [χ2 (2, n = 96) = 18.08, p < 0.001]. This association was consistent across all types of dementia. Posterior hypoperfusion patterns were more likely to indicate a diagnosis of AD including posterior cortical atrophy. Anterior hypoperfusion patterns were more likely to indicate a non-AD diagnosis such as FTD (n = 22) (mean ACE-3 score = 67.68 ± 20.09). Mixed hypoperfusion patterns were more frequently associated with non-AD diagnoses including primary progressive aphasia (mean ACE-3 score = 71.72 ± 13.97). SPECT Hypoperfusion Patterns and ACE ACE was completed in 98 (94%) patients. One-way ANOVA with post hoc Bonferroni correction did not reveal a significant difference between total ACE-3 scores or sub-domain scores and the different hypoperfusion patterns identified on SPECT imaging. 99mTc-HMPAO
SPECT and MRI One hundred patients had structural imaging of the brain with MRI. MRI was not possible in 4 patients (for reasons including cardiac pacemaker insertion and claustrophobia). Of 100 MRI scans, 35 were interpreted as normal, and of these 32 (91.42%) were found to have an abnormal perfusion pattern on SPECT (p < 0.001). SPECT imaging was universally abnormal in those with atrophy on MRI. The presence of atrophy did not correlate with the severity of dementia (p > 0.05).
The differential diagnosis of EOD relies upon the clinical assessment supported by neuroimaging and neuropsychological evaluation. Clinical diagnostic criteria in recent use for AD [including iterations of the Diagnostic and Statistical Manual of Mental Disorders (DSM) and International Classification of Diseases (ICD)] provide either good diagnostic sensitivity at the expense of specificity or vice versa (pooled averages with 81% sensitivity and 70% specificity) when compared with postmortem data [24].
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Discussion
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The National Institute on Aging and the Alzheimer’s Association Workgroups have recently revised the NINCDS-ADRDA criteria for AD to incorporate biomarkers in an attempt to improve diagnostic accuracy [25]. A dynamic change in biomarker profiles during the evolution of AD progression has been postulated, with cerebral hypoperfusion predating regional atrophy changes on structural imaging and emergence of cognitive symptoms [26]. 99m Tc-HMPAO SPECT is a helpful neuroimaging diagnostic tool which could potentially be added to the current repertoire of diagnostic modalities to increase the accuracy of diagnostic assessments. Recently, published guidelines have suggested that SPECT can be used to differentiate between AD, VaD, FTD, and DLB in cases where diagnostic uncertainty exists [27, 28]. Individual studies evaluating the diagnostic utility of SPECT imaging, however, have differed in terms of sample size, patient characteristics, clinical diagnostic criteria employed, cognitive testing, and imaging acquisition [17, 29]. Studies to date have also focused on the diagnostic utility of SPECT in older adults with AD compared, predominantly, to cognitively unimpaired controls [30]. In those with EOD, symptoms often present differently than in older adults, with symptoms including aphasia, apraxia, agnosia, and visual disturbance rather than typical amnestic syndromes [31]. The pathology, sparing the hippocampi, may manifest with different HMPAO SPECT cerebral hypoperfusion patterns than those seen in later-onset AD. SPECT imaging provides a reflection of blood flow patterns in the brain. As cerebral perfusion is closely linked to cerebral metabolism, hypoperfusion patterns should parallel, if not predate, neuronal loss. By investigating cerebral perfusion patterns identified by 99mTcHMPAO SPECT imaging in our cohort, we were able to compare hypoperfusion patterns with the clinical diagnoses and establish that SPECT can successfully differentiate between earlyonset AD and non-AD diagnoses. Posterior hypoperfusion patterns were found to strongly correlate with AD diagnoses. The non-AD group, including primary progressive aphasia and corticobasal syndrome, was heterogenous with complex hypoperfusion patterns. A large number of patients with these syndromic diagnoses were unsurprisingly also found to have mixed (anterior and posterior) hypoperfusion patterns. SPECT appears to be of particular diagnostic value in differentiating AD from FTD and AD from normal controls. The Neary criteria or Lund-Manchester clinical criteria for FTD do not exclude disorders that may affect frontotemporal structures such as AD, and FTD patients will also usually meet the NINCDS-ADRDS criteria for AD; therefore, an additional diagnostic tool such as SPECT may be helpful to aid differentiating AD from FTD. Consistent with previous studies, SPECT imaging was also able to detect perfusion changes prior to the presence of cerebral atrophy on structural imaging. In our study, imaging was performed 6 weeks after clinical assessment. The duration from symptom onset to the time of clinical assessment ranged from 6 months to 4 years. Despite this wide range in the disease duration at the time of imaging, SPECT hypoperfusion patterns demonstrated a high degree of sensitivity compared to clinical diagnoses, suggesting it is a marker of early as well as more advanced disease. Longitudinal studies are necessary to investigate the change in the sensitivity of perfusion change over time. The clinical utility of sequential imaging has not been reported. Our results demonstrated a higher sensitivity than previously described for SPECT imaging in the diagnosis of AD. This higher value may reflect our cohort of selected patients with wellcharacterised symptoms established through a joint neurology and psychiatry assessment. The use of the ACE-3 also allowed a more robust characterisation of cognitive domains compared with the MMSE used in similar studies. Previous studies have also investigated cognitive symptoms in all age groups; younger adults are likely to have less mixed/ambiguous pathology, which may also have potentially impacted favourably on SPECT sensitivity. Another functional imaging modality widely employed is positron emission tomography (PET), where patterns of hypometabolism (reduced glucose uptake in FDG-PET) are used to
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differentiate between dementia syndromes. The development of specific tracers such for amyloid PET imaging in AD appears promising. A study investigating the use of FDG-PET compared to the pathological diagnosis of AD in clinically ambiguous cases was found to yield a sensitivity of 93% and a specificity of 63%. Two SPECT studies in patients with pathological diagnoses of AD reported sensitivities of 86 and 63%, and specificities of 73 and 93%, respectively [32, 33]. Ebmeier [34] concluded that SPECT and PET are equally sensitive in aiding the differential diagnosis of dementia in challenging cases, with SPECT having the additional benefit of being the less costly than PET [35]. The main structural imaging modality used in dementia is MRI. Differing patterns of atrophy can be attributed to the different dementia syndromes: AD = atrophy beginning in the entorhinal cortex and hippocampus, FTD = atrophy in the frontal lobe, and VaD = white matter ischaemia in the frontal white matter and lacunar infarcts [36]. The structural correlation can be used to improve the interpretation of functional imaging [18]. Both FTD and early-onset AD, for example, can demonstrate a predominantly anterior distribution of hypoperfusion on SPECT imaging. MRI-based high-dimensional pattern classification has shown an accuracy of 84% in differentiating AD from FTD [37]. Boutoleau-Bretonnière et al. [38] reported that MRI has a specificity of 88% in diagnosing AD in clinically ambiguous cases, and combined MRI and SPECT have an increased specificity of 93%. From a practical point of view, there may be contraindications to the use of MRI, such as the presence of metallic devices, claustrophobia, and poor tolerance of imaging in patients with cognitive impairment, in which case SPECT is particularly useful. In our study, atrophy on MRI was assessed by visual inspection reflecting interpretation as it occurs in routine clinical practice. There exist some quantification software packages for the measurement of atrophy. Few studies have reported the utility of quantitative imaging modalities in routine clinical practice; however, their use may add greater diagnostic sensitivity and improve inter- and intra-rater reliability. A further prospective evaluation of these methods would be helpful in future studies. Whilst our results are promising, there are a number of limitations to consider. Histopathological confirmation of clinical diagnoses is currently lacking; prospective studies with postmortem correlation are required before robust conclusions of the diagnostic utility of SPECT can be made. Further to this, imaging was assessed by single raters blinded to clinical diagnoses, reflecting routine clinical practice. Whilst good inter-observer agreeance has been proven using visual inspection of SPECT hypoperfusion patterns, this methodology is limited by its subjectivity and lack of reproducibility [39]. Given the subjectivity which may be inherent in the visual inspection of SPECT hypoperfusion, future studies may benefit from the assessment of scans by different radiologists, therefore enabling further assessment of the inter- and intra-rater reliability. Quantitative image analysis might also feasibly increase the diagnostic accuracy. In particular, more detailed analysis investigating specific anatomical regions of interest implicated in degenerative dementias using voxel analysis may yield an increased sensitivity in distinguishing between different dementia syndromes [40, 41]. The ability to robustly differentiate between dementia syndromes is crucial in enabling the diagnosis and management of patients with cognitive impairment. Challenges in the diagnosis of patients presenting with cognitive symptoms under the age of 65 years using current clinical guidelines reinforce the need for sensitive and specific biomarkers. Results from this study suggest that 99mTc-HMPAO SPECT imaging is a useful adjunct in the diagnosis of those with dementia syndromes and that earlier supportive changes are seen on SPECT prior to their detection on conventional structural imaging. However, before recommending the routine use of SPECT in the diagnostic workup of patients with EOD, longitudinal prospective studies with ideally histopathological disease confirmation are required.
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Acknowledgements S.P. is funded by a fellowship from NHS Research Scotland.
Disclosure Statement The authors have no conflicts of interest to declare.
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Original Research Article
The Diagnostic Utility of 99mTc-HMPAO SPECT Imaging: A Retrospective Case Series from a Tertiary Referral Early-Onset Cognitive Disorders Clinic Amanda Swan a Shuna Colville b
Briony Waddell c Guy Holloway b, d Zubair Khan e Suvankar Pal b, c
Thomas Bak b
a College of Medicine and Veterinary Medicine, and b Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, c Division of Clinical Neurosciences, Western General Hospital, and Departments of d Old Age Psychiatry and e Nuclear Medicine, NHS Lothian, Edinburgh, UK
Key Words Early-onset dementia · SPECT imaging · Alzheimer’s disease · Structural imaging modalities Abstract Background/Aims: Patients with early-onset dementia (EOD) often present atypically, making an accurate diagnosis difficult. Single-photon emission-computed tomography (SPECT) provides an indirect measure of cerebral metabolic activity and can help to differentiate between dementia subtypes. This study aims to investigate the clinical utility of SPECT imaging in the diagnosis of early-onset Alzheimer’s disease. Methods: All patients attending a tertiary referral clinic specialising in EOD between April 2012 and October 2013 were included in the study. Statistical analysis of SPECT patterns with clinical diagnoses, Addenbrooke’s Cognitive Examination version 3 scores, and magnetic resonance imaging (MRI) atrophy was undertaken. Results: The results demonstrated a highly significant association between SPECT hypoperfusion patterns and clinical diagnoses. SPECT changes were demonstrated more frequently than MRI atrophy. Conclusions: The results suggest that SPECT imaging may be a useful adjunct to clinical evaluation and a more sensitive biomarker than standard structural imaging. © 2015 S. Karger AG, Basel
Introduction
Dr. Suvankar Pal Consultant Neurologist and NHS Scotland Research Fellow Anne Rowling Regenerative Neurology Clinic 49 Little France Crescent, Edinburgh EH16 4SB (UK) E-Mail suvankar.pal @ ed.ac.uk
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Early-onset dementia (EOD), defined as functionally impairing and progressive cognitive symptoms arising in adults aged 65 years or younger, incurs substantial personal, familial, caregiver, and societal burden [1]. The most common cause is early-onset Alzheimer’s disease
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(AD) [2]. Other aetiologies include frontotemporal dementia (FTD), vascular dementia (VaD), and dementia with Lewy bodies (DLB) as well as rarer degenerative syndromes such as progressive supranuclear palsy and corticobasal syndrome [3]. These disorders are diagnostically challenging, untreatable, progressive, and uniformly fatal [4]. There is substantial heterogeneity in the clinical presentation and imaging findings between dementia subtypes [5]. Furthermore, individuals with early-onset AD often present atypically with progressive deficits in visuospatial function or language, often more marked than typical amnestic presentations seen in older adults [6]. A timely diagnosis obviates prolonged uncertainty, unnecessary investigations, delays in the initiation of symptomatic treatments, and incorrect recruitment of poorly characterised patients into clinical trials [7, 8]. A definitive diagnosis may be achieved by histopathological examination of invasive brain biopsy or postmortem tissue, or by molecular genetic testing in a minority with an inherited dementia [9]. Clinical diagnostic criteria recently used for AD often fail to robustly differentiate accurately between AD and non-AD pathology, with up to 40% of the patients diagnosed with non-AD dementias identified as having pathology consistent with AD at postmortem in some series. Single-photon emission-computed tomography (SPECT) brain imaging provides a measure of the cerebral blood flow. 99mTc-hexamethylpropyleneamine oxime (99mTc-HMPAO, CeretecTM) is a small lipophilic compound which distributes in the brain to reflect the regional cerebral blood flow [10]. Specific regional and volumetric hypoperfusion patterns have been described for different types of dementia [11–13]. Brain perfusion is related to metabolic activity, and, therefore, SPECT offers an opportunity to examine cerebral activity [13, 14]. This functional imaging modality introduces an added dimension to structural neuroimaging techniques, such as computed tomography (CT) and magnetic resonance image (MRI), currently used in the routine clinical evaluation of patients with cognitive impairment. SPECT perfusion patterns may also act as a reliable biomarker predating atrophy identified using structural imaging modalities [15, 16], with characteristic patterns of hypoperfusion that differ between different dementia subtypes. Previous studies of SPECT imaging in dementia have included older adults and predominantly focused on discriminating AD patients from cognitively intact individuals [17]. Studies investigating the diagnostic utility of SPECT in differentiating AD from non-AD dementias in younger adults are limited, tending to be based on small numbers of patients, with evaluation of cognitive symptoms limited to Mini-Mental State Examination (MMSE) scores [18]. There is also little data on the additional diagnostic utility of SPECT compared to conventionally available structural neuroimaging techniques such as MRI. Aims The primary aim of this study was to investigate the diagnostic utility of 99mTc-HMPAO SPECT imaging in a tertiary referral cognitive disorders clinic specialising in the diagnosis of EOD. Specifically, our study aimed to determine the correlation between different dementia syndromes and hypoperfusion patterns on SPECT imaging and to investigate whether SPECT imaging provided additional clinical diagnostic support beyond that of routinely employed structural imaging.
Data Collection Consecutive patients attending the Anne Rowling Regenerative Neurology Cognitive Disorders Clinic at the University of Edinburgh over an 18-month period between April 2012 and October 2013 were retrospectively screened. The clinical phenotypic information and investigation results were extracted from the Edinburgh Cognitive Diagnosis Audit Research and Treatment (ECOG-DART) register.
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Methods
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Consecutive patients, in whom 99mTc- HMPAO SPECT imaging was undertaken as part of their diagnostic workup, were included for analysis. Patients were excluded if SPECT imaging was not performed, which was the case in patients where: (1) a clinical diagnosis of subjective memory symptoms was soundly made [with Addenbrooke’s Cognitive Examination (ACE) scores >90/100]; (2) a clear diagnosis of static cognitive impairment secondary to trauma or hypoxic brain injury was made; (3) cognitive impairment was thought to be secondary to significant alcohol excess or the effect of sedating drugs (psychotropics/analgesics); (4) features were consistent with extrapyramidal degenerative syndromes and 123I-FP-CIT (DaT) imaging was more appropriate than SPECT (e.g. Lewy body dementia, progressive supranuclear palsy, or multiple system atrophy); (5) clinical findings were consistent with HIV-associated cognitive impairment; (6) cognitive impairment was associated with systemic conditions such as epilepsy/anticonvulsant treatment/transient epileptic amnesia, hypoglycaemia/diabetes, hepatic failure, or systemic vasculitis; (7) features were consistent with genetic causes of cognitive impairment and in the presence of diagnostic genotyping (such as Huntington’s disease); (8) cognitive impairment occurred at an older age (>65 years), and where (9) further investigations were declined. Ethical approval for investigating the patients’ symptoms, cognitive profiles, clinical test results, and phenotypes was gained from the Scotland A Research Ethics Committee. Clinical Assessment The initial patient assessment was performed by a neurologist and an old-age psychiatrist and included a structured history and a neurological examination as well as the ACE version 3 (ACE-3). Clinical diagnoses were reached following this assessment using established diagnostic criteria including the NINCDS-ADRDA [19] and DSM-IV criteria for AD, the Lund-Manchester criteria for FTD [20, 21], the NINDS-AIREN criteria for VaD [22], and the McKeith International Consensus Consortium Criteria for DLB [23]. Imaging Analysis and Interpretation MRI structural imaging and 99mTc-HMPAO SPECT imaging were performed within 6 weeks of the initial assessment. One nuclear medicine physician and one nuclear medicine physicist assessed SPECT hypoperfusion by visual inspection blinded to clinical diagnosis. This method closely reflects routine clinical practice. 99m
Tc-HMPAO SPECT Images were acquired using a gamma camera GE Discovery NM/CT 670. The patients were placed in a darkened, quiet room for 20 min before 500 MBq of 99mTc-HMPAO was injected. The imaging was performed 2 h later with the patients lying in a supine position. The acquisition parameters were as follows: H-mode, zoom –1.5, matrix 128 × 128, 360° rotation, 3° increments, and 120 × 20 s frame time. Data were then reconstructed with OSEM reconstruction using 5 iterations and 10 subsets applying a Chang attenuation correction (threshold 5, coefficient 0.11). The images were visually inspected and reported by nuclear medicine physicians with expertise in dementia. The visual inspection involved an initial interpretation of the structural imaging, the evaluation of visually processed orthogonal images, followed by a comparison with normal healthy libraries. Hypoperfusion patterns were reported as ‘anterior’ (frontotemporal), ‘posterior’ (temporoparietal and occipital), or ‘mixed’.
Statistical Analyses Statistical analysis was conducted using SPSS (19.0). The correlation between SPECT imaging and clinical dementia diagnosis was analysed using Fisher’s exact test. The χ2 test was used to investigate for an association between the clinical diagnosis and the different patterns of hypoperfusion. One-way analysis of variance (ANOVA) with post hoc Bonferroni correction was used to determine differences in the ACE-3 total scores and sub-scores across the hypoperfusion groups. The McNemar test was employed to investigate for statistically significant differences between structural imaging and SPECT scan results. Independent t tests were used to determine differences between ACE-3 scores and structural imaging results. Acceptable levels of significance were set at p < 0.05.
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Structural Imaging The structural imaging of the brain was performed with MRI (sagittal T1 FLAIR volume, axial T2, sagittal cube FLAIR, coronal 3D volume, and T2 hippocampal sections) or CT if MRI was contraindicated. Radiologists with expertise in dementia imaging reviewed all images. The scans were graded as ‘normal’ or ‘abnormal’ (global atrophy, focal atrophy, or vascular change) and correlated with SPECT imaging findings.
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Results
Patient Characteristics A total of 224 patients were screened, of whom 104 (46.4%) met the inclusion criteria; 48 patients were male (46.2%) and 56 female (53.8%). The mean age was 61 years. One hundred patients were clinically diagnosed with dementia: 51 had AD diagnoses and 49 had non-AD diagnoses including behavioural variant FTD, primary progressive aphasia, mixed dementia (VaD and AD dementia syndromes), and VaD. The mean disease duration was 18 months (range 6 months to 4 years). The mean ACE-3 score of the AD group was 64.02 ± 17.38 (range 17–82) in the AD group and 70.59 ± 15.67 (range 9–82) in the non-AD group. 99mTc-HMPAO
SPECT Analysis Of the 104 SPECT scans conducted, 4 demonstrated normal perfusion. These patients met the clinical diagnostic criteria for dementia (mean ACE-3 score = 75.75 ± 15.92). The concordance of the presence of hypoperfusion on SPECT with a clinical diagnosis of dementia was 96.2%. 99mTc-HMPAO
SPECT Hypoperfusion Patterns Forty-two (40.4%) SPECT scans demonstrated posterior hypoperfusion, 19 (18.3%) anterior hypoperfusion, and 39 (37.5%) a mixed hypoperfusion pattern. The χ2 test found a highly significant association between hypoperfusion pattern and clinical diagnosis [χ2 (2, n = 96) = 18.08, p < 0.001]. This association was consistent across all types of dementia. Posterior hypoperfusion patterns were more likely to indicate a diagnosis of AD including posterior cortical atrophy. Anterior hypoperfusion patterns were more likely to indicate a non-AD diagnosis such as FTD (n = 22) (mean ACE-3 score = 67.68 ± 20.09). Mixed hypoperfusion patterns were more frequently associated with non-AD diagnoses including primary progressive aphasia (mean ACE-3 score = 71.72 ± 13.97). SPECT Hypoperfusion Patterns and ACE ACE was completed in 98 (94%) patients. One-way ANOVA with post hoc Bonferroni correction did not reveal a significant difference between total ACE-3 scores or sub-domain scores and the different hypoperfusion patterns identified on SPECT imaging. 99mTc-HMPAO
SPECT and MRI One hundred patients had structural imaging of the brain with MRI. MRI was not possible in 4 patients (for reasons including cardiac pacemaker insertion and claustrophobia). Of 100 MRI scans, 35 were interpreted as normal, and of these 32 (91.42%) were found to have an abnormal perfusion pattern on SPECT (p < 0.001). SPECT imaging was universally abnormal in those with atrophy on MRI. The presence of atrophy did not correlate with the severity of dementia (p > 0.05).
The differential diagnosis of EOD relies upon the clinical assessment supported by neuroimaging and neuropsychological evaluation. Clinical diagnostic criteria in recent use for AD [including iterations of the Diagnostic and Statistical Manual of Mental Disorders (DSM) and International Classification of Diseases (ICD)] provide either good diagnostic sensitivity at the expense of specificity or vice versa (pooled averages with 81% sensitivity and 70% specificity) when compared with postmortem data [24].
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Discussion
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The National Institute on Aging and the Alzheimer’s Association Workgroups have recently revised the NINCDS-ADRDA criteria for AD to incorporate biomarkers in an attempt to improve diagnostic accuracy [25]. A dynamic change in biomarker profiles during the evolution of AD progression has been postulated, with cerebral hypoperfusion predating regional atrophy changes on structural imaging and emergence of cognitive symptoms [26]. 99m Tc-HMPAO SPECT is a helpful neuroimaging diagnostic tool which could potentially be added to the current repertoire of diagnostic modalities to increase the accuracy of diagnostic assessments. Recently, published guidelines have suggested that SPECT can be used to differentiate between AD, VaD, FTD, and DLB in cases where diagnostic uncertainty exists [27, 28]. Individual studies evaluating the diagnostic utility of SPECT imaging, however, have differed in terms of sample size, patient characteristics, clinical diagnostic criteria employed, cognitive testing, and imaging acquisition [17, 29]. Studies to date have also focused on the diagnostic utility of SPECT in older adults with AD compared, predominantly, to cognitively unimpaired controls [30]. In those with EOD, symptoms often present differently than in older adults, with symptoms including aphasia, apraxia, agnosia, and visual disturbance rather than typical amnestic syndromes [31]. The pathology, sparing the hippocampi, may manifest with different HMPAO SPECT cerebral hypoperfusion patterns than those seen in later-onset AD. SPECT imaging provides a reflection of blood flow patterns in the brain. As cerebral perfusion is closely linked to cerebral metabolism, hypoperfusion patterns should parallel, if not predate, neuronal loss. By investigating cerebral perfusion patterns identified by 99mTcHMPAO SPECT imaging in our cohort, we were able to compare hypoperfusion patterns with the clinical diagnoses and establish that SPECT can successfully differentiate between earlyonset AD and non-AD diagnoses. Posterior hypoperfusion patterns were found to strongly correlate with AD diagnoses. The non-AD group, including primary progressive aphasia and corticobasal syndrome, was heterogenous with complex hypoperfusion patterns. A large number of patients with these syndromic diagnoses were unsurprisingly also found to have mixed (anterior and posterior) hypoperfusion patterns. SPECT appears to be of particular diagnostic value in differentiating AD from FTD and AD from normal controls. The Neary criteria or Lund-Manchester clinical criteria for FTD do not exclude disorders that may affect frontotemporal structures such as AD, and FTD patients will also usually meet the NINCDS-ADRDS criteria for AD; therefore, an additional diagnostic tool such as SPECT may be helpful to aid differentiating AD from FTD. Consistent with previous studies, SPECT imaging was also able to detect perfusion changes prior to the presence of cerebral atrophy on structural imaging. In our study, imaging was performed 6 weeks after clinical assessment. The duration from symptom onset to the time of clinical assessment ranged from 6 months to 4 years. Despite this wide range in the disease duration at the time of imaging, SPECT hypoperfusion patterns demonstrated a high degree of sensitivity compared to clinical diagnoses, suggesting it is a marker of early as well as more advanced disease. Longitudinal studies are necessary to investigate the change in the sensitivity of perfusion change over time. The clinical utility of sequential imaging has not been reported. Our results demonstrated a higher sensitivity than previously described for SPECT imaging in the diagnosis of AD. This higher value may reflect our cohort of selected patients with wellcharacterised symptoms established through a joint neurology and psychiatry assessment. The use of the ACE-3 also allowed a more robust characterisation of cognitive domains compared with the MMSE used in similar studies. Previous studies have also investigated cognitive symptoms in all age groups; younger adults are likely to have less mixed/ambiguous pathology, which may also have potentially impacted favourably on SPECT sensitivity. Another functional imaging modality widely employed is positron emission tomography (PET), where patterns of hypometabolism (reduced glucose uptake in FDG-PET) are used to
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differentiate between dementia syndromes. The development of specific tracers such for amyloid PET imaging in AD appears promising. A study investigating the use of FDG-PET compared to the pathological diagnosis of AD in clinically ambiguous cases was found to yield a sensitivity of 93% and a specificity of 63%. Two SPECT studies in patients with pathological diagnoses of AD reported sensitivities of 86 and 63%, and specificities of 73 and 93%, respectively [32, 33]. Ebmeier [34] concluded that SPECT and PET are equally sensitive in aiding the differential diagnosis of dementia in challenging cases, with SPECT having the additional benefit of being the less costly than PET [35]. The main structural imaging modality used in dementia is MRI. Differing patterns of atrophy can be attributed to the different dementia syndromes: AD = atrophy beginning in the entorhinal cortex and hippocampus, FTD = atrophy in the frontal lobe, and VaD = white matter ischaemia in the frontal white matter and lacunar infarcts [36]. The structural correlation can be used to improve the interpretation of functional imaging [18]. Both FTD and early-onset AD, for example, can demonstrate a predominantly anterior distribution of hypoperfusion on SPECT imaging. MRI-based high-dimensional pattern classification has shown an accuracy of 84% in differentiating AD from FTD [37]. Boutoleau-Bretonnière et al. [38] reported that MRI has a specificity of 88% in diagnosing AD in clinically ambiguous cases, and combined MRI and SPECT have an increased specificity of 93%. From a practical point of view, there may be contraindications to the use of MRI, such as the presence of metallic devices, claustrophobia, and poor tolerance of imaging in patients with cognitive impairment, in which case SPECT is particularly useful. In our study, atrophy on MRI was assessed by visual inspection reflecting interpretation as it occurs in routine clinical practice. There exist some quantification software packages for the measurement of atrophy. Few studies have reported the utility of quantitative imaging modalities in routine clinical practice; however, their use may add greater diagnostic sensitivity and improve inter- and intra-rater reliability. A further prospective evaluation of these methods would be helpful in future studies. Whilst our results are promising, there are a number of limitations to consider. Histopathological confirmation of clinical diagnoses is currently lacking; prospective studies with postmortem correlation are required before robust conclusions of the diagnostic utility of SPECT can be made. Further to this, imaging was assessed by single raters blinded to clinical diagnoses, reflecting routine clinical practice. Whilst good inter-observer agreeance has been proven using visual inspection of SPECT hypoperfusion patterns, this methodology is limited by its subjectivity and lack of reproducibility [39]. Given the subjectivity which may be inherent in the visual inspection of SPECT hypoperfusion, future studies may benefit from the assessment of scans by different radiologists, therefore enabling further assessment of the inter- and intra-rater reliability. Quantitative image analysis might also feasibly increase the diagnostic accuracy. In particular, more detailed analysis investigating specific anatomical regions of interest implicated in degenerative dementias using voxel analysis may yield an increased sensitivity in distinguishing between different dementia syndromes [40, 41]. The ability to robustly differentiate between dementia syndromes is crucial in enabling the diagnosis and management of patients with cognitive impairment. Challenges in the diagnosis of patients presenting with cognitive symptoms under the age of 65 years using current clinical guidelines reinforce the need for sensitive and specific biomarkers. Results from this study suggest that 99mTc-HMPAO SPECT imaging is a useful adjunct in the diagnosis of those with dementia syndromes and that earlier supportive changes are seen on SPECT prior to their detection on conventional structural imaging. However, before recommending the routine use of SPECT in the diagnostic workup of patients with EOD, longitudinal prospective studies with ideally histopathological disease confirmation are required.
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Acknowledgements S.P. is funded by a fellowship from NHS Research Scotland.
Disclosure Statement The authors have no conflicts of interest to declare.
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