**2. Neuroprotective effects of lithium: relevance to pathology of Alzheimer's disease**

The neuroprotective effect of lithium in bipolar patients has been reflected in neuroimaging studies, starting in 2000, when Moore et al. [4] in a research letter to the Lancet suggested a lithium-induced increase in human brain gray matter. Since then, several researches on this topic have been published. The prefrontal cortex, anterior cingulate, and hippocampus made the brain structures most frequently shown to be influenced by either short- or long-term lithium treatment. The results of cross-sectional and prospective studies on this issue were recently reviewed by Hajek and Weiner [5].

Among cross-sectional studies, the most frequently reported pattern was larger gray matter volumes in patients currently treated with lithium compared to those currently not on lithium. The association between lithium treatment and higher gray matter volume was reported regardless of mood state and diagnostic subtype [5]. Our research showed that bipolar patients receiving lithium had larger hippocampal volumes than non-lithium patients and comparable to healthy controls [6].

In a prospective study, Monkul et al. [7] performed a voxel-based morphometry analysis in healthy persons receiving lithium in therapeutic doses for 4 weeks. They found a significant increase in gray matter in the left and right dorsolateral prefrontal cortices and the left anterior cingulate region. Yucel et al. [8] made neuroimaging study in BD patients receiving lithium up to 2 months and for 2–4 years showing a bilateral increase in hippocampal volume in both groups. Moore et al. [9] extended their results published 9 years earlier as they found that an increase in total gray matter volume in the prefrontal cortex of depressed bipolar subjects after 4 weeks of lithium administration was significant only in lithium responders.

The neuroimaging studies were also performed to compare lithium with valproate, carbamazepine, and antipsychotics, given to BD patients. In a paper of Lyoo et al. [10] including 22 BD patients treated with either lithium or valproate, the gray matter increased in lithium group, with maximum effect at weeks 10–12 which was still evident at 16 weeks of treatment. Such an increase was also associated with positive clinical response. On the other hand, patients receiving valproate did not show any significant changes in gray matter volume. Germana et al. [11] in their study of 74 remitted bipolar patients receiving long-term prophylactic treatment with lithium, valproate, carbamazepine, or antipsychotics observed that the volume of gray matter in some brain structures (the right subgenual anterior cingulate gyrus, the left postcentral gyrus, the hippocampus/amygdala complex, and the insula) was greater in patients receiving lithium than all other pharmacological treatments.

The main pathology of the AD includes the intracellular accumulation of neurofibrillary tangles, connected with abnormal tau protein phosphorylation, and extracellular deposition of amyloid-beta (Aβ) plaques. Such changes may be present even several years before symptom manifestation. However, in recent years, the evidence has been accumulated that some other factors may be both pathogenic and playing a role in the progress of the illness. They include, among others, dysregulated glycogen synthase kinase-3 (GSK-3) activity, mitochondrial dys-

Over the last two decades, the evidence accumulated for neuroprotective effects of lithium as important mechanisms of this ion in mood disorders. These effects were reflected by an increase in cerebral gray matter volume in lithium-treated subjects and also related to a possible influence of lithium on some pathogenic mechanisms operating in the AD. Such neurobiological mechanisms of lithium which may be relevant to AD pathogenesis, and treatment will be characterized in the first part of this article. They make lithium a candidate for use as a therapeutic drug in this illness [3]. In the recent decade, a negative association between lithium use and dementia has been shown in most epidemiological studies, including two most recent papers regarding a concentration of lithium in drinking water. In this article, preliminary studies of using lithium in the treatment of mild cognitive impairment (MCI) and

**2. Neuroprotective effects of lithium: relevance to pathology of** 

The neuroprotective effect of lithium in bipolar patients has been reflected in neuroimaging studies, starting in 2000, when Moore et al. [4] in a research letter to the Lancet suggested a lithium-induced increase in human brain gray matter. Since then, several researches on this topic have been published. The prefrontal cortex, anterior cingulate, and hippocampus made the brain structures most frequently shown to be influenced by either short- or long-term lithium treatment. The results of cross-sectional and prospective studies on this issue were

Among cross-sectional studies, the most frequently reported pattern was larger gray matter volumes in patients currently treated with lithium compared to those currently not on lithium. The association between lithium treatment and higher gray matter volume was reported regardless of mood state and diagnostic subtype [5]. Our research showed that bipolar patients receiving lithium had larger hippocampal volumes than non-lithium patients and comparable

In a prospective study, Monkul et al. [7] performed a voxel-based morphometry analysis in healthy persons receiving lithium in therapeutic doses for 4 weeks. They found a significant increase in gray matter in the left and right dorsolateral prefrontal cortices and the left anterior cingulate region. Yucel et al. [8] made neuroimaging study in BD patients receiving lithium up to 2 months and for 2–4 years showing a bilateral increase in hippocampal volume in both groups. Moore et al. [9] extended their results published 9 years earlier as they found that an increase in total gray matter volume in the prefrontal cortex of depressed bipolar subjects after 4 weeks of lithium administration was significant only in lithium responders.

function, inflammation, and oxidative stress [2].

80 Alzheimer's Disease - The 21st Century Challenge

AD that show some promise will also be presented.

recently reviewed by Hajek and Weiner [5].

**Alzheimer's disease**

to healthy controls [6].

Thus, there is reasonable evidence showing that lithium administration can result in an increase of brain gray matter volume both in healthy subjects and in patients with BD which may be associated with its neuroprotective effect at a clinical level. The replicated substantiation for this has not been demonstrated for any other mood-stabilizing drug. The mechanism of the increase is not clear. The MRI changes are probably not related to the effect of lithium on tissue water or magnetic properties. Since the studies of magnetic resonance spectroscopy showed the association between lithium treatment and increased N-acetyl aspartate, localized in neurons, this may suggest an effect of lithium on neurons, which may involve an increase in the number of neurons, dendritic arborization, or neutrophil [5].

Several biochemical targets have been involved in the neurotrophic and neuroprotective effect of lithium which may be relevant to its possible disease-modifying treatment in the AD. The most important include the increased expression of neurotrophins [mainly brain-derived neurotrophic factor (BDNF)], the inhibition of glycogen synthase kinase-3 (GSK-3), modulation of the phosphatidylinositide (PI) cascade, inhibition of the protein kinase C (PKC), and increased expression of the B-cell lymphoma 2 (Bcl-2). As a result of such actions, lithium increases cell survival by promoting neurogenesis in the adult brain and by inhibiting cell death (apoptosis) cascades [12].

BDNF belongs to the neurotrophin family, along with nerve growth factor (NGF) and neurotrophin-3 (NT-3), NT-4, NT-5, and NT-6. These neurotrophins play an important role for the survival and function of neurons. BDNF regulates the activity of various neurotransmitters, e.g., glutamate, gamma-aminobutyric acid, dopamine, and serotonin. Experimental studies showed that lithium enhances the BDNF system. In clinical studies, lithium treatment increases the blood level of BDNF [13].

GSK-3 modulates a number of cellular processes, among others, cell apoptosis, and the inhibition of GSK-3 results in an antiapoptotic effect. GSK-3 is also a key enzyme in the metabolism of amyloid precursor protein and in the phosphorylation of the tau protein, the main pathological processes in AD. Lithium inhibits GSK-3 activity, and the evidence for this has accumulated in recent two decades, using various experimental models. Therefore, the GSK-3 can be considered as one of the most important therapeutic targets of lithium, and the GSK-3 inhibition by this ion can make an essential mechanism of its therapeutic action in mood disorders [14]. In experimental studies, using the cultures of rat neurons, it was shown that lithium reduces GSK-3 mRNA [15]. In mutant tau transgenic mice with neurofibrillary pathology, lithium delays the progress of neurofibrillary tangles, and in the *Drosophila* fly, adult-onset model of the AD, lithium alleviates amyloid-beta pathology. Both these effects are thought to be obtained by lithium inhibition of the GSK-3 [16, 17]. About the GSK-3 inhibition by lithium, the effect of this ion on autophagy regulation should also be indicated, the signaling pathway of which is associated with the mammalian target of rapamycin (mTOR) [18].

In their publication in 2005, Dunn et al. [27] reported that among 19,328 participants selected from a General Practice Research Database, more subjects with dementia were treated with Li compared to control subjects without dementia. However, mood disorders are the most frequent indication for Li treatment and also belong to the strongest risk factors for dementia, and as this study did not control for compliance/optimal treatment, it may have simply detected the increased risk of dementia in mood disorders. Terao et al. [28] investigated clinical records of 1423 outpatients at a university psychiatric department and compared patient treated with lithium to age- and the gender-matched control group who had never been prescribed with lithium. Patients who had previously received lithium and/or were currently on lithium had significantly better Mini Mental State Examination (MMSE) scores than the control patients. Nunes et al. [29] studied the occurrence of AD in 66 elderly BD patients assessed during euthymia, receiving long-term lithium therapy, and in 48 age-matched patients who were not recently taking lithium. The percentage of patients with dementia was 19% in the first group and 7% in the second group. The diagnosis of the AD was made in three patients (5%) receiving lithium and in 16 patients (33%) who were not taking lithium, which suggests that lithium treatment may reduce the prevalence of AD in patients with bipolar disorder. Angst et al. [30] studied subjects with bipolar disorder (N = 220) and major depressive disorder (N = 186) followed from 1965 to 1985, receiving long-term treatment with lithium, clozapine, or antidepressants. In the whole group, the prevalence of dementia showed a significant association with age. However, when an analysis of the 88 patients with dementia was performed, the association with age was lost, and there was a trend to an inverse correlation between

Lithium and Alzheimer's Disease: Experimental, Epidemiological, and Clinical Findings

http://dx.doi.org/10.5772/intechopen.74239

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Two papers coming from the University of Copenhagen employed the Danish nationwide register of lithium prescriptions. In the first one, a comparison was made for the diagnosis of dementia or AD between 16,238 persons who had purchased lithium at least once during inpatient or outpatient treatment and 1,487,177 persons from the general population who had never bought lithium. Those who had bought lithium at least once had the 1.5-fold higher rate of dementia than the persons not taking lithium. However, those who continued treatment with lithium had the rate of dementia decreased to the same level as that for the general population. Such a decrease was exclusive to lithium because persons receiving anticonvulsant drugs had the risk of dementia increased with the duration of treatment [31]. The second study followed up 4856 patients which received a diagnosis of a manic or mixed episode or bipolar disorder at their first psychiatric contact for the period of 1995–2005 (103.6/10000 person-years). The percentages of patients receiving given drug were as follows: lithium 50.4%, anticonvulsants 36.7%, antidepressants 88.1%, and antipsychotics 80.3%. During the follow-up period, 216 patients were diagnosed with dementia. It was found that a reduced rate of dementia in BD patients was connected with long-term treatment with lithium. On the other hand, such a phenomenon was not observed with continued treatment with anticonvulsants, antidepressants,

In 2015, Gerhard et al. [33] examined the association of lithium and dementia risk in a large claim-based US cohort of publicly insured older adults with bipolar disorder (n = 41,931), including individuals ≥50 years who did not receive dementia-related services during the prior year. Each follow-up day was classified by past-year cumulative duration of lithium use.

lithium administration and the severity of dementia.

or antipsychotics [32].

The PI pathway plays a role in signal transduction mechanisms connected with the action of multiple neurotransmitters. Lithium significantly influences this pathway which resulted in the inositol-depletion hypothesis of lithium action, as an essential therapeutic mechanism in mood disorders. Lithium inhibits the inositol monophosphatase (IMPase) and many other phases of the PI pathway [12]. The effect of lithium on the PI pathway is also connected with enhancing autophagy by the mTOR-independent pathway [18].

Protein kinase C (PKC) is an enzyme associated with the PI pathway and plays a role in the action of many neurotransmitters and other cellular mechanisms. It has been found that lithium inhibits the activity of PKC that may contribute to its regulation of intracellular signaling and increasing neuroplasticity [12].

Bcl-2 is a protein playing a significant role in cellular resilience and plasticity, among others, by inhibiting apoptosis. Experimental studies demonstrated an increase of Bcl-2 in the brain by lithium treatment. Enhancing by lithium the expression of Bcl-2-associated athanogene (bag-1) augments the antiapoptotic effect, by mitigating glucocorticoid receptor nuclear translocation [12].

Morris and Berk [19] suggested some additional mechanisms of lithium action which may be important in the treatment of AD, such as the effects on mitochondrial function, calcium homeostasis, inflammation, microglial activation, glutamate excitotoxicity, and oxidative stress. Most of these processes are connected with the mechanisms described above.

Lithium produces a significant increase in mitochondrial performance in human brain tissue, the main factors of such effect being the inhibition of GSK-3 and activation of mTOR [20]. This cation also desensitizes brain mitochondria to the damaging effects of calcium influx [21] and increases mitochondrial levels of Bcl-2 [22]. As peripheral and neuro-inflammation, together with the chronic activation of microglia, constitutes an important element in the development of the AD, there is evidence that lithium can ameliorate various aspects involved in the pro-inflammatory response. These include the generation of tumor necrosis factor-alpha and interleukin-1 beta by microglia, and this effect is obtained via the inhibition of GSK-3 [23]. Lithium also exhibits a protective effect against the development of glutamate neurotoxicity, which is a consequence of chronic microglial activation, and this effect is due to the upregulation of BDNF [24]. In clinical conditions, lithium administration causes a decrease in markers of oxidative stress such as catalase and superoxide dismutase [25].
