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J. Endocrinol. Invest. 30: 491-496, 2007

Key-words: Hashimoto’s thyroiditis, hypothyroidism, cerebral blood flow, Tc-99m HMPAO, SPECT.

Correspondence: M. Kaya, MD, Hospital of the University of Trakya, De-partment of Nuclear Medicine, 22030 Edirne, Turkey.

E-mail: meryemk@trakya.edu.tr

Accepted January 10, 2007.

Assessment of alterations in regional cerebral blood flow in patients with hypothyroidism due to Hashimoto’s thyroiditis

M. Kaya1, T.F. Cermik1, D. Bedel1, Y. Kutucu1, C. Tuglu2, Ö.N. Yigitbasi1 1Department of Nuclear Medicine, Hospital of the University of Trakya; 2Hospital of the University of Trakya, Psychiatry, Edirne, Turkey

ABSTRACT. Aim: The aim of this study was to as-sess regional cerebral blood flow (rCBF) using detailed semiquantative analysis of Tecnethium-99m hexamethylpropyleneamine (HMPAO) brain single-photon emission computered tomography (SPECT) in patients with hypothyroidism due to autoimmune thyroiditis. Patients, material and methods: Twenty patients (mean age: 42±9 yr) and 12 control subjects (mean age: 35.4±8.5 yr) were included in this study. The corticocerebellar rCBF ratios were obtained from 52 cerebral ar-eas on 6 transaxial slices. By using control group rCBF ratios, lower reference values (RLV) (aver-age ratio –2 SD) were calculated and the regions below RLV having an rCBF ratio were considered as abnormal decrease (hypoperfused) areas. Re-sults: Significant reduced rCBF rates were meas-ured for 15 (29%) cortical regions for the patient group. The areas in which significant reduced rCBF were demonstrated in the patient group

were as follows: a) in the right hemisphere: su-perior frontal (slice 1 and 2), inferior frontal (slice 1), anterior temporal (slice 1 and 2), precentral gyrus (slice 1 and 2), postcentral gyrus (slice 1 and 2), and parietal cortex; b) in the left hemi-sphere: superior frontal (slice 1 and 2), inferior frontal (slice 1), caudate nucleus, and parietal cortex. The hypoperfusion was calculated in 154 (14%, 94 right and 60 left) cortical regions out of 1040 regions in the patient group. Conclu-sion: These findings indicate that the alteration of rCBF in patients with hypothyroidism due to Hashimoto’s thyroiditis before T4 therapy can be demonstrated with brain SPECT. Additionally, the degree of rCBF abnormalities could be de-termined with brain SPECT in patients with hy-pothyroidism due to Hashimoto’s thyroiditis with or without neurologic or psychiatric symptoms. (J. Endocrinol. Invest. 30: 491-496, 2007)©2007, Editrice Kurtis

INTRODUCTION

The thyroid hormone is important both for the functional development and maturation of the cen-tral nervous system and for its proper functioning throughout the whole life. Whereas the connection between the lack of thyroid hormone in congenital hypothyroidism and mental retardation is well docu-mented (1), hypothyroidism in adults is believed to be associated with a variety of somatic, neuropsy-chological, and psychiatric symptoms such as inat-

tentiveness, inability to concentrate, memory deficit, psychomotor slowing, depressive mood state, anxi-ety, and sometimes persecution complexes (2). The term autoimmune thyroiditis encompasses a number of different entities; the most important are chronic goitrous (Hashimoto’s) thyroiditis and chronic atrophic thyroiditis. The common cause of acquired hypothyroidism is Hashimoto’s thyroid-itis, which is 7-fold more common in women with increasing incidence during middle-age (3). The diagnosis of Hashimoto’s thyroiditis depends on the presence of elevated thyroid-specific autoan-tibodies, i.e. thyreoperoxidase antibodies and thy-reoglobulin antibodies (4). Some neuroimaging studies using single-photon emission computed tomography (SPECT) revealed the regional cer-ebral blood flow (rCBF) abnormalities in patients with mildly and severe hypothyroidism (5, 6). This study is designed to assess rCBF using detailed

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semi-quantative analysis of Tecnethium-99m hex-amethylpropyleneamine (HMPAO) brain SPECT in patients with hypothyroidism due to Hashimoto’s thyroiditis before T4 therapy.

MATERIALS AND METHODSPatientsTwenty patients (3 males, 17 females) ranging in age 27 from 52 (mean age: 42±9 yr) participated in this study. The normal control group consisted of 12 subjects (6 males, 6 females), from 25 to 54 yr old (35.4±8.5). SPECT scans were performed before T4 therapy and SPECT scans were also performed after T4 therapy for 4 pa-tients. The exclusion criteria of this study were: age >60 yr old, being under psychiatric medication, and having a suspicion of cerebral vascular disease. The local Ethics Committee approved this investigation, and each patient gave informed consent prior to participation in the study.

Thyroid function testsSerum TSH, free T3 (FT3), free T4 (FT4), anti-thyreoperoxidase auto-antibodies (anti-TPO Ab) and anti-thyroglobulin antibodies (anti-Tg Ab) were measured with chemiluminescent enzyme im-

munoassay methods (Immulite 1000, DPC-Diagnostic Products Corporation, Los Angels, CA).

Brain perfusion SPECTTecnethium-99m hexamethylpropyleneamine (Tc-99m HMPAO) was used as the brain perfusion agent. Patients were placed in a supine position in a quite room with dimmed lights and were allowed to relax with their eyes open while given iv administra-tion of 925 MBq Tc-99m HMPAO. The patients were asked not to move or talk for at least 10 min following the injections. SPECT imaging was performed 60-90 min after the injections using a dual-headed Siemens E-Cam camera (Siemens Inc., Erlangen, Germany). One hundred twenty-eight planar images were ac-quired over 360° with an acquisition time of 30 sec per frame. The camera was fitted with a low-energy, high-resolution (LEHR) collimator. Data were obtained in a 128x128 matrix and images were reconstructed by filtered back projection with a Butterworth prefilter (cut off 0.6, order 7) and a Ramp filter. The images were corrected for uniform Chang’s attenuation correction (μ=0.15 cm–1). Transaxial slices were reoriented parallel to anterior com-missure/posterior commissure (AC-PC) line to obtain sagittal and coronal reconstructions. Each reconstructed slice had a thickness of 4 mm and these slices displayed cerebellar, cerebral cortical, and subcortical lobes.

Fig. 1 - Regions of interest on six transax-ial SPECT slices are displayed as follows: 1. Slice: C= cerebellum; 2. Slice: iF1= inferior frontal cortex (1), aT1= anterior temporal cortex (1), posterior temporal cortex (1); 3. Slice: iF2= inferior frontal cortex (2), aT2= anterior temporal cortex (2), posterior temporal cortex (2), Oc1= occipital cortex (1), Cc1= cingulate cortex (1), nC1= caudate nucleus (1), Pu= puta-men, Th1= thalamus (1); 4. Slice: iF3= in-ferior frontal cortex (3), Prc1= precentral gyrus (1), pT3= posterior temporal cor-tex (3), Oc2= occipital cortex (2), nC2= caudate nucleus (2), Th2= thalamus (2); 5. Slice: sF1= superior frontal cortex (1), Prc2= precentral gyrus (2), Poc1= post-central gyrus (1); 6. Slice: sF2= superior frontal cortex (1), Prc3= precentral gyrus (3), Poc2= postcentral gyrus (2), Pc= pari-etal cortex. R: Right.

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Semi-quantitative analysisFollowing the visual assessment of image slices, transaxial slices were used in the semiquantitative analysis. The average counts per pixel were calculated within the 54 irregular regions of in-terest (ROI) on the right and left cortical, subcortical brain, and cerebellar areas (27 from each hemisphere) on 6 transaxial slices with the aim of this research. The corticocerebellar rCBF ratios were obtained through the division of average counts obtained from 52 regions into the average counts of ipsilateral cerebellum separately. The brain regions, from which counts were taken, and ROI’s drawing method were shown in Figure 1. Reference lower values (RLV) (average values – 2 SD) were calculated within each of the 52 regions by using healthy control rCBF ratios. In the patient group, the regions below RLV having an rCBF ratio were regarded as abnormal decrease (hypoperfused) areas.

Data analysisConventional methods were used to generate descriptive sta-tistics. Regional blood flow ratios taken from the patient group and the control group were compared by Mann-Whitney U test;

p-values <0.05 were considered to significantly represent the dif-ference between the two populations.

RESULTS

The characteristics of the patients and their labora-tory results regarding thyroid gland functions were listed in Table 1. All patients had clinical and labo-ratory evidence of severe hypothyroidisms. Six pa-tients had low FT3 and FT4 levels, 9 patients had only low FT4 levels. Median values for the 52 regions [26 right (R) + 26 left (L)], from which counts were taken for the patient and the control groups, were indicated in Table 2. The hypoperfusion was calculated in 14% (94 R + 60 L) of 1040 brain regions in the patient group. The sum of the distributions of these regions regarding spe-cific regions was shown in Table 2. In the comparison made between the patient group and the healthy

Table 1 - Sex, age and laboratory data in the patients.

Patient no. Gender Age(yr)

FT3(pg/ml)

FT4(ng/dl)

TSH(IU/ml)

Anti-TG(IU/ml)

Anti-TPO(IU/ml)

Normal Range 1.8 - 4.2 0.8 – 1.9 0.4 - 4 0 - 40 0 - 35

1 F 32 4.17 0.63 44 2189 115

2 M 52 1.00 0.20 75 151 155

3 F 44 2.98 0.77 49 300 420

4 F 36 2.14 0.47 75 146 206

5 F 37 1.00 0.20 75 300 286

6 F 34 2.80 0.41 75 2193 1000

7 F 31 4.01 0.45 75 3000 1000

8 F 42 2.34 0.49 55 61 105

9 F 45 2.41 0.43 57 28.9 409

10 F 51 1.62 0.32 75 3000 1000

11 M 33 3.00 3.28 62 3000 1000

12 F 40 3.21 0.92 17 20 1000

13 M 56 3.09 0.95 31 145 1000

14 F 27 2.04 0.50 69 242 1000

15 F 49 1.12 0.32 75 20 10

16 F 48 2.14 0.54 75 140 750

17 F 51 1.00 0.50 75 489 1000

18 F 45 1.26 0.30 75 60.5 16

19 F 27 3.38 1.21 75 38 1000

20 F 49 2.49 0.72 34 322 149

Mean±SD 41.1±8.9 2.50±1.00 0.70±0.70 64±17 963±1278 581±442

FT3: free T3; FT4: free T4; anti-TG: anti-thyroglobulin; anti-TPO: anti-thyreoperoxidase, M: male; F: female.

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control group, statistically significant reduced rCBF rates were measured for 9 (6 R + 3 L) different cortical regions for the patient group. The regions, in which significantly reduced regional blood flow rates were demonstrated in the patient group, were as follows: a) in the right hemisphere: superior frontal cortex (slice 1 and 2), inferior frontal cortex (slice 1), anterior temporal cortex (slice 1 and 2), precentral gyrus (slice

1 and 2), postcentral gyrus (slice 1 and 2), postcen-tral gyrus (slice 1 and 2) and parietal cortex; b) in the left hemisphere: superior frontal cortex (slice 1 and 2), inferior frontal cortex (slice 1), parietal cortex and caudate nucleus (Table 2). The number of hypoperfused regions for 4 of the pa-tients, who were applied brain SPECT after a T4 treat-ment, was as follows during the hypothyroidism: 4

Table 2 - Median values for cortico-cerebellar regional blood flow rates belonging to 26 right and left cerebral areas of patient and control group and p-values.

Right hemisphere Left hemisphereThe sum of

hypoperfused area (right+left)Mean±SD Patient

groupControl subjects p Patient

groupControl subjects p

Cingulate cortex (1) 0.96 0.99 0.371 1.00 0.99 0.846 5 (3+2)

Cingulate cortex (2) 0.95 0.95 0.969 0.94 1.00 0.243 2 (2+0)

Superior frontal cortex (1) 0.89 0.95 0.049* 0.89 0.94 0.043* 5 (3+2)

Superior frontal cortex (2) 0.88 0.96 0.004* 0.86 0.92 0.017* 15 (8+7)

Inferior frontal cortex (1) 0.82 0.91 0.008* 0.84 0.91 0.018* 8 (6+2)

Inferior frontal cortex (2) 0.91 0.95 0.150 0.94 0.96 0.330 6 (4+2)

Inferior frontal cortex (3) 0.93 0.95 0.228 0.93 0.97 0.312 6 (4+2)

Anterior temporal cortex (1) 0.85 0.91 0.011* 0.88 0.87 0.907 9 (8+1)

Anterior temporal cortex (2) 0.90 0.96 0.043* 0.89 0.92 0.267 4 (1+3)

Posterior temporal cortex (1) 0.93 0.93 0.785 0.92 0.96 0.572 2 (2+0)

Posterior temporal cortex (2) 0.91 0.96 0.073 0.93 0.96 0.312 4 (4+0)

Posterior temporal cortex (3) 0.94 0.98 0.243 0.93 0.98 0.243 0

Precentral gyrus (1) 0.92 0.98 0.029* 0.92 0.94 0.213 4 (3+1)

Precentral gyrus (2) 0.89 0.94 0.039* 0.88 0.89 0.330 8 (6+2)

Precentral gyrus (3) 0.92 0.94 0.414 0.89 0.90 0.216 5 (0+5)

Postcentral gyrus (1) 0.89 0.92 0.043* 0.91 0.94 0.161 5 (4+1)

Postcentral gyrus (2) 0.88 0.98 0.002* 0.90 0.94 0.148 18 (12+6)

Parietal cortex 0.88 0.96 0.008* 0.91 0.99 0.012* 15 (7+ 8)

Occipital cortex (1) 0.90 0.92 0.572 0.92 0.88 0.414 4 (3+1)

Occipital cortex (2) 0.87 0.94 0.067 0.92 0.90 0.938 11 (6+5)

Caudate nucleus (1) 0.86 0.90 0.167 0.85 0.87 0.161 6 (4+2)

Caudate nucleus (2) 0.81 0.87 0.350 0.75 0.84 0.020* 3 (0+3)

Putamen (1) 0.92 0.96 0.150 0.90 0.95 0.119 3 (2+1)

Putamen (2) 0.88 0.89 0.938 0.86 0.92 0.139 2 (0+2)

Thalamus (1) 0.83 0.84 0.938 0.80 0.82 0.267 0

Thalamus (2) 0.85 0.85 0.613 0.78 0.83 0.155 4 (2+2)

Total 154 (94+60)

*Significant

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regions of the R hemisphere in patient no. 4; 11 re-gions of the R and 9 regions of the L hemisphere in patient no. 5; 9 regions of the R and 1 region of the L hemisphere in patient no. 6; 19 regions of the R and 8 regions of the L hemisphere in patient no. 10. All hypoperfusion regions in these patients were improved after the T4 therapy on brain SPECT used based on RBL for each of the 52 regions.

DISCUSSION

It is now well established that significant distur-bances of the thyroid function in the mature brain may deeply alter mental function influencing cog-nition and emotion. In adult life hypothyroidism is associated with changes in mood and intellectual performance, and severe hypothyroidism can mimic melancholic depression and dementia (2, 7). Psychi-atric symptoms include impaired short-term memory and other cognitive dysfunctions of between 66% and 90%, and depression in 40% (8). Although there are no methods for direct in vivo measurements of brain thyroid metabolism, functional brain imaging techniques to evaluate cerebral blood flow and me-tabolism have recently been used in patients with hypothyroidism. Cerebral metabolism using posi-tron emission tomography with F-18- flourodeoxy-glucose in patients who had undergone total thy-roidectomy for thyroid carcinoma was examined in a recent study. During the hypothyroidism, patients showed diffusely decreased regional cerebral blood flow and cerebral glucose metabolism. There were no focal defects suggesting globally reduced brain activity (9).Among the most robust changes seen in the present study, decreased rCBF was observed in bilateral frontal and parietal cortex, and R anterior temporal cortex, R pre- and post-central gyrus, and L caudate nucleus. These results partially comply with the pre-vious report including the reduced rCBF in patients with transient hypothyroidism after thyroidectomy (5). The reduced rCBF in bilateral parietal, occipi-tal, and frontal lobes in patients with moderate or severe depression were demonstrated in the same study. Also, they suggested that significant reduc-tion of rCBF in parietal cortex should be associated with cognitive dysfunction (5). Using P-31 magnetic-resonance spectroscopy, specific changes in frontal metabolism were shown in patients with hypothy-roidism (10). Although no patients were subjected to cognitive examination in our cohort, the remarkable hypoperfusion in frontal and parietal cortex may be related to depression and cognitive dysfunction. In fact, frontal cortex has repeatedly been implicated in the pathophysiology of depression (11-13).

A decreased activity of pre-central gyrus (motor cor-tex or supplementary motor area) and post-central gyrus (somatosensory cortex) in the R hemisphere was seen in our patients. These findings were cor-roborated with the findings of the two studies done by Krausz et al. (6) and Schraml et al. (14). However, these regions have not consistently demonstrated decreased blood flow in patients with diagnosed neuropsychiatric disorders or symptoms. Anterior temporal cortex in the R hemisphere was another region of decreased activity during in our patients. According to the literature, the entire de-pressive syndrome would be compatible with the decreased activity in the temporal cortex (15-18). Patients with hypothyroidism may also be present together with depression and emotional disturbanc-es. Mendez et al. demonstrated that dysthymia and anxiety were particularly associated with the R tem-poral hypoperfusion in patients with frontotemporal dementia (19). Moreover, early temporal involve-ment of their suggestion is associated with frivolous behavior and R temporal involvement is associated with emotional disturbances.In humans, the caudate nucleus is activated in tasks requiring preparation and selection of movements based on information stored in working memory (20), new learning (21, 22), and planning (23). Thy-roid deficiency causes a marked maturational delay in caudate neuronal proliferation, the elaboration of neuronal networks and attainments of mature syn-aptic contents and membranes (24). The hypoper-fusion of the caudate nucleus and pre- and post-cen-tral gyrus in patients with hypothyroidism might be related to psychomotor slowing. The improvement of rCBF in 4 patients after T4 ther-apy suggests that thyroid hormone therapy is effec-tive for the recovery of rCBF alteration in Hashimoto’s thyroiditis. This result was supported by the previous two studies (4, 25), but not by the other research (6).The present study included a uniform group of indi-viduals with hypothyroidism due to Hashimoto’s thy-roiditis before T4 therapy. Although none of the pa-tients had any neurological and psychiatric symptoms and medications, a limitation of the present study was the lack of an objective assessment of mood and cognitive status. The other drawback of our study was that the age and sex of the normal control group did not exactly match with the patient group.

CONCLUSION

The results of the present study indicate that the al-teration of rCBF in patients with hypothyroidism due to autoimmune thyroiditis before T4 therapy can be revealed with brain SPECT. Additionally, the degree

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of rCBF abnormalities could be determined with brain SPECT in patients with hypothyroidism due to autoimmune thyroiditis with or without neurologic or psychiatric symptoms.

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