Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: Randomised controlled trial

Laboratory of Neuroscience (LIM 27) Department and Institute of Psychiatry, Faculty of Medicine, University of São Paulo, Rua Dr. Ovídio Pires de Campos 785, 05403-010 - São Paulo, SP, Brazil. .
The British journal of psychiatry: the journal of mental science (Impact Factor: 7.99). 05/2011; 198(5):351-6. DOI: 10.1192/bjp.bp.110.080044
Source: PubMed

ABSTRACT Two recent clinical studies support the feasibility of trials to evaluate the disease-modifying properties of lithium in Alzheimer's disease, although no benefits were obtained from short-term treatment.
To evaluate the effect of long-term lithium treatment on cognitive and biological outcomes in people with amnestic mild cognitive impairment (aMCI).
Forty-five participants with aMCI were randomised to receive lithium (0.25-0.5 mmol/l) (n = 24) or placebo (n = 21) in a 12-month, double-blind trial. Primary outcome measures were the modification of cognitive and functional test scores, and concentrations of cerebrospinal fluid (CSF) biomarkers (amyloid-beta peptide (Aβ(42)), total tau (T-tau), phosphorylated-tau) (P-tau). Trial registration: NCT01055392.
Lithium treatment was associated with a significant decrease in CSF concentrations of P-tau (P = 0.03) and better perform-ance on the cognitive subscale of the Alzheimer's Disease Assessment Scale and in attention tasks. Overall tolerability of lithium was good and the adherence rate was 91%.
The present data support the notion that lithium has disease-modifying properties with potential clinical implications in the prevention of Alzheimer's disease.

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Available from: Breno Satler Diniz, Sep 26, 2015
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    • "Epidemiological investigations demonstrated a reduced risk of progressing to dementia among bipolar disorder patients in long-term treatment with lithium [Nunes et al. 2007]. In addition, patients with amnestic mild cognitive impairment (MCI) showed cognitive and functional stabilization with long-term treatment with lithium, also with reduced phosphorylated tau in cerebrospinal fluid, making this therapy a promising strategy [Forlenza et al. 2011]. Table 1 presents a summary of current pharmacological agents in AD. "
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    Therapeutic Advances in Drug Safety 07/2015; 6(4):151-165. DOI:10.1177/2042098615592116
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    • "Drugs with potential disease-modifying properties for AD can modulate neurotrophic systems. Long-term lithium treatment for patients with amnestic MCI has been shown to attenuate cognitive decline and Tau phosphorylation (Forlenza et al. 2011). Lithium administration can also increase BDNF levels and exert additional neuroprotective effects in patients at risk of AD (de Sousa et al. 2011). "
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    ABSTRACT: There is little information on the dynamics of BDNF in the CSF in the continuum between healthy aging, MCI and AD. We included 128 older adults (77 with amnestic MCI, 26 with AD and 25 healthy controls). CSF BDNF level was measured by ELISA assay, and AD biomarkers (Aβ42, T-Tau and P-Tau181) were measured using a Luminex xMAP assay. CSF BDNF levels were significantly reduced in AD subjects compared to MCI and healthy controls (p = 0.009). Logistic regression models showed that lower CSF BDNF levels (p = 0.008), lower CSF Aβ42 (p = 0.005) and lower MMSE scores (p = 0.007) are significantly associated with progression from MCI to AD. The present study adds strong evidence of the involvement of BDNF in the pathophysiology of neurodegenerative changes in AD. Interventions aiming to restore central neurotrophic support may represent future therapeutic targets to prevent or delay the progression from MCI to AD.
    Neuromolecular medicine 07/2015; 17(3). DOI:10.1007/s12017-015-8361-y · 3.68 Impact Factor
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    • "This observation , however, is not conclusive by itself because the cognitive measures we analyzed were neither comprehensive nor targeted for testing any specific hypothesis. Prior research has yielded mixed results (Wingo et al., 2009; Forlenza et al., 2011), calling into question the impact of lithium on cognitive function. Nonetheless, the lack of cognitive difference between Li and NoLi reduces the possibility of recall bias confounding patient reporting of prescribed medication. "
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    ABSTRACT: Relative to healthy controls, lithium free bipolar patients exhibit significant gray matter abnormalities. Lithium, the long-time reference standard medication treatment for bipolar disorder, has been proposed to be neuro-protective against these abnormalities. However, its effects on cortical thickness and hippocampal subfield (HSF) volumes remain unstudied and unclear, respectively, in bipolar disorder. This study included 342 healthy controls (HC), 51 lithium free PBD patients (NoLi), and 51 PBD patients taking lithium (Li). Regional gray matter thickness and HSF volume values were extracted from 3T MRI images. After matching NoLi and Li samples, regions where HC differed from either Li or NoLi were identified. In regions of significant or trending HC-NoLi difference, Li-NoLi comparisons were made. No significant HC-Li thickness or HSF volume differences were found. Significantly thinner occipital cortices were observed in NoLi compared to HC. In these regions, Li consistently exhibited non-significant trends for greater cortical thickness relative to NoLi. Significantly less volume was observed in NoLi compared to both HC and Li in right HSFs. Our results suggest that PBD in patients not treated with Li is associated with thinner occipital cortices and reduced HSF volumes compared with HC. Patients treated with Li exhibited significantly larger HSF volumes than NoLi, and those treated with Li were no different from HC in cortical thickness or hippocampal volumes. This evidence directly supports the hypothesis that Li may counteract the locally thinner and smaller gray matter structure found in PBD.
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