Brain, Behavior, and Immunity xxx (2014) xxx–xxx

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Cognitive and affective dysfunctions in autoimmune thyroiditis Thomas Leyhe a,⇑, Karsten Müssig b,c a

Center of Old Age Psychiatry, Psychiatric University Hospital, Basel, Switzerland Department of Endocrinology and Diabetology, University Hospital Düsseldorf, Düsseldorf, Germany c Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany b

a r t i c l e

i n f o

Article history: Received 19 December 2013 Received in revised form 7 March 2014 Accepted 14 March 2014 Available online xxxx Keywords: Hashimoto’s thyroiditis Hashimoto’s encephalopathy Anti-TPO antibodies Anti-CNS antibodies Affective disorders Cognition Psychosocial well-being

a b s t r a c t Hashimoto’s thyroiditis (HT) is the most frequent cause of hypothyroidism in areas with sufficient iodine intake. While the impact of thyroid function on mood and cognition is well known, only in the recent years, an increasing number of studies report on the association of HT with cognitive and affective disturbances also in the euthyroid state. Recent imaging studies have shown that these impairments are accompanied by altered brain perfusion, in particular, in the frontal lobe and a reduced gray matter density in the left inferior gyrus frontalis. Brain function abnormalities in euthyroid patients with HT may be subtle and only detected by specific testing or even severe as it is the case in the rare neuropsychiatric disorder Hashimoto’s encephalopathy (HE). The good response to glucocorticoids in patients with HE indicates an autoimmune origin. In line with this, the cognitive deficits and the high psycho-social burden in euthyroid HT patients without apparent signs of encephalopathy appear to be associated with anti-thyroid peroxidase auto-antibody (TPO Abs) levels. Though in vitro studies showing binding of TPO Abs to human cerebellar astrocytes point to a potential direct role of TPO Abs in the pathogenesis of brain abnormalities in HT patients, TPO Abs may function only as a marker of an autoimmune disorder of the central nervous system. In line with this, anti-central nervous system auto-antibodies (CNS Abs) which are markedly increased in patients with HT disturb myelinogenesis in vitro and, therefore, may impair myelin sheath integrity. In addition, in HT patients, production of monocyte- and T-lymphocyte-derived cytokines is also markedly increased which may negatively affect multiple neurotransmitters and, consequently, diverse brain neurocircuits. Ó 2014 Elsevier Inc. All rights reserved.

1. Introduction Autoimmune thyroiditis (AIT) is a usually painless chronic lymphocytic inflammation of the thyroid gland in the absence of signs or symptoms of systemic infection. Within the course of the disease, thyroid function gradually declines. In the presence of overt hypothyroidism, diagnosis of Hashimoto’s thyroiditis (HT) can be made. In contrast, the sole detection of thyroid auto-antibodies (TAA) does not allow this diagnosis. In the beginning of the disease, a usually subclinical hyperthyroidism can occur resulting from the inflammation process and the subsequent liberation of preformed thyroid hormones (Fatourechi et al., 1971). This transient overt hyperthyroidism followed by a sudden onset of hypothyroidism is also known as hashitoxicosis. AIT is the most common organspecific autoimmune disease and represents the most frequent ⇑ Corresponding author. Address: Center of Old Age Psychatry, Psychiatric University Hospital, Wilhelm Klein-Strasse 27, CH-4012 Basel, Switzerland. Tel.: +41 (0)61 325 53 53; fax: +41 (0)61 325 55 85. E-mail address: [email protected] (T. Leyhe).

cause of hypothyroidism in areas of sufficient iodine intake (Vanderpump and Tunbridge, 2002). Women are ten times more often affected than men. AIT is characterized by a familial predisposition and the association with other autoimmune diseases, such as vitiligo, pernicious anemia, or coeliac disease. Hormonal changes during puberty, parturition, or menopause as well as stressful life events favor the development of thyroid autoimmunity (Pearce et al., 2003). Thyroid function has significant impact on cognitive functioning and mood in humans. Overt hypothyroidism is associated with diverse neuropsychological and psychiatric disorders, such as attention deficits, concentration and memory impairments, psychomotor retardation, depressive mood, anxiety, and delusions of persecution (Bauer et al., 2008). Even if not shown by all studies, there are hints that minor deficits of cognitive functions, including memory and verbal fluency, occur already in subclinical hypothyroidism (Baldini et al., 1997; Monzani et al., 1993). Furthermore, subclinical hypothyroidism is associated with an increased risk of depression and dementia (Davis et al., 2003). The strong influence of thyroid hormones on

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neuropsychiatric functions has been shown also in several intervention studies. Application of triiodothyronine (T3) accelerates the response to tricyclic antidepressants and some studies indicate that T3 may improve the therapeutic response to antidepressants in refractory depressed patients. Furthermore, adjunct treatment with supraphysiological doses of thyroxine (T4) ameliorates the depressive symptomatic and helps to stabilize the long-term course of bipolar and unipolar disorders, in particular in females refractory to standard treatment (Bauer et al., 2008). While the correlations between thyroid function disorders and neuropsychiatric alterations are known for many years (Whybrow et al., 1969), only in the recent years an increasing number of studies point to an association between AIT and cognitive and affective disorders also in the euthyroid state. Brain imbalances in euthyroid patients with AIT may be subtle and only detected by specific testing, or severe as it is the case in the rare neuropsychiatric disorder Hashimoto’s encephalopathy (HE). 2. Hashimoto’s encephalopathy HE is also known as Hashimoto’s encephalitis and steroidresponsive encephalopathy associated with autoimmune thyroiditis (SREAT). Though its aetiology and pathogenesis remain elusive, the characteristic high levels of TAA in blood and cerebrospinal fluid (CSF) as well as good response to glucocorticoid treatment indicate, however, an autoimmune origin. In a recent comprehensive overview, 96% of the patients receiving glucocorticoids responded well to this treatment (Chong et al., 2003). In some cases, therapy of HE requires, in addition to glucocorticoids, treatment of the thyroid function disorder and potential seizures (Leyhe et al., 2007). In 95–100% of cases increased anti-thyroid peroxidase autoantibodies (TPO Abs) and in 73% of cases anti-thyroglobulin autoantibodies (Tg Abs) are detected in the sera of affected patients, though there is no correlation between the TAA levels and the severity of clinical symptoms (Kothbauer-Margreiter et al., 1996). TPO Abs are also found in the CSF of patients with HE (Ferracci et al., 2003). Owing to the binding of TPO Abs to human cerebellar astrocytes (Blanchin et al., 2007), these TAA may contribute to the pathogenesis of HE. Alternatively, TPO Abs may represent only a marker for another autoimmune disease of the brain. According with this assumption, in the serum of a female with typical clinical, laboratory, and electrophysiological signs of HE, Oide et al. detected an anti-neuronal auto-antibody targeting a protein with a mass of 36 kDa which is found in the human cortex (Oide et al., 2004). In an additional study, anti-neuronal autoantibodies were detected in serum and CSF of patients with HE. These auto-antibodies were directed against two enzymes which are expressed in endothelial cells, glial cells, and neurons of the brain: dimethylargininase-I (DDAHI, 31 kDa) and aldehyd reductase-I (AKRIAI, 36 kDa) (Gini et al., 2008). The development of HE could be also based on vasculitic changes of the central nervous system (CNS). This assumption results from the brain autopsy findings of a 77-year-old female patient who showed increased TPO Abs, electroencephalogram (EEG) alterations, and glucocorticoid-sensitive neuropsychiatric symptoms before her death of heart failure. Histology revealed vasculitic infiltrates consisting predominantly of CD3-positive T cells in veins and venules of the brainstem. In addition, lymphocytic infiltrates were also found in the leptomeninx of the cortex, cerebellum, and brainstem (Nolte et al., 2000). Vasculitic changes of the posterior cerebral arteries and left posterior infarction, as shown by magnetic resonance imaging (MRI), were also found in a female HT patient with neurological abnormalities comprising right upper quadrant anopsia and subtle right-sided sensory loss and weakness. The patient’s history was unremarkable for

cardiovascular risk factors, systemic vasculitis, or thromboembolic disorders (Becker et al., 2002). Based on the clinical symptoms, two subtypes of HE are differentiated: a relapsing and remitting vasculitis type with stroke-like episodes and only subtle cognitive deficits and a chronic progressive type characterized by rapidly developing dementia and psychiatric symptoms. Besides, both types can be associated with tremor, myoclonus, seizures, and vigilance disturbances including coma, hypersomnia, and ataxia (Kothbauer-Margreiter et al., 1996). After the description of a 49-year-old patient with HT by Brain et al. in 1966 who suffered from disturbances of consciousness, confusion, hallucinations, hemiparesis, aphasia, tremor, and relapsing stroke-like episodes (Brain et al., 1966), in the following years several additional patients with increased TAA and noninfectious encephalopathy have been reported in the literature as single case reports. In 2003, Chong et al. reviewed a total of 85 cases published till then. Women significantly predominated with 81% of cases. Mean age was 44 years. The clinical symptoms comprised seizures (66% of patients), myoclonus (38% of patients), psychosis (36% of patients), and stroke-like episodes (27% of patients) (Chong et al., 2003). In light of the broad range of clinical symptomatology that included focal neurological deficits as well as diffuse brain alterations (Hartmann et al., 2000), diagnosis of HE is, in the end, a diagnosis of exclusion. In 78% of cases in which CSF analysis was performed protein concentration was increased without pleocytosis (Chong et al., 2003), indicating a blood-CSF barrier disturbance or, alternatively, an intrathecal synthesis of immunoglobulins (Ferracci et al., 2003). Ninety-eight percent of cases in which EEG was done showed pathological findings (Chong et al., 2003). The extent of EEG changes usually correlated with the severity of the clinical picture. In parallel to the improvement of the clinical symptoms the EEG normalizes (Laske et al., 2004; Müssig et al., 2005; Schäuble et al., 2003). Characteristic EEG findings in HE comprise generalized slowing which can be continuous or intermittent and diffuse or focal as well as delta waves (Ferracci et al., 2003). Brain imaging was unremarkable in most of the patients (Chong et al., 2003). Seldomly abnormalities are found (Hartmann et al., 2000). While in one third of patients, thyroid function was stable, in the majority of patients, thyroid function was impaired, in terms of silent (40% of cases) and overt (23% of cases) hypothyroidism and hyperthyroidism (7% of cases) (Chong et al., 2003). The thyroid gland is frequently enlarged (Kothbauer-Margreiter et al., 1996). 3. Cognition in euthyroid HT patients In addition to neuropsychiatric symptoms, such as stroke-like episodes, seizures, disorientation, hallucinations, myoclonus, and ataxia, patients with HE can also suffer from cognitive deficits. In particular, verbal and visual memory as well as concentration are affected (Cummings et al., 2007; Kothbauer-Margreiter et al., 1996). Without doubt, HE is an extreme form of a deterioration of the CNS in patients with HT. Thus, it arises the question whether cognitive deficits can also be found in euthyroid HT patients without such signs of encephalopathy. To answer this question, we investigated systematically euthyroid patients with HT for cognitive deficits using an established, standardized, neuropsychological test battery in comparison with patients with thyroid diseases of non-autoimmune origin (Leyhe et al., 2008). Neuropsychological testing included the examination of executive function, visual and verbal memory, and working memory. Executive functions comprise organizing, task prioritizing, managing time efficiently, and decision making and are primarily located in the prefrontal cortex. Visual and verbal memory refers to the ability to store and retrieve visual and verbal information and is localized to the medial temporal lobe. Working memory comprises subsystems that temporarily store and manipulate visual images or verbal

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information involved in the performance of complex cognitive tasks such as reasoning, comprehension, and certain types of learning. The frontal cortex, parietal cortex, anterior cingulate, and the basal ganglia are crucial for working memory. However, comparison of both groups did not reveal significant differences for executive function, visual and verbal memory, and working memory (Leyhe et al., 2008). But significantly more patients of the HT group showed results below the normal range in the d2 test which assesses attention and response inhibition, indicating a subtle brain function alteration in a subgroup of HT patients. Other cerebro-organic causes of cognitive deficits were ruled out by EEG and MRI. Furthermore, HT patients with results below the normal range in the d2 test showed a significant increased mean value of TPO Abs compared to HT patients with normal test results (Leyhe et al., 2008). The exact role of TPO Abs remains currently unclear. In light of a previous study showing the binding of TPO Abs to human cerebellar astrocytes (Blanchin et al., 2007), TPO Abs could play a direct role in the pathogenesis. Alternatively, TPO Abs could represent a marker of another autoimmune disease of the CNS. In line with this assumption, we found a markedly increased antibody reactivity against CNS and gangliosides in patients with HT compared to patients with other thyroid diseases (Müssig et al., 2009). Anti-CNS auto-antibodies (CNS Abs) are associated with the occurrence of neuropsychiatric symptoms in connective disorders, such as systemic lupus erythematosus (SLE), comprising organic brain syndrome, psychosis as well as subtle neurological (cephalgia, paresthesia) and psychiatric symptoms (reactive depression, mood swings) (Weiner et al., 2000). In light of previous in vitro studies showing that CNS Abs containing serum markedly disturbed myelinogenesis (Dorfman et al., 1979), CNS Abs may impair the myelin sheath. Also anti-ganglioside antibodies (ganglioside Abs) have been detected in SLE patients with neuropsychiatric involvement (Hirano et al., 1980). Antibodies targeted against brain-specific antigens, including gangliosides, are associated with

(a)

cognitive deficits, psychosis, and depression in patients with SLE (Zandman-Goddard et al., 2007). A previous animal study that revealed an inhibition of axon regeneration by ganglioside Abs points to a potential role of these antibodies in the pathogenesis of autoimmune disorders of the CNS (Lehmann et al., 2007). The clinical evaluation of the antibodies directed against CNS tissue and gangliosides did neither reveal an association with the prevalence of depression or other neuropsychiatric diseases nor with alterations of cognitive functions as assessed with a neuropsychological test battery (Müssig et al., 2009). Therefore, the exact role of CNS and ganglioside Abs which are markedly increased in HT patients remains to be established in future studies. A further mechanism which may link HT to brain imbalances involves cytokines. Previous studies showed an increased monocyte cytokine production, including monocyte chemoattractant protein-1 (MCP-1), and T-lymphocyte cytokine production, including interferon gamma (INF-c) and tumor necrosis factor alpha (TNF-a), in patients with HT. In addition, the monocyte and T-lymphocyte cytokine patterns were associated with the TPO Abs levels (Kokkotou et al., 2002; Karanikas et al., 2005). In line with these results, a previous study showed a decrease of interleukin-12 (IL-12) serum levels in parallel to the reduction of TPO Abs after substitutive treatment with L-thyroxine in patients with HT (Guclu et al., 2009). Inflammatory cytokines appear to negatively impact multiple neurotransmitters, comprising serotonin, dopamine, and glutamate, by altering their synthesis, release, and reuptake. These deleterious effects result in alterations of diverse brain neurocircuits and, consequently, in significant impairments in motor activity and motivation as well as anxiety, arousal, and alarm (Miller et al. 2013). The potential mechanisms how HT may contribute to brain imbalances are summarized in Fig. 1. In light of the key role of the left inferior frontal gyrus (LIFG) for attention and response inhibition, i.e., the cognitive functions which are impaired in a subgroup of HT patients, we studied the

(b)

(c)

B lymphocyte

B lymphocyte

Abs production

T lymphocyte

Abs production

Monocyte

Cytokine production

TPO Abs

TNF-α

Neuron

MCP-1

INF-γ

Astrocyte CNS Abs

Synapsis

Fig. 1. Potential mechanisms how euthyroid Hashimoto’s thyroiditis (HT) may contribute to brain imbalances. (a) Anti-thyroid peroxidase auto-antibodies (TPO Abs) bind to human astrocytes and could, consequently, play a direct role in the pathogenesis. (b) Anti-central nervous system auto-antibodies (CNS Abs) which are markedly increased in patients with HT disturb myelinogenesis in vitro and, therefore, may impair myelin sheath integrity. (c) Monocyte cytokine production, including monocyte chemoattractant protein-1 (MCP-1), and T-lymphocyte cytokine production, including interferon gamma (INF-c) and tumor necrosis factor alpha (TNF-a), are markedly increased in patients with HT. Inflammatory cytokines negatively impact multiple neurotransmitters, comprising serotonin, dopamine, and glutamate, by altering their synthesis, release, and reuptake resulting in alterations of diverse brain neurocircuits.

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association between the performance in the d2 test and the gray matter (GM) density of the LIFG in euthyroid HT patients in comparison to patients with non-autoimmune thyroid diseases (Leyhe et al., 2013). The GM density in the opercular part of the LIFG was significantly associated with the result in the d2 test in patients with HT, but not in the control group. Furthermore, GM density was significantly reduced when comparing HT patients with control patients that scored in the lower third during the d2 test. Thus, in patients with HT in contrast to other thyroid disorders, performance in the d2 test appears to depend on GM density of the LIFG and particularly low results were associated with reduced GM density of this brain region. In line with the morphological brain changes in the frontal lobe of HT patients with attention deficits, two previous imaging studies showed impairments in the brain perfusion in euthyroid HT patients (Piga et al., 2004; Zettinig et al., 2003), in particular in the frontal lobe (Piga et al., 2004). 4. Psychosocial well-being in euthyroid HT patients In addition to cognitive impairments, several studies point to a diminished psychosocial well-being in patients with HT despite euthyroid state. In a recent work, we found a poorer physical and psychic well-being in TPO Abs-positive HT patients compared to TPO Abs-negative HT patients despite stable thyroid function in both groups (Müssig et al., 2012). TPO Abs were associated with several categories of the established Symptom Checklist-90-R (SCL-90R), including the three global scores GSI (Global Severity Index) which measures the overall psychological distress, PSDI (Positive Symptom Distress Index) which measures the intensity of symptoms, and PST (Positive Symptom Total) which reports number of self-reported symptoms. Furthermore, HT patients positive for TPO-Abs showed poorer results in the three domains somatization, obsessive–compulsive symptoms, and depression (Müssig et al., 2012). In a previous study, Bianchi et al. (2004) had already demonstrated that in euthyroid HT patients a number of scales of the Short Form-36 (SF-36) questionnaire, comprising physical role functioning, emotional role functioning, general health perceptions, and social role functioning, and of the Nottingham Health Profile (NHP) questionnaire, such as social isolation and pain, were impaired compared to normal ranges from the general population. In accordance with these results, Ott et al. (2011) reported significant differences for a number of SF-36 scales, including general health perceptions, physical role functioning, vitality, social role functioning, and mental health, in patients with TPO Abs exceeding more than twofold of the upper reference range compared to patients with TPO Abs below the defined cut-off value. Besides, patients with TPO Abs above the cut-off value reported significantly more often symptoms on a symptom questionnaire, such as chronic fatigue, dry hair, easy fatigability, dysphagia, and chronic irritability. The total symptom score associated with the TPO Abs level (Ott et al., 2011). Moreover, TPO Abs reactivity appears to predict future health perception. In a stepwise regression analysis with the three global scores of the SCL90-R GSI, PSDI, and PST at present as dependent variables and age, disease duration, thyroid-stimulating hormone (TSH) levels, and TPO Abs reactivity three years earlier as independent variables, TPO Abs reactivity was the only parameter that predicted a poorer psychosocial well-being, as assessed by the three global scores (Müssig et al., 2012). These impairments may predispose to overt psychiatric diseases and the question arises whether HT is associated with psychiatric, especially affective disorders. 5. Affective disorders in HT patients In recent years, several studies investigated the association of HT with affective disorders. Gold et al. (1982) found in 15% of

inpatients with depressive disorders thyroid dysfunctions. A greater part of this group had positive TPO Abs. Also Fountoulakis et al. (2004) found in depressive patients significantly more TAA than in healthy controls. In another study nearly 70% of depressive inpatients showed positive TAA (König et al., 1999). An epidemiological investigation (Pop et al., 1998) demonstrated in perimenopausal women with positive TAA a markedly elevated risk for depressive symptoms. This finding was confirmed by another epidemiological study (Carta et al., 2004) that showed an increased risk in subjects with increased TAA to develop an anxiety disorder or a depression. In the same direction pointed the results of a case-control study revealing that subjects with HT had higher frequencies of lifetime depressive episode, generalized anxiety disorders, and social phobia whilst no differences were found between subjects with goitre and controls (Carta et al., 2005). Also Bunevicius et al. (2007) found particularly in perimenopausal female patients more frequently affective symptoms. In contrast, a great epidemiological study from Scandinavia (Engum et al., 2005) did not demonstrate an association between TAA and depressive symptoms. Kupka et al. (2002) showed in outpatients with bipolar disorders compared with healthy controls or inpatients with other psychiatric diagnoses significantly higher rates of subjects with elevated TAA. This finding was confirmed in a Dutch study (Oomen et al., 1996) particularly in patients with rapid cycling of bipolar disorders. Moreover a twin study indicated that AIT is associated with a genetic vulnerability to develop a bipolar disorder, i.e. it could be an endophenotype of the bipolar disorder (Vonk et al., 2007). Also it was shown that female offspring of bipolar parents have an increased risk to develop AIT (Hillegers et al., 2007). In contrast, an Italian study did not detect increased TAA in patients with rapid-cycling or non-rapid-cycling bipolar disorders (Bartalena et al., 1990). Also Hornig et al. (1999) did not find in inpatients of a retrospective study a clear association of affective symptoms and TAA, just like an American study in hospitalized patients (Haggerty et al., 1997). In an own study, the comparison of depressed patients with elevated and normal TAA revealed that 63.2% of patients with positive TAA and only 28.6% of patients with negative TAA had a clinically severe degree of the current depressive episode. Thus, patients with positive TAA had significantly more often a major depressive episode than patients with normal TAA (Leyhe et al., 2009). A recent single-photon emission computed tomography (SPECT) study found an asymmetry of the parietal cerebral blood flow only in depressed patients with AIT, but not in depressives without autoimmune thyroid disease (Hardoy et al., 2011). In addition, Eller et al. (2010), although showing no significant difference in the prevalence of TAA in depressed patients compared with healthy controls, demonstrated a statistical trend that depressed patients who did not respond to treatment with the selective serotonin reuptake inhibitor escitalopram, exhibited increased TAA. Overall, the presence of TAA appears to be associated with poor response to antidepressant therapy (Prange et al., 1990). In total, though not shown in all studies, there is strong evidence that the presence of TAA plays a role in mood disorders even in euthyroid metabolic state. Recently, it was demonstrated that high TPO Abs titres correlate with increased frequencies of T cells producing Th/Tc1 cytokines in HT pointing to a link between thyroid autoimmunity and immunological changes (Karanikas et al., 2005). There is also evidence for the involvement of the immune system in depression from previous studies (Irwin and Miller, 2007). In depressed patients, alterations of the immune system result in an increased total number of white blood cells as well as the number and percentage of neutrophils and lymphocytes. Enumeration of subsets of lymphocytes has also revealed that depression is associated with a decrease in the number and percentage of lymphocytes (B cells, T cells, T helper cells, and T suppressor/cytotoxic

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cells), as well as a decrease in the circulating number of cells that express the natural killer cell phenotype (Zorilla et al., 2001). In addition, increased levels of cytokines, such as interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), und gamma-Interferon (IFN-gamma), have been found (Seidel et al., 1996; Sluzewska et al., 1996). Also it is discussed whether the application of cytokines or interferons can cause depressive disorders (Leonard, 2001; Zephir et al., 2003). Depressive disorders occur at high rates in patients with multiple sclerosis (MS). The immunopathology of this disease may be involved in the clinical expression of affective disorders (Goldman Consensus Group, 2005). In mice with experimental autoimmune encephalomyelitis (EAE), a depression-like behavioral syndrome has been demonstrated. EAE and depression are associated with common physiological alterations, including impaired serotonergic neurotransmission and the activation of the neuroendocrine and inflammatory cytokine systems (Pollak et al., 2000). Several studies showed that cytokines influence the metabolism of multiple neurotransmitters such as serotonin, dopamine, and glutamate through impact on their synthesis, release, and reuptake. Cytokines also activate the kynurenine pathway, which not only depletes tryptophan, the primary amino acid precursor of serotonin, but also generates neuroactive metabolites that can significantly influence the regulation of dopamine and glutamate (Miller et al., 2013; Catena-Dell’Osso et al., 2013). In summary there might be a link between thyroid autoimmunity, alterations in the immune system and neurotransmitter changes that could cause depressive disorders, influence the course of disease and weaken the response to antidepressant treatment. 6. Conclusions Thyroid dysfunctions are known to be associated with alterations of brain function. In recent years, however, there is growing evidence that HT is associated with affective and psycho-social impairments despite an euthyroid state. Though in vitro studies point to a potential direct role of TPO Abs in the pathogenesis of these brain abnormalities, TPO Abs may function only as a marker of an autoimmune disorder of the CNS. In line with this, CNS Abs as well as monocyte and T-lymphocyte-derived cytokines are markedly increased in HT and may negatively impact brain integrity and function. To further elucidate the association between HT and affective and psycho-social impairments, the impact of CNS Abs positivity and increased cytokine levels on cognitive and affective function should be evaluated in future longitudinal studies. Furthermore, it would be of interest whether CNS Abs or inflammatory cytokines are more frequently found in the CSF of HT patients. Autopsy studies analyzing TAA, CNS Abs, and inflammatory cytokines in relevant brain regions, such as the LIFG, could bring further insight in the pathophysiology of the brain function alterations in HT patients. References Baldini, I.M., Vita, A., Mauri, M.C., Amodei, V., Carrisi, M., Bravin, S., Cantalamessa, L., 1997. Psychopathological and cognitive features in subclinical hypothyroidism. Prog. Neuropsychopharmacol. Biol. Psychiatry 21, 925–935. Bartalena, L., Pellegrini, L., Meschi, M., Antonangeli, L., Bogazzi, F., Dell´ Osso, L., Pinchera, A., Placidi, G.F., 1990. Evaluation of thyroid function in patients with rapid cycling and nonrapid-cycling bipolar disorder. Psychiatry Res. 34, 13–17. Bauer, M., Goetz, T., Glenn, T., Whybrow, P.C., 2008. The thyroid-brain interaction in thyroid disorders and mood disorders. J. Neuroendocrinol. 20, 1101–1114. Becker, H., Hofmann, M., Von Einsiedel, H., Conrad, B., Sander, D., 2002. Umschriebene Vaskulitis mit Posteriorinfarkt bei Hashimoto-Encephalopathie. Nervenarzt 73, 376–379. Bianchi, G.P., Zaccheroni, V., Solaroli, E., Vescini, F., Cerutti, R., Zoli, M., Marchesini, G., 2004. Health-related quality of life in patients with thyroid disorders. Qual. Life Res. 13, 45–54.

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