Download Pilot Study of the Relationship between Thyroid Status and

1
A pilot study of the relationship between thyroid status and
neuropsychiatric symptoms in patients with Alzheimer disease
ZHANG Nan,1,2 DU Hong-jian,1,2 WANG Jing-hua,2 and CHENG Yan,1,2
1 Department of Neurology, Tianjin Medical University General Hospital, Tianjin,
China
2 Tianjin Neurological Institute; Key Laboratory of Post-trauma Neuro-repair and
Regeneration in Central Nervous System, Ministry of Education; Tianjin Key
Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin,
China
Address for correspondence:
CHENG Yan
Department of Neurology, Tianjin Medical University General Hospital,
154, Anshan Road, Heping District, Tianjin, China
Tel: 8622-60814504;
Fax: 8622-27837604;
email: [email protected]
This work was funded by the Tianjin Science and Technology Development Project
of Colleges and Universities (grant no. 20110116).
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Background Growing evidence links alternation of the thyroid function to the
pathogenesis and progression of Alzheimer disease (AD). However, only a few
studies evaluate the association between thyroid hormone levels and neuropsychiatric
manifestations in patients with AD. This study was designed to investigate the
relationship of thyroid hormone levels and neuropsychiatric symptoms in euthyroid
patients with AD.
Method Forty patients with AD (26 women and 14 men), with no prior AD treatment
within 4 weeks before study entry, were evaluated on their thyroid status (total
triiodothyronine [TT3], total thyroxine [TT4] and thyroid-stimulating hormone
[TSH]), cognition (Mini-Mental State Examination [MMSE] and Alzheimer’s disease
Assessment Scale–Cognitive Subscale [ADAS-cog]), neuropsychiatric symptoms
(Neuropsychiatric Inventory [NPI]) and depression (Hamilton Rating Scale for
Depression [HAMD17]). The unique relationship between thyroid hormones and
cognitive function and mood was examined with multivariate linear regression
analyses. The thyroid status between the neuropsychiatric symptoms group and the
non-neuropsychiatric symptoms group was examined with independent-samples t-test.
Results In euthyroid AD patients with agitation and irritability has lower TSH serum
level than those without these symptoms. (t=-2.130, P<0.05; t=-2.657, P<0.05), and
core score of HAMD is significant associated with the serum level of TSH (β=0.395,
P<0.01). There is no significant association between thyroid hormone levels and
cognition (MMSE, ADAS-cog and its subscale score).
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Conclusions There might be a relationship between thyroid hormone levels and the
neuropsychiatric symptoms in euthyroid patients with AD.
Key words: Alzheimer disease; cognition; depression; neuropsychiatric symptom;
thyroid
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Introduction
ALZHEIMER’S DISEASE (AD) is a degenerative disorder of the central nervous
system (CNS) characterized by loss of neurons in the limbic system, association
neocortex, and basal forebrain accompanied by neuritic plaques, neurofibrillary
tangles, and neuropil thread formation. The relationship between the thyroid status
and the risk of dementias in particular Alzheimer disease (AD), as well as cognition
decline, has been extensively investigated over the last two decades. Van Osch et. [1]
found lower thyroid-stimulating hormone (TSH), as an independent risk factor, was
associated with the increased risk of AD for more than twofold. The Framingham
study [2] found low and high TSH levels were associated with an increased risk of
incident AD in women. Kalmijn et. and Thomas et. [3, 4] demonstrated that the
deviation of thyroid hormone levels could be a risk for AD. Volpato et. [5] found the
low thyroxine (T4) levels, within the normal range, were associated with a greater risk
of cognitive decline over a 3-year period in older women. However, a prospective,
observational, population-based follow-up study found thyrotropin (TSH) and free
thyroxine (FT4) levels were not associated with cognitive impairment and depressive
symptoms [6].
Moreover, the subclinical thyroid disease and the variations in thyroid function
within the normal range had been demonstrated to be related to cognitive impairment
in the healthy elderly, as well as in the patients with dementias. Several studies [7-10]
have reported that subclinical hypothyroidism (normal T4 with elevated TSH), even
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the alteration of TSH levels were within the normal range, are associated with
cognitive impairment in older individuals. Prinz et al. [11] suggested that the variate
of total thyroxine (TT4) within the normal range is positively associated with general
cognition in the healthy elderly men. Stuerenburg [12] suggested that elevated FT4
would aggravate the cognition impairment and associate with depression in AD
patients.
Thyroid is closely associated with the cognition in the persons with dementia and
the healthy elderly, as well as the mood and the other psychiatric symptoms in the
former. It has been observed that hypothyroidism and hyperthyroidism have
significant neuropsychiatric implications [13, 14]. For example, the central nervous
system activity in patients with hypothyroidism will slow down with the clinical
symptoms of depressed mood, emotional liability, and apathy. Patients with
hyperthyroidism frequently present with impaired concentration, anxiety, and
irritability. Although it has been demonstrated that the thyroid function plays a role in
the cognition of the patients with AD, the relationship is unclear between thyroid
status and the neuropsychiatric symptoms in euthyroid patients with AD. In a
previous study, Stern [15] found FT4 concentrations were negatively correlated with
self-reported feelings of fear and fatigue in euthyroid patients with Alzheimer disease,
but no significant relationships between thyroid hormones and cognition and other
depressive and anxiety symptoms were found. Thus we assume that the lower thyroid
level may associate with the earlier cognition decline as well as apathy and depression,
while high thyroid level may relate to agitation and irritability. In this study, we try to
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explore the association between the normal ranged thyroid function and the
neuropsychiatric symptoms in the patients with AD by evaluating the thyroid status
and the neuropsychiatric symptoms.
METHODS
Ethics
An informant was required to participate in the interviews. Written informed
consent approved by the Ethics Committee of Tianjin Medical University General
Hospital was obtained from all participants and caregivers. The study procedure had
been fully explained as well as the potential risks and benefits.
Participants
Diagnosis of probable AD was made according to the criteria of the Diagnostic
and Statistical Manual of Mental Disorders, fourth edition (DSM-Ⅳ) [16] and of the
National Institute of Neurologic and Communicative Disorders and Stroke and the
Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) [17].
Consecutive subjects were from the memory clinic of General Hospital of Tianjin
Medical University, age ranged from 50-90, Mini-Mental State Examination (MMSE)
score of 3 to 24, with reliable caregivers. All patients enrolled in this study had brain
imaging evaluation (computed tomography or magnetic resonance imaging,
performed within past 12 months. All patients had no prior AD treatment, including
but not limited to acetyl-cholinesterase inhibitors (AchEIs) and memantine, within 4
7
weeks before the study entry. Exclusion criteria included a history of thyroid disease,
cerebral vascular disorders, head injury, dementia or clinically significant neurologic
disease due to conditions other than Alzheimer disease, serious and unstable medical
conditions, concomitant anti-depressants and other psychotropic medications,
concomitant amiodarone and other medications may alter thyroid hormone levels, or
delirium at the time of assessment.
Procedures
Clinical assessment of cognition and neuropsychiatric symptoms, and blood
concentration of thyroid hormones (TT3, TT4, and TSH), were conducted within two
days of recruitment of each subject.
Thyroid Hormone Measurement
Fasting serum samples were obtained between 8:00 to 9:00 hours AM and
immediately sent to the laboratory. Ultrasensitive measurement of TSH, TT3 and TT4
were performed for all subjects. The measurement was conducted in accordance with
the standardized laboratory procedures of the Bayer ADVIA Centaur_ immunoassay
system.
Instruments
Cognition
The (MMSE) [18] was applied as a brief indicator of cognitive impairment.
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Global cognition was measured with the Alzheimer’s disease Assessment
Scale–Cognitive Subscale (ADAS-cog) [19], a 12 item scale of memory, language,
orientation, and praxis functions. For further analyses, 11 items (except attention) of
the ADAS-cog were aggregated into 3 clusters referred to the previous publication of
ADAS-Cog factor analysis: language (commands, language, comprehension of
spoken language, word finding), memory (word recall, naming objects and fingers,
orientation,
word
recognition,
remembering
test
instructions),
and
praxis
(constructional praxis, ideational praxis) [20].
Neuropsychiatric symptoms
Neuropsychiatric symptoms were evaluated by the Neuropsychiatric Inventory
(NPI) [21]. Total frequency and severity scores for all 12 items served as the primary
outcome variables in data analyses. Item score >1 was regarded as the existence of
this particular symptom.
Depression
Depression was evaluated by the 17-item Hamilton Rating Scale for Depression
(HAMD17) [22]. Assessments included the HAMD17 total score and score of the
factor so called depression/retardation (sum of Items 1, 2, 3, 7 and 8), which reflects
the core symptoms of depression [23].
A trained investigator who was blind to the subjects’ thyroid status administered
the MMSE, ADAS-Cog, NPI and HAMD.
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Statistical Analysis
Data analyses were conducted with the Statistical Package for the Social
Sciences (SPSS V13.0). The unique relationship between thyroid hormones and
cognitive function and mood was examined with multivariate linear regression
analyses, because thyroid hormones may also be related to age and education. We
also performed independent-samples t-test (two-tailed) to examine the thyroid status
between the neuropsychiatric symptoms group and the non-neuropsychiatric
symptoms group. And results were considered significant at the level of P<0.05.
RESULTS
Forty patients with AD (26 women and 14 men) aged from 54 to 80 years were
enrolled in this study from Oct 19, 2006 to Jul 2, 2007. Participants’ average age was
67.08 years (SD = 6.9), with an average schooling of 9.25 years (SD = 5.0).
Demographic and clinical characteristics of the subjects are presented in Table 1.
A paired-sample test showed no significant differences in the serum level of TT3,
TT4, and TSH between men and women.
Multivariate linear regression analyses were then conducted to examine the
relationship between thyroid hormone concentrations, demographics and cognitive
and mood measurements (Table 2, Table 3). Age, education, illness duration and
scores of scales were independent variable, and the thyroid hormone levels were
dependent variable. There were no significant correlation between age, education,
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illness duration and thyroid hormone levels. Core score of HAMD is significant
associated with the serum level of TSH (β=0.395, P<0.01). There was no significant
association between thyroid hormone levels and cognition (MMSE and ADAS-cog
total score, and three clusters of ADAS-cog).
The neuropsychiatric symptoms results indicated that AD patients with agitation
and irritability had lower TSH serum level than those without these symptoms.
(t=-2.130, P<0.05; t=-2.657, P<0.05) (Table 4).
DISCUSSION
It had been recognized that there are three stages of thyroid hormone (TH)
dependent neurological development in humans, which include 16-20 weeks
post-conception, the remainder of pregnancy after the onset of foetal thyroid function,
and the neonatal and post-natal period. During these stages, thyroid hormone
exposure influences neuronal proliferation and migration of neurons in the cerebral
cortex, hippocampus and medial ganglionic eminence. During the second stage,
thyroid hormone dependent processes include neurogenesis, neurone migration,
axonal outgrowth, dendritic branching and synaptogenesis, together with the initiation
of glial cell differentiation and migration and the onset of myelination. During the
third stage, migration of granule cells in the hippocampal dentate gyrus and
cerebellum, pyramidal cells in the cortex and Purkinje cells in the cerebellum are
sensitive to thyroid hormones and thyroid hormone-dependent gliogenesis and
myelination continues [24]. The thyroid function plays important role in both
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neurodevelopment process and neurodegenerative process [25]. It is possible that the
thyroid function is related to the Alzheimer’s disease.
Although the neuropathologic mechanism of altered thyrotropin levels occur
before or after the onset of AD is unclear, it is generally assumed that the thyroid
dysfunction increases AD risk by a direct adverse effect of thyroxine depletion on
cholinergic neurons, adverse effects of excessive levels of thyroid hormone, and
vascular-mediated mechanisms. According to several in vitro and in vivo studies
[26-28], TH might play a role in the development of AD by regulate the amyloid
precursor protein (APP) gene expression and the accumulation of β-amyloid peptide.
The presence of oxidative stress and the decrease of anti-oxidant metabolites have
been confirmed in hyperthyroid patients [29]. Exposure to TH has been shown to
augment necrotic neuron death [25]. The cognitive impairment is believed to be
associated with the cholinergic cell death and the result of acetylcholine deficit in AD.
A small case-control study showed increased reverse triiodothyronine (rT3) levels and
an increased rT3 to T4 ratio in the cerebrospinal fluid (CSF) of patients with AD,
suggesting the presence of abnormal intracerebral TH metabolism and brain
hypothyroidism [30].
Circulating TH enter the CSF via the choroid plexus. Although in vivo studies
illustrated that the circulating TH levels do not properly reflect TH metabolism in the
CNS [31-34], evidence existed in the clinical studies showed that the thyroid function
plays an important role in the cognition in euthyroid elderly [5, 11] or subclinical
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hypothyroidism adults without dementia [35]. In this preliminary cross-sectional
study in euthyroid patients with AD, significant positive associations had been found
between TH concentrations and aspects of behavior and mood, i.e., lower serum level
of TSH with higher levels of agitation and irritability from NPI, and higher TSH with
depression from core subscale of HAMD17. Similarly, Wahlin et al. [36] demonstrated
a positive relationship between TSH and depressive mood symptoms (Comprehensive
Psychopathological Rating Scale, CPRS) in nondemented adults between the ages of
75 to 96 years. These results were also consistent with the previously reported finding
that high TSH levels are associated with depression [37, 38]. The mechanisms of the
association between TH and neuropsychiatric symptoms in AD patients were unclear.
As our knowledge, a prospective population-based cohort study [39] about the
relationship between thyroid function and AD and its neuropathology confirmed that
higher total thyroxine was associated with higher number of neocortical neuritic
plaques and neurofibrillary tangles. And neurofibrillary tangles, especially in the
frontal cortex, were associated with psychosis and behavioral symptoms in AD
patients [40, 41]. Furthermore a recent study demonstrated that TSH level was
significantly inversely correlated with regional cerebral blood flow (rCBF) in the
middle and inferior temporal regions of right cerebral hemisphere in patients with AD
[42]. The major functions of TSH are to maintain the biosynthesis and secretion of the
T4 and T3. These results suggest that TSH may be more sensitive to neuropsychiatric
symptoms in AD patients than T3 and T4, that reflect the fact that TSH is the major
modulator of thyroid functioning.
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No significant relationships have been detected between TH and cognitive
functioning, as measured by the MMSE, ADAS-Cog and its subscales. This is
consistent with the result of previous research [15] that has also failed to identify a
significant relationship between global cognition (MMSE and ADAS-cog) and
current TH concentrations in euthyroid patients with AD. However, more
comprehensive, sensitive and specific cognition assessment instruments should be
implemented in the further study. It is also possible that free T3 and free T4 may be
associated with cognitive function impairment in AD patients. We should measure
more thyroid hormones in further study.
Although these associations between thyroid status and neuropsychiatric
symptoms were identified, the cross-sectional design and small sample size limit the
interpretation of these findings. No gender difference was found in this pilot study in
terms of the correlation of thyroid function and neuropsychiatric symptoms in patients
with AD, however in the Framingham study low and high thyrotropin levels were
both associated with an increased risk of incident AD in women but not in men [2].
The findings of this study should be tested in larger sample and gender issue should
be carefully considered. Moreover, it is worthwhile to explore the possibility of
regulation of thyroid function in the treatment of neuropsychiatric disorder in AD
In conclusion, this preliminary study indicates a possible relationship between
thyroid state and neuropsychiatric symptoms in euthyroid patients with AD. This may
be helpful in understanding the mechanism of neuropsychiatric disorder in patients
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with AD and exploring new therapeutic strategy.
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References
1. van OLA, Hogervorst E, Combrinck M, Smith AD. Low thyroid-stimulating
hormone as an independent risk factor for Alzheimer disease. Neurology 2004; 62(11):
1967-1971. ( PMID:15184598)
2. Tan ZS, Beiser A, Vasan RS, Au R, Auerbach S, Kiel DP, et al. Thyroid function
and the risk of Alzheimer disease: the Framingham Study. Arch Intern Med 2008;
168(14): 1514-1520. (PMID:18663163)
3. Kalmijn S, Mehta KM, Pols HA, Hofman A, Drexhage HA, Breteler MM.
Subclinical hyperthyroidism and the risk of dementia. The Rotterdam study. Clin
Endocrinol (Oxf) 2000; 53(6): 733-737. (PMID:11155096)
4. Thomas DR, Hailwood R, Harris B, Williams PA, Scanlon MF, John R. Thyroid
status in senile dementia of the Alzheimer type (SDAT). Acta Psychiatr Scand 1987;
76(2): 158-163. (PMID:3118642)
5. Volpato S, Guralnik JM, Fried LP, Remaley AT, Cappola AR, Launer LJ. Serum
thyroxine level and cognitive decline in euthyroid older women. Neurology 2002;
58(7): 1055-1061. (PMID:11940692)
6. Gussekloo J, van EE, de Craen AJ, Meinders AE, Frolich M, Westendorp RG.
Thyroid status, disability and cognitive function, and survival in old age. JAMA 2004;
292(21): 2591-2599. (PMID:15572717)
16
7. Baldini IM, Vita A, Mauri MC, Amodei V, Carrisi M, Bravin S, et al.
Psychopathological and cognitive features in subclinical hypothyroidism. Prog
Neuropsychopharmacol Biol Psychiatry 1997; 21(6): 925-935. (PMID:9380789)
8. Osterweil D, Syndulko K, Cohen SN, Pettler-Jennings PD, Hershman JM,
Cummings JL, et al. Cognitive function in non-demented older adults with
hypothyroidism. J Am Geriatr Soc 1992; 40(4): 325-335. (PMID:1556359)
9. van BMP, Menheere PP, Bekers O, Hogervorst E, Jolles J. Thyroid function,
depressed mood, and cognitive performance in older individuals: the Maastricht
Aging Study. Psychoneuroendocrinology 2004; 29(7): 891-898. (PMID:15177704)
10. Wahlin A, Bunce D, Wahlin TB. Longitudinal evidence of the impact of normal
thyroid stimulating hormone variations on cognitive functioning in very old age.
Psychoneuroendocrinology 2005; 30(7): 625-637. (PMID:15854779)
11. Prinz PN, Scanlan JM, Vitaliano PP, Moe KE, Borson S, Toivola B, et al. Thyroid
hormones: positive relationships with cognition in healthy, euthyroid older men. J
Gerontol A Biol Sci Med Sci 1999; 54(3): M111-116. (PMID:10191837)
12. Stuerenburg HJ, Arlt S, Mueller-Thomsen T. Free thyroxine, cognitive decline
and depression in Alzheimer's disease. Neuro Endocrinol Lett 2006; 27(4): 535-537.
(PMID:17136019)
13. Cummings J, Benson DF, LoVerme S Jr. Reversible dementia. Illustrative cases,
17
definition, and review. JAMA 1980; 243(23): 2434-2439. (PMID:6990044)
14. Stern RA, Prange AJ. Neuropsychiatric aspects of endocrine disorders. In: Kaplan
HI, Sadock BJ, eds. Comprehensive Textbook of Psychiatry, 4th ed. Baltimore:
Williams & Wilkins; 1995: 241–251.
15. Stern RA, Davis JD, Rogers BL, Smith KE, Harrington CJ, Ott BR, et al.
Preliminary study of the relationship between thyroid status and cognitive and
neuropsychiatric functioning in euthyroid patients with Alzheimer dementia. Cogn
Behav Neurol 2004; 17(4): 219-223. (PMID:15622018)
16. American psychiatric assosition. Diagnostic and statistical manual of mental
disorders. 4 th ed. Washington: American Psychiatric Press; 1994: 147–154.
17. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical
diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under
the auspices of Department of Health and Human Services Task Force on Alzheimer's
Disease. Neurology 1984; 34(7): 939-944. (PMID:6610841)
18. Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method
for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12(3):
189-198. (PMID:1202204)
19. Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer's disease. Am
J Psychiatry 1984; 141(11): 1356-1364. (PMID:6496779)
18
20. Pomara N, Ott BR, Peskind E, Resnick EM. Memantine treatment of cognitive
symptoms in mild to moderate Alzheimer disease: secondary analyses from a
placebo-controlled randomized trial. Alzheimer Dis Assoc Disord 2007; 21(1): 60-64.
(PMID:17334274)
21. Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J.
The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in
dementia. Neurology 1994; 44(12): 2308-2314. (PMID:7991117)
22. HAMILTON M. A rating scale for depression. J Neurol Neurosurg Psychiatry
1960; 23: 56-62. (PMID:14399272)
23. Hudson JI, Perahia DG, Gilaberte I, Wang F, Watkin JG, Detke MJ. Duloxetine in
the treatment of major depressive disorder: an open-label study. BMC Psychiatry
2007; 7: 43. (PMID:17725843)
24. Williams GR. Neurodevelopmental and neurophysiological actions of thyroid
hormone. J Neuroendocrinol 2008; 20(6): 784-794. (PMID:18601701)
25. Latasa MJ, Belandia B, Pascual A. Thyroid hormones regulate beta-amyloid gene
splicing and protein secretion in neuroblastoma cells. Endocrinology 1998; 139(6):
2692-2698. (PMID:9607774)
26. Belandia B, Latasa MJ, Villa A, Pascual A. Thyroid hormone negatively regulates
the transcriptional activity of the beta-amyloid precursor protein gene. J Biol Chem
19
1998; 273(46): 30366-30371. (PMID:9804800)
27. O'Barr SA, Oh JS, Ma C, Brent GA, Schultz JJ. Thyroid hormone regulates
endogenous amyloid-beta precursor protein gene expression and processing in both in
vitro and in vivo models. Thyroid 2006; 16(12): 1207-1213. (PMID:17199430)
28. Bianchi G, Solaroli E, Zaccheroni V, Grossi G, Bargossi AM, Melchionda N, et al.
Oxidative stress and anti-oxidant metabolites in patients with hyperthyroidism: effect
of treatment. Horm Metab Res 1999; 31(11): 620-624. (PMID:10598831)
29. Chan RS, Huey ED, Maecker HL, Cortopassi KM, Howard SA, Iyer AM, et al.
Endocrine modulators of necrotic neuron death. Brain Pathol 1996; 6(4): 481-491.
(PMID:8944318)
30. Sampaolo S, Campos-Barros A, Mazziotti G, Carlomagno S, Sannino V, Amato G,
et al. Increased cerebrospinal fluid levels of 3,3',5'-triiodothyronine in patients with
Alzheimer's disease. J Clin Endocrinol Metab 2005; 90(1): 198-202.
(PMID:15483087)
31. Dratman MB, Crutchfield FL, Gordon JT, Jennings AS. Iodothyronine
homeostasis in rat brain during hypo- and hyperthyroidism. Am J Physiol 1983;
245(2): E185-193. (PMID:6881331)
32. Leonard JL. Regulation of T3 production in the brain. Acta Med Austriaca 1992;
19 Suppl 1: 5-8. (PMID:1519453)
20
33. Silva JE, Leonard JL, Crantz FR, Larsen PR. Evidence for two tissue-specific
pathways for in vivo thyroxine 5'-deiodination in the rat. J Clin Invest 1982; 69(5):
1176-1184. (PMID:7068853)
34. Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR. Biochemistry, cellular
and molecular biology, and physiological roles of the iodothyronine
selenodeiodinases. Endocr Rev 2002; 23(1): 38-89. (PMID:11844744)
35. Lindeman RD, Schade DS, LaRue A, Romero LJ, Liang HC, Baumgartner RN, et
al. Subclinical hypothyroidism in a biethnic, urban community. J Am Geriatr Soc
1999; 47(6): 703-709. (PMID:10366170)
36. Wahlin A, Wahlin TB, Small BJ, Backman L. Influences of thyroid stimulating
hormone on cognitive functioning in very old age. J Gerontol B Psychol Sci Soc Sci
1998; 53(4): P234-239. (PMID:9679515)
37. Haggerty JJ Jr, Prange AJ Jr. Borderline hypothyroidism and depression. Annu
Rev Med 1995; 46: 37-46. (PMID:7598471)
38. Haggerty JJ Jr, Stern RA, Mason GA, Beckwith J, Morey CE, Prange AJ Jr.
Subclinical hypothyroidism: a modifiable risk factor for depression. Am J Psychiatry.
1993. 150(3): 508-510. (PMID:8434671)
39. de Jong FJ, Masaki K, Chen H, Remaley AT, Breteler MM, Petrovitch H, et al.
Thyroid function, the risk of dementia and neuropathologic changes: the
21
Honolulu-Asia aging study. Neurobiol Aging 2009; 30(4): 600-606.
(PMID:17870208)
40. Tekin S, Mega MS, Masterman DM, Chow T, Garakian J, Vinters HV, et al.
Orbitofrontal and anterior cingulate cortex neurofibrillary tangle burden is associated
with agitation in Alzheimer disease. Ann Neurol 2001; 49(3): 355-361.
(PMID:11261510)
41. Sultzer DL, Mahler ME, Mandelkern MA, Cummings JL, Van Gorp WG, Hinkin
CH, et al. The relationship between psychiatric symptoms and regional cortical
metabolism in Alzheimer's disease. J Neuropsychiatry Clin Neurosci 1995; 7(4):
476-484. (PMID:8555751)
42. Kimura N, Kumamoto T, Masuda H, Hanaoka T, Hazama Y, Okazaki T, et al.
Relationship between thyroid hormone levels and regional cerebral blood flow in
Alzheimer disease. Alzheimer Dis Assoc Disord 2011; 25(2): 138-143.
(PMID:20975518)
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Table 1. Demographic and Clinical Characteristics
Demographic and Clinical Characteristics
Mean(SD)
Age(years)
Education(years)
Illness Duration (years)
Height(cm)
Weight(kg)
MMSE
ADAS-cog
NPI
HAMD17
TT3(nmol/L)
TT4(nmol/L)
TSH(uU/ml)
67.08(6.92)
9.25(5.04)
3.58(1.77)
160.55(8.23)
60.90(11.17)
13.80(5.81)
36.18 (14.85)
16.45(16.15)
8.53(3.36)
2.00(0.52)
113.52 (31.01)
1.86 (1.30)
Reference range for TT3=0.92-2.79 nmol/L; TT4=58.1-140.6 nmol/L; TSH=0.3-5.0 uU/ml.
Table 2. Multivariate regression analysis of Thyroid Hormone Concentrations,
Demographics, Cognition and Mood Variables
Outcome Measurements
Age
Education
Duration
ADAS-cog (total score)
MMSE (total score)
HAMD17 (total score)
TT3
TT4
TSH
β
P
β
P
β
P
-0.006
0.024
-0.114
0.002
-0.006
0.053
0.643
0.263
0.092
0.893
0.859
0.117
-0.543
1.286
-2.108
0.363
1.475
1.743
0.496
0.331
0.602
0.680
0.450
0.395
0.019
0.039
0.144
-0.013
0.008
0.022
0.561
0.477
0.392
0.715
0.920
0.796
All statistical tests P>0.05
Table 3. Multivariate regression analysis of Thyroid Hormone Concentrations,
Demographics, ADAS-cog and HAMD Factor Scores
Outcome Measurements
Age
Education
Duration
ADAS-cog (language)
ADAS-cog (memory)
ADAS-cog (praxis)
HAMD17 (core)
*P<0.01
TT3
TT4
TSH
β
P
β
P
β
P
-0.010
0.005
-0.107
0.003
-0.020
0.085
0.107
0.458
0.818
0.113
0.922
0.284
0.139
0.070
-0.809
0.943
-1.824
-0.734
-0.213
1.145
2.360
0.341
0.517
0.673
0.716
0.862
0.756
0.530
-0.007
-0.010
0.002
-0.044
-0.081
0.118
0.395*
0.806
0.853
0.991
0.537
0.071
0.037
0.005*
23
Table 4. Comparison of Thyroid Hormone Concentrations among Groups with/without Neuropsychiatric Symptoms with NPI
Outcome Measurements
TT3
A
Delusions
Hallucinations
Agitation
Dysphoria
Anxiety
Apathy
Irritability
Euphoria§
Disinhibition§
Aberrant motor behavior
Nighttime behavior disturbances
Appetite and eating abnormalities
†
B
TT4
‡
1.95(0.45)
1.89(0.35)
2.03(0.44)
1.92(0.34)
1.96(0.42)
2.05(0.33)
1.96(0.45)
2.01(0.64)
2.39(0.79)
1,95(0.63)
2.13(0.72)
2.18(0.81)
1.99(0.55)
2.06(0.61)
1.97(0.45)
1.93(0.36)
2.00(0.53)
2.08(0.67)
2.10(0.68)
2.02(0.49)
†
TSH
B
‡
t
A
-0.753
-1.870
0.389
-1.065
-0.750
0.353
-0.591
NA
NA
-0.489
-0.940
-0.068
112.25(30.82)
110.41(29.11)
114.75(32.06)
114.34(30.56)
114.87(29.57)
104.00(23.10)
114.80(32.03)
116.15(32.51)
124.25(36.64)
111.47(30.16)
112.16(32.79)
108.11(37.99)
115.20(32.19)
111.60(30.34)
113.54(30.40)
109.42(31.89)
112.54(31.65)
113.48(34.10)
119.07(29.81)
122.38(26.46)
B‡
t
1.72(1.03)
1.88(1.20)
1.51(1.06)
1.58(1.05)
1.71(1.06)
1.23(0.78)
1.39(0.69)
2.16(1.74)
1.78(1.68)
2.44(1.48)
2.32(1.56)
2.45(1.97)
1.97(1.35)
2.56(1.67)
1.88(1.19)
1.60(1.20)
1.86(1.35)
1.81(1.62)
2.21(1.38)
1.83(0.89)
-0.857
0.169
-2.130||
-1.627
-1.026
-1.882
-2.657||
NA
NA
0.126
-1.471
0.068
t
A
-0.362
-1.042
0.325
0.208
0.469
-1.025
0.320
NA
NA
0.005
-0.983
-0.691
†
† A is non-neuropsychiatric symptoms group. ‡ B is neuropsychiatric symptoms group. § No further statistical analyses due to the sample size. || P<0.05.