Dement Geriatr Cogn Disord 2015;39:360–367 DOI: 10.1159/000375298 Accepted: January 10, 2015 Published online: April 14, 2015
© 2015 S. Karger AG, Basel 1420–8008/15/0396–0360$39.50/0 www.karger.com/dem
Original Research Article
Evaluation of Regional Cerebral Blood Flow in Alzheimer’s Disease Patients with Subclinical Hypothyroidism Megumi Haji Noriyuki Kimura Takuya Hanaoka Yasuhiro Aso Makoto Takemaru Teruyuki Hirano Etsuro Matsubara Department of Neurology, Faculty of Medicine, Oita University, Oita, Japan
Key Words Subclinical hypothyroidism · Alzheimer’s disease · Brain perfusion single photon emission computed tomography · Statistical parametric mapping · Regional cerebral blood flow Abstract Background: This study examined regional cerebral blood flow (rCBF) in Alzheimer’s disease (AD) patients with and without subclinical hypothyroidism (SCH). Methods: Eleven AD patients with SCH and 141 AD patients without SCH underwent brain perfusion single photon emission computed tomography (SPECT). The SPECT data were analyzed by statistical parametric mapping (SPM8) and FineSRT. Results: AD patients with SCH showed a significantly decreased rCBF mainly in the temporal lobe and thalamus, whereas those without SCH showed a significantly decreased rCBF in the parietotemporal lobe and cingulate gyrus as well as the frontal lobe. Conclusion: Our findings suggest that SCH may affect cerebral perfusion in regions associated with the memory function. © 2015 S. Karger AG, Basel
Introduction
Dr. Noriyuki Kimura Department of Neurology Faculty of Medicine, Oita University Idaigaoka 1-1, Hasama, Yufu, Oita 879-5593 (Japan) E-Mail noriyuki @ med.oita-u.ac.jp
Downloaded by: UCSF Library & CKM 169.230.243.252 - 4/29/2015 9:01:02 AM
Clinical thyroid disorders are well-known reversible causes of neuropsychiatric symptoms and secondary or reversible dementia [1]. Increasing evidence indicates that subclinical hypothyroidism (SCH), and even variations in thyroid function within the normal range, are associated with mood disturbances and cognitive impairment [2, 3]. Therefore, screening for thyroid function is recommended for elderly patients with cognitive impairment. SCH, defined as a normal thyroid hormone level in the presence of a high thyroid-stim-
361
Dement Geriatr Cogn Disord 2015;39:360–367 DOI: 10.1159/000375298
© 2015 S. Karger AG, Basel www.karger.com/dem
Haji et al.: Evaluation of Regional Cerebral Blood Flow in Alzheimer’s Disease Patients with Subclinical Hypothyroidism
ulating hormone (TSH) level [4], is relatively common in elderly people. Previous clinical studies have demonstrated that patients with SCH exhibit cognitive impairment, such as memory loss, or verbal fluency impairment [4–6]. Although demented patients with SCH are commonly encountered in daily clinical practice, there is less objective evidence supporting the effect of SCH on brain function in patients with Alzheimer’s disease (AD). Brain perfusion single photon emission computed tomography (SPECT) is used to evaluate cerebral function and measure regional cerebral blood flow (rCBF). Here we analyzed SPECT data obtained from AD patients with SCH and with normal thyroid function using statistical parametric mapping (SPM) and region of interest (ROI) analysis methods. SPECT studies in patients with overt hypothyroidism revealed a decreased mean global CBF and a decreased rCBF, mainly in the parietal and occipital lobes [7, 8]. Few studies, however, have evaluated cerebral perfusion in patients with SCH or in AD patients with SCH. The aim of the present study was to objectively evaluate the rCBF in AD patients with SCH using SPM8 and FineSRT. Subjects and Methods
Brain SPECT Imaging After intravenous injection of 99mTc ethyl cysteinate dimer (600 MBq; FUJIFILM RI Pharma Co., Ltd., Japan), its passage to the brain was monitored using a rectangular large-field gamma camera (e.cam Signature; Toshiba Medical, Japan). The Patlak plot method was used on the 99mTc ethyl cysteinate dimer cerebral blood perfusion SPECT to measure the mean global CBF. Data comprising a sequence of 120 frames were acquired at a rate of 1 frame per second with a 128 × 128 matrix. Ten minutes after the angiography, SPECT images were obtained using a rotating dual-head gamma camera equipped with low-energy, high-resolution, and parallel-hole collimators. The energy windows were set at 140 keV ± 20%, and 90 views were obtained
Downloaded by: UCSF Library & CKM 169.230.243.252 - 4/29/2015 9:01:02 AM
Subjects A total of 167 outpatients with late-onset AD (59 men, 108 women; onset at the age of 65 years or after; mean age, 78.7) consecutively underwent a clinical evaluation, an analysis of thyroid hormone levels, and brain perfusion SPECT at the Department of Neurology, Oita University Hospital, between 2006 and 2013. AD was diagnosed according to the criteria for probable AD of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) [9]. The Mini-Mental State Examination (MMSE) was used to evaluate cognitive function. Routine laboratory tests, including TSH, free triiodothyronine (fT3), and free thyroxine (fT4) levels, were performed according to previous studies (normal ranges: TSH, 0.35–4.94 μIU/ml; fT3, 1.7–3.71 pg/ml; fT4, 0.7–1.48 ng/dl) [10]. SCH was defined as normal levels of fT3 and fT4 in the presence of a high TSH level [4]. Eight patients were excluded from this study due to arrhythmia or incomplete information, including neuropsychological testing and global CBF values. Moreover, of the total of 167 AD patients, 5 who had overt hypothyroidism (3.0%) and 2 patients with subclinical hyperthyroidism (1.0%) were also excluded. Thus, of the remaining 152 AD patients (51 men, 101 women; mean age, 79.0 ± 5.7 years) who were included in the SPECT study, 11 were patients with SCH (7 men, 4 women; mean age, 82.1 ± 8.2 years) and 141 were patients with normal hormone levels (45 men, 96 women; mean age, 78.7 ± 5.5 years). Brain perfusion SPECT was performed before hormone replacement treatments in AD patients with SCH. Information regarding age, sex, educational level, MMSE score, and thyroid hormone levels was extracted from the medical records. We also studied 21 age- and sex-matched control subjects (9 men, 12 women; mean age, 80.0 ± 4.9 years) who had no neurological disorders, cognitive impairment, or abnormal thyroid hormone levels. A voxel-by-voxel group analysis using SPM8 and quantitative analysis using FineSRT was performed to detect differences in rCBF between AD patients and controls. Between-group comparisons between AD patients with and those without SCH were performed with the χ2 test for sex distribution and a MannWhitney U test for age at examination, disease duration, MMSE score, and mean global CBF. A p value of
© 2015 S. Karger AG, Basel 1420–8008/15/0396–0360$39.50/0 www.karger.com/dem
Original Research Article
Evaluation of Regional Cerebral Blood Flow in Alzheimer’s Disease Patients with Subclinical Hypothyroidism Megumi Haji Noriyuki Kimura Takuya Hanaoka Yasuhiro Aso Makoto Takemaru Teruyuki Hirano Etsuro Matsubara Department of Neurology, Faculty of Medicine, Oita University, Oita, Japan
Key Words Subclinical hypothyroidism · Alzheimer’s disease · Brain perfusion single photon emission computed tomography · Statistical parametric mapping · Regional cerebral blood flow Abstract Background: This study examined regional cerebral blood flow (rCBF) in Alzheimer’s disease (AD) patients with and without subclinical hypothyroidism (SCH). Methods: Eleven AD patients with SCH and 141 AD patients without SCH underwent brain perfusion single photon emission computed tomography (SPECT). The SPECT data were analyzed by statistical parametric mapping (SPM8) and FineSRT. Results: AD patients with SCH showed a significantly decreased rCBF mainly in the temporal lobe and thalamus, whereas those without SCH showed a significantly decreased rCBF in the parietotemporal lobe and cingulate gyrus as well as the frontal lobe. Conclusion: Our findings suggest that SCH may affect cerebral perfusion in regions associated with the memory function. © 2015 S. Karger AG, Basel
Introduction
Dr. Noriyuki Kimura Department of Neurology Faculty of Medicine, Oita University Idaigaoka 1-1, Hasama, Yufu, Oita 879-5593 (Japan) E-Mail noriyuki @ med.oita-u.ac.jp
Downloaded by: UCSF Library & CKM 169.230.243.252 - 4/29/2015 9:01:02 AM
Clinical thyroid disorders are well-known reversible causes of neuropsychiatric symptoms and secondary or reversible dementia [1]. Increasing evidence indicates that subclinical hypothyroidism (SCH), and even variations in thyroid function within the normal range, are associated with mood disturbances and cognitive impairment [2, 3]. Therefore, screening for thyroid function is recommended for elderly patients with cognitive impairment. SCH, defined as a normal thyroid hormone level in the presence of a high thyroid-stim-
361
Dement Geriatr Cogn Disord 2015;39:360–367 DOI: 10.1159/000375298
© 2015 S. Karger AG, Basel www.karger.com/dem
Haji et al.: Evaluation of Regional Cerebral Blood Flow in Alzheimer’s Disease Patients with Subclinical Hypothyroidism
ulating hormone (TSH) level [4], is relatively common in elderly people. Previous clinical studies have demonstrated that patients with SCH exhibit cognitive impairment, such as memory loss, or verbal fluency impairment [4–6]. Although demented patients with SCH are commonly encountered in daily clinical practice, there is less objective evidence supporting the effect of SCH on brain function in patients with Alzheimer’s disease (AD). Brain perfusion single photon emission computed tomography (SPECT) is used to evaluate cerebral function and measure regional cerebral blood flow (rCBF). Here we analyzed SPECT data obtained from AD patients with SCH and with normal thyroid function using statistical parametric mapping (SPM) and region of interest (ROI) analysis methods. SPECT studies in patients with overt hypothyroidism revealed a decreased mean global CBF and a decreased rCBF, mainly in the parietal and occipital lobes [7, 8]. Few studies, however, have evaluated cerebral perfusion in patients with SCH or in AD patients with SCH. The aim of the present study was to objectively evaluate the rCBF in AD patients with SCH using SPM8 and FineSRT. Subjects and Methods
Brain SPECT Imaging After intravenous injection of 99mTc ethyl cysteinate dimer (600 MBq; FUJIFILM RI Pharma Co., Ltd., Japan), its passage to the brain was monitored using a rectangular large-field gamma camera (e.cam Signature; Toshiba Medical, Japan). The Patlak plot method was used on the 99mTc ethyl cysteinate dimer cerebral blood perfusion SPECT to measure the mean global CBF. Data comprising a sequence of 120 frames were acquired at a rate of 1 frame per second with a 128 × 128 matrix. Ten minutes after the angiography, SPECT images were obtained using a rotating dual-head gamma camera equipped with low-energy, high-resolution, and parallel-hole collimators. The energy windows were set at 140 keV ± 20%, and 90 views were obtained
Downloaded by: UCSF Library & CKM 169.230.243.252 - 4/29/2015 9:01:02 AM
Subjects A total of 167 outpatients with late-onset AD (59 men, 108 women; onset at the age of 65 years or after; mean age, 78.7) consecutively underwent a clinical evaluation, an analysis of thyroid hormone levels, and brain perfusion SPECT at the Department of Neurology, Oita University Hospital, between 2006 and 2013. AD was diagnosed according to the criteria for probable AD of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) [9]. The Mini-Mental State Examination (MMSE) was used to evaluate cognitive function. Routine laboratory tests, including TSH, free triiodothyronine (fT3), and free thyroxine (fT4) levels, were performed according to previous studies (normal ranges: TSH, 0.35–4.94 μIU/ml; fT3, 1.7–3.71 pg/ml; fT4, 0.7–1.48 ng/dl) [10]. SCH was defined as normal levels of fT3 and fT4 in the presence of a high TSH level [4]. Eight patients were excluded from this study due to arrhythmia or incomplete information, including neuropsychological testing and global CBF values. Moreover, of the total of 167 AD patients, 5 who had overt hypothyroidism (3.0%) and 2 patients with subclinical hyperthyroidism (1.0%) were also excluded. Thus, of the remaining 152 AD patients (51 men, 101 women; mean age, 79.0 ± 5.7 years) who were included in the SPECT study, 11 were patients with SCH (7 men, 4 women; mean age, 82.1 ± 8.2 years) and 141 were patients with normal hormone levels (45 men, 96 women; mean age, 78.7 ± 5.5 years). Brain perfusion SPECT was performed before hormone replacement treatments in AD patients with SCH. Information regarding age, sex, educational level, MMSE score, and thyroid hormone levels was extracted from the medical records. We also studied 21 age- and sex-matched control subjects (9 men, 12 women; mean age, 80.0 ± 4.9 years) who had no neurological disorders, cognitive impairment, or abnormal thyroid hormone levels. A voxel-by-voxel group analysis using SPM8 and quantitative analysis using FineSRT was performed to detect differences in rCBF between AD patients and controls. Between-group comparisons between AD patients with and those without SCH were performed with the χ2 test for sex distribution and a MannWhitney U test for age at examination, disease duration, MMSE score, and mean global CBF. A p value of
