The Evaluation of the Perfusion Pattern of SPET with 99Mtc-HMPAO in the Diagnosis of Alzheimer

The Evaluation of the Perfusion Pattern of SPET With 99mTc-HMPAO in the Diagnosis of Alzheimer’s Disease

SEDAGHAT FERESHTEH1, COSTA VASSILIKI2, GOTZAMANI-PSARRAKOU ANNA3, DEDOUSI ELENI1, DIMITRIADIS ATHANASIOS4, PSARRAKOS KYRIAKOS3, BALOYANNIS STAVROS2

1Department of Nuclear Medicine, AHEPA University Hospital, S. Kiriakidi 1, 54636 Thessaloniki- GREECE 21th Department of Neurology, Memory Unit, AHEPA University Hospital, S. Kiriakidi 1, 54636 Thessaloniki-GREECE 3Department of Medical Physics, AHEPA University Hospital, S. Kiriakidi 1, 54636 Thessaloniki-GREECE 4Department of Radiology of AHEPA University Hospital, S. Kiriakidi 1, 54636 Thessaloniki-GREECE

Abstract: - Reduction in regional cerebral blood flow (rCBF) in SPET, particularly in temporo-parietal region, is well established in patients suffered from Alzheimer’s disease (AD). The aim of this study is the evaluation of the perfusion pattern of SPET in the patients with probably Alzheimer’s disease (pAD) referred to us. Patients and methods: 40 subjects were selected among patients consecutively investigated for suspected dementia at the first memory clinic of AHEPA hospital of Thessaloniki for 2 years and were divided in two groups A and B. 33 patients with probable AD in group A, and the other group contained 7 patients: one male without dementia but with a positive family history of AD, and 4 patients with other diagnosis. Each patient was injected with 555 MBq 99mTc-HMPAO (Ceretec- Amersham). The gold standard of diagnosis, was the follow-up-based diagnosis. Results: In the group A the patients based on NINDS-ADRDA criteria and SPET were diagnosed as described in following subgroups: a) strongly suggestive of AD(ssAD): 16 scans demonstrated bilateral temporoparietal hypoperfusion (BTPH). Fifteen of these patients showed to be AD after one year follow up( accuracy 94%) and one of them suffered from brain atrophy. b) suggestive of AD (sAD): from 8 scans demonstrating bilateral temporal hypoperfusion (BTH), 5 of them were diagnosed as AD after one year follow up. One scan showed left temporoparietal deficit (unilateral temporoparietal hypoperfusion) (UTPH) that showed to suffer from AD, these patterns were interpreted as suggestive of AD (sAD) and had the accuracy of 66%. c)Vascular dementia (VD): one case had the evidence of VD d) Mixed dementia (Mix): One patient showed evidence of (VD) and AD (Mix). e) multinfarct dementia (MID) with 3 patients. f) frontotemporal dementia (FTD): 2 scans demonstrated bilateral frontotemporal hypoperfusion (BFTH) that showed to suffer from frontotemporal dementia (FTD) and g) Atrophic brain (AT): one scan with global perfusion reduction showed to be brain atrophy. The sensitivity of the perfusion pattern of SPET in the cases of ssAD was 71% with the specificity of 89%. It is notable that all the patients with the diagnosis of AD, including the non-demented patient, in the group B with a positive history family, had left temporal hypoperfusion. Also in five patients with ssAD and the diagnosis of AD, left occipital cortex had perfusion defect too. Conclusion: The perfusion pattern of SPET in the cases of ssAD and sAD together in the diagnosis of AD have a high sensitivity (100%) but rather low specificity. Since the presence of false positive cases was in the sAD subgroup (BTH) that reduced our specificity, it seems we should change this parameter or find another diagnostic test, with high specificity, to accompany SPET. In this way we will be more successful in early diagnosis of AD. Brain SPET may be a crucial aid in the differentiating of dementias, making therapeutic decisions specially by differentiating AD from MID.

Key-words: - SPET, Alzheimer’s disease, perfusion pattern, dementia, temporoparietal hypoperfusion 1 Introduction flow (rCBF), and metabolism reduction in AD AD accounts for about 70% of all cases of compared with control subjects[13-17]. dementia in the elderly and places enormous The aim of this prospective study is the evaluation burdens on the patient, on the family and on of SPET, and it’s perfusion patterns in the society. A definitive diagnosis of AD requires diagnosis of AD in patients referred to us. biopsy (rarely done) or autopsy confirmation, and pathophysiologically is characterized by dense and neuritic amyloid plaques, intraneuronal 2 Patients and methods neurofibrillary tangles, neuronal and synaptic loss 40 subjects were selected among patients and deficits in neurotransmitter functions[1-4]. consecutively investigated for suspected dementia Special anatomic and functional features make at the first memory clinic of AHEPA hospital of the brain a unique organ, substantially different Thessaloniki for 21/2 years and were divided in from the other organs of the human body. Most of two groups A and B. 33 patients with probable these differences are encountered within the AD (fulfilled NINCDS-ADRDA criteria) (age circulatory system, particularly in the regulation range 56-83 yr., 21 female ,12 male) were of perfusion and metabolism. In most conditions, included in group A, and the other group adequate oxygen and glucose are provided to each contained 7 patients (age range 57-82 yr.): one cerebral region according to its metabolic need, male without dementia but with a positive family which is determined by physiologic neuronal history of AD, and 4 patients with other diagnosis. activity. Hence, CBF is coupled to neuronal The CT scan and SPET examinations were from activity[5-8]. routine exams included in the dementia Single photon emission tomography (SPET) investigation. 30 healthy control subjects were imaging of the brain provides useful functional included in the study. 27 of them were selected information of cerebral blood flow. This from groups of control subjects used in other information is often complementary to the studies that were undertaken SPET at the same anatomic detail provided by structural Nuclear Medicine Department [18]. neuroimaging techniques such as CT or MRI. As Each patient was injected with 555 MBq (15mci) functional impairment in cerebral diseases often 99mTc-HMPAO (hexamethylpropyleneamine precedes structural changes and also, functional oxime, Ceretec- Amersham) in a quiet and bright abnormalities can be present in several neurologic room in the Nuclear Medicine Department of and psychiatric disorders without the presence of AHEPA hospital with patient eyes opened. Each a structural defect, so SPET plays an important one had an iv line at least 15 minutes before the role in diagnosis of such disorders. Today the injection of the agent. most widely used radiopharmaceuticals for rCBF Tomography was started within 45 min after SPET are 99mTc-labelled compounds. After injection of the tracer. The patient was in a supine intravenous injection, these lipophilic compounds position with his head stabled with a special belt. cross the intact blood brain barrier, distribute in Images were acquired using a single headed the brain proportional to local blood flow and are ADAC gamma camera equipped with a low retained in the brain with a fixed regional energy high resolution (LEHR) collimator. The distribution for a sufficient time period to permit total acquisition took 30 minutes and consisted of image acquisition. The peak brain activity is 120 projections aquired for 15 seconds into a 64  reached within 2 min post-injection. Since there is 64 acquisition matrix. The images were processed no redistribution, the initial tracer uptake and on a Sun Pegasys computer and were distribution remain almost unchanged for several reconstructed with Butterworth filter back hours and are independent of rCBF variations projection. Slices were generated parallel to the occurring after the fixation time[9-12]. orbitomeatal line. A number of studies using SPET and positron The attenuation correction and reorientation were emission tomography (PET), have established a done on reconstructed brain images. The images bilateral temporoparietal regional cerebral blood were visually evaluated and then the region of interest (ROI) with the size of 4  4 pixels was used to measure the mean count accounting for who suffered from frontotemporal dementia based blood flow (rCBF) in the following regions: right on behavioral changes in follow up. g) Atrophic and left frontal(RF,LF), right medial and lateral brain (At): one scan with global perfusion temporal (RTm, RTl), left medial and lateral reduction showed to be brain atrophy (table1). temporal(LTm, LTl), right and left parietal Figure1 shows transaxial slices of a normal scan, (RP,LP), right and left occipital (RO, LO) and BTPH in AD, MID, BFTH in FTD patient , and cerebellum (CER) in transaxial and coronal slices. global hypoperfusion . Based on visually evaluation, if needed, the ROI Six patients in group A had a positive family was done in every other region of the brain too. history. Patients with a mini mental state exam The coronal slices were used to study the (MMSE) score of 0-11, 12-20 and 21-28 were temporal lobes. Semiquantitative rCBF analysis categorized as having severe, moderate and mild using cortex to cerebellum ratio was done. There AD, respectively. The prevalence of AD by age was no patient with cerebellar disease. The group and MMSE score group are demonstrated control group was used to set the mean and SD of in the diagrams 1 and 2. the semiquantitative analysis for each brain Group B consisted of: one non-demented region. The semiquantitative analysis is not patient with a positive history family that had left applied to this study, as this study aimed to show temporal lobe hypoperfusion. A patient with a practically what happens in clinical use of SPET. history of chronic lung disease and dementia who The patients were followed up every 3 months at had evidence of multinfarct changes in SPET. the memory clinic. Since in no cases, biopsy or One patient with white matter and periventricular autopsy was performed, follow-up of patients for lesions in MRI, low B12 level and with right at least one year was our gold standard of temporal lobe hypoperfusion in SPET that was diagnosis. hospitalized for further investigation. It is suspected to have dementia due to B12 deficiency. From 2 patients with coronary artery disease, who 3 Results had undertaken bypass surgery, one showed From 33 patients in the group A with a mixed type of dementia in SPET and the other had primary clinical diagnosis (NINDS-ADRDA MID. Another patient with Parkinson’s disease criteria) of pAD, 21 of them showed to have AD and dementia, had bilateral temporal and frontal based on follow-up (clinical diagnosis accuracy hypoperfusion in SPET, and a hypothyroid patient was 64%). These patients based on clinical had normal SPET that will be followed up. None diagnosis and SPET images were diagnosed as of these patients had BTPH. (table 2). following subgroups: a) SSAD: 16 of these It is notable that all the patients with the patients demonstrated BTPH, a pattern strongly diagnosis of AD, including the non-demented suggestive of AD. Fifteen of these patients subject but with positive family history of AD showed to be AD after one year follow showed hypoperfusion in left temporal region. up( primary clinical diagnosis + SPET accuracy There was a high negative predictive value for 94%) and one of them suffered from brain normal SPET scan since there was no patient with atrophy. b) SAD: 8 patients showed (BTH). 5 of the diagnosis of AD and normal SPET. Also no them showed to suffer from AD and three of them AD was found in patients with images that are had vascular dementia (VD) based on follow up. typical of MID, and no patients in group B had one showed (UTPH) that showed to be AD. these BTPH. patterns can be suggestive of AD . c) VD: one The CT scans of the patients were normal or patient with infarct changes and ischemic showed mild atrophy or ventricular widening changes on CT scan too that showed to suffer (except in one patient with ischemic changes) that from vascular dementia based on one year follow can not account for the perfusion abnormalities up. d) Mix: one patient showed evidence of VD seen on brain SPET. and AD. e) MID: three subjects showed evidence of multinfarct dementia, confirmed by one year follow up. f) FTD: two patients showed (BFTH) 4 Discussion The role of SPET in dementia for clinical Parkinson’s disease (PD) and hypoperfusion can diagnosis, follow-up, and research objectives has mimic AD( temporo-parietal deficit), however the been well described in literature and different defects are more prominent and extensive in sensitivities and specificities for bilateral AD[3]. With knowledge of the clinical diagnosis, temporoparietal reduction are reported[19-22,10]. the hypoperfusion in the patient with PD in group Bergman et al (1997)has reported a sensitivity of B, can be due to PD alone or coexisting with AD. 55% [23]. Testa et al (1988) has found sensitivity So we see that the SPET couldn’t specify the and specificity of 65% and 94% respectively [24]. perfusion changes in this patient but helped us to The sensitivity of 96% and specificity of 89% is exclude cortical infarct changes. reported in another study for temporoparietal reduction[25]. In our study, the sensitivity of the perfusion 5 Conclusion pattern of SPET in the cases of ssAD was 71% The perfusion pattern of SPET in the cases of with the specificity of 89% and accuracy of ssAD and sAD together in the diagnosis of AD 94%.And the sensitivity of the perfusion patterns have a high sensitivity but rather low specificity. of SPET in the cases of ssAD and sAD together Since the presence of false positive cases, in the was 100%, with the specificity reduced to 66%. sAD subgroup with bilateral temporal As the disease has different stages we suppose hypoperfusion, is the reason of specificity that different perfusion patterns may exist in reduction in our study, it seems we should change different stages of AD. this parameter or find another diagnostic test, with Bradley K. M. et al (2002) in a study of the high specificity, to accompany SPET, to be more perfusion changes in SPET taken in life, with the successful in early diagnosis of AD. Braak pathological stages( entorinal, limbic, Brain SPET has an impact on the differentiatin of neocortical) of AD in postmortem brains, dementias, therapeutic decisions specially by demonstrated that reduced perfusion in the differentiating AD from MID. There is still a need anterior medial temporal lobes, subcallosal region to an agreement for how images should be and the posterior cingulate region, appears interpreted, especially in the cases of mild AD, to between the entorhinal and limbic stage. Large extract clinically useful information. posterior temporoparietal defects appear between Interdisciplinary cooperation is of crucial the limbic and neocortical stage and frontal lobe importance for optimizing the SPET yield in defects is the last that appear. The time course of clinical practice. these perfusion defects is said to be relatively long, suggesting that perfusion changes may be a diagnostic aid in staging AD in life[26]. 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Classification of mild Alzheimer’s disease by artificial [ 31] Matsuda H, Kanetaka H, Ohnishi T et al, Brain neural network analysis of SPET data, Nucl Med SPET abnormalities in Alzheimer’s disease before Commun, 18, 1997, 805-810. and after atrophy correction, Eur J Nucl Med Mol [ 20] McMurdo M, Grant D, Kennedy N et al, The value Imaging, 29, 2002,1502-1505. of HMPAO SPECT scanning in the diagnosis of early [ 32] Elgh E, Sundstrom T, Nasman B et al, Memory Alzheimer’s disease in patients attending a memory functions and rCBF (99m)Tc-HMPAO SPET: clinic, Nucl Med Commun, 15, 1994,15, 405-409. developing diagnostics in Alzheimer's disease, Eur J Nucl Med Mol Imaging, 29, 2002 ,1140-1148. Table 1: RT LT N Sex Age F. his MMSE CT PCl. D RF LF RP LP RO LO m l m l Cl.D+SPET Fol-up D 1 M 74 - 0 mi.a pAD ssAD AD 2 F 56 - 12 mi.a pAD ssAD AD 3 F 62 - 12 ven.wid pAD ssAD AD 4 F 61 - 14 mi.a pAD sAD AD 5 F 73 - 17 n pAD ssAD AD 6 F 80 - 16 mi.a pAD At At 7 M 74 - 23 mo.a pAD ssAD At 8 M 78 + 23 n pAD ssAD AD 9 F 84 + 19 mi.a pAD ssAD AD 10 F 78 - 19 mi.a pAD sAD AD 11 F 79 - 15 mi.a pAD ssAD AD 12 F 86 + 22 n pAD ssAD AD 13 M 80 - 16 ven.wid pAD ssAD AD 14 F 78 - 10 mi.a pAD inf Mix Mix 15 F 83 - 12 isc pAD+VD inf inf VD VD 16 F 75 + 15 mi.a pAD mul MID MID 17 F 73 + 12 ven.wid pAD sAD AD 18 M 83 - 13 mi.a pAD sAD AD 19 F 73 - 23 n pAD sAD AD 20 F 75 - 9 n pAD ssAD AD 21 M 70 + 27 mi.a pAD sAD VD 22 F 78 - 16 n pAD sAD VD 23 M 77 - 22 n pAD ssAD AD 24 F 56 - 15 n pAD ssAD AD 25 M 61 - 16 n pAD ssAD AD 26 M 73 - 4 * pAD ssAD AD 27 F 74 - 19 n pAD ssAD AD 28 F 65 20 n pAD FTD FTD 29 M 82 - 15 mi.a pAD sAD AD 30 M 71 - 13 n pAD sAD VD 31 F 65 - 27 n pAD FTD FTD 32 F 69 - 19 n pAD mul MID MID 33 M 73 - 17 mod.a pAD mul MID MID : blood flow reduction

Table 2:

RT LT N Sex Age F. his MMSE CT Cl.D RF LF RP LP RO LO m l m l Cl.D+SPET Fol-up D. 1 M 57 + 30 n n Fol-up Fol-up 2 M 82 - 17 mi.a COPD+VD mul MID MID 3 F 74 - 29 * B12 d Fol-up B12 d. 4 M 71 - 9 isc CAD+VD isc isc isc Mix Mix 5 M 76 - 18 mi.a PD+VD Mix PD+FTD 6 M 68 - 28 isc CAD+VD mul MID MID 7 F 76 - 28 mi.a hypoth. N Fol-up

10 s t

n 8 e i t a

e 2 b m u 0 N 30-59 60-69 70-79 80-89

Diagram 1:

14 s t

n 12 e i t

a 10 p

m 2 u N 0 severe moderate mild

Diagram 2:

Figure1:

Legends:

Table 1: The results of the group A, F. his: family history, PCl.D: primary clinical diagnosis, mi. a: mild atrophy, n: normal, ven. wid: ventricular widening, mod. a: moderate atrophy, pAD: probable AD, ssAD: strongly suggestive AD, sAD: suggestive AD, inf: infarct defect, Mix: mixed dementia, mul: multiple infarcts, MID: multinfarct dementia, RF: right frontal, LF: left frontal, RT: right temporal, LT: left temporal, m: medial, l: lateral, Cl.D+SPET: clinical diagnosis and SPET, Fol-up D: follow-up diagnosis, VD: vascular dementia

Table 2: The results of the group B, * white matter lesion in MRI, B12 d.: vitamin B12 deficiency, PD: Parkinson’s disease, FTD: fronto-temporal dementia, hypoth: hypothyroidism, isc: ischemic type defect

Diagram 1: Prevalance by age group

Diagram 2: Prevalance by MMSE stage

Figure1: Left to right transaxial slices of a normal scan, bilateral temporoparietal hypoperfusion in AD, multinfarct dementia, frontotemporal hypoperfusion (FTD) and global hypoperfusion in atrophic brain.