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

  • Orestes V. Forlenza (a1), Breno S. Diniz (a1), Márcia Radanovic (a1), Franklin S. Santos (a1), Leda L. Talib (a1) and Wagner F. Gattaz (a1)...

Abstract

Background

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.

Aims

To evaluate the effect of long-term lithium treatment on cognitive and biological outcomes in people with amnestic mild cognitive impairment (aMCI).

Method

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 (Aβ42), total tau (T-tau), phosphorylated-tau) (P-tau). Trial registration: NCT01055392.

Results

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%.

Conclusions

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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Copyright

Corresponding author

Orestes V. Forlenza, MD, PhD, 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. Email: forlenza@usp.br

Footnotes

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See editorial, pp. 336–337, this issue.

The present work was supported by Conselho Nacional de Pesquisa Científica (CNPq, Project 554535/2005-0), Alzheimer's Association (NIRG-08-90688) and FundaçÃo de Amparo à Pesquisa do Estado de São Paulo (FAPESP, Project 02/13633-7). The Laboratory of Neuroscience (LIM-27) receives financial support from AssociaçÃo Beneficente Alzira Denise Hertzog da Silva (ABADHS).

Declaration of interest

None.

Footnotes

References

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

  • Orestes V. Forlenza (a1), Breno S. Diniz (a1), Márcia Radanovic (a1), Franklin S. Santos (a1), Leda L. Talib (a1) and Wagner F. Gattaz (a1)...
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eLetters

The impact of lithium treatment in phosphorylated Tau

Lu�sa Lagarto, Psychiatric Trainee
29 June 2011

We read with interest the article by Forlenza et al. (1). Given the relevance of the topic, with important clinical implications, we would like to make a contribution to the discussion of the results.

The authors present, as a main finding of the study, that “long-term lithium treatment was associated with a significant reduction in CSF concentration of P-tau”. This conclusion seems to be conflicting with the data presented in the Results section. In fact, as showed in Table 2, while “participants treated with lithium had a decrease in the concentrations of P-tau” this difference was not statistically significant(P= 0.15). The same can be said in respect to the control group in which “a slight increase was observed in participants who received placebo” although again not statistically significant (P= 0.07). Accordingly, the Pvalue of 0.02 presented in Figure 2 can be misleading as it appears to suggest that a significant reduction of P-Tau was observed in the treatment group, which was not the case. Instead, this P value refers to the comparison between groups regarding a new variable (end-point minus baseline values). In other words, the diference between the initial and final values of P-tau was higher in the lithium group (78.9 pg/mL, s.d. 24.3) compared with the placebo group (5.6 pg/mL, s.d. 11.4) and this diference was statistically significant (P= 0.02).

Although this study failed to show an overall benefit of lithium in the evolution of CSF biomarkers, a significant reduction of P-tau concentration was observed in patients non-converting to Alzheimer´s disease. This finding is in line with the extensive preclinical data demonstrating that lithium can successfully lower tau neuropathology, particularly in its early stages (2). Moreover these results raise the question whether the neuroprotective effect of lithium may be confined to a distinct sub-group of patients with mild cognitive impairment. Future studies should address not only this question but also clarify the optimaldose and duration of the pharmacological intervention.

In summary, considering the urgent need for disease-specific therapeutic strategies for Alzheimer’s disease, the results reported by Forlenza et al. provide a starting point for future investigations, focusing on prevention of the disease.

References:

(1) Forlenza OV, Diniz BS, Radanovic M, Santos FS, Talib LL, Gattaz WF. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. Br J Psychiatry. 2011 May;198(5):351-6.

(2) Avila J, Wandosell F, Hernández F. Role of glycogen synthase kinase-3 in Alzheimer's disease pathogenesis and glycogen synthase kinase-3 inhibitors. Expert Rev Neurother. 2010 May;10(5):703-10.
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Conflict of interest: None Declared

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Lithium and neuroprotection: beyond classical mechanisms of psychopharmacology

Orestes V. Forlenza, Associate Professor
16 June 2011

We agree with the comments by B. Underwood reinforcing that the mechanisms by which lithium may exert a neuroprotective effect in patientswith amnestic mild cognitive impairment (1) still must be clarified. The inhibition of glycogen synthase kinase-3 (GSK-3B) by lithium is a plausible effect, given its pivotal role in the pathogenesis of Alzheimer’s disease, but most likely not the only one. In addition to the prevailing mechanism of action involving the inhibition of inositol monophosphatase and downstream effects towards the up-regulation of autophagy, many other neurobiological effects have been attributed to lithium. These include the inhibition of apoptosis and the up-regulation of neurotrophic cascades (2). The modification of these intracellular signaling systems by lithium has been shown to yield neurotrophic and/or neuroprotective effects, which have been consistently demonstrated in cell culture and animal models. These effects are probably unspecific and may be beneficial to patients with distinct psychiatric and neurodegenerative diseases, including bipolar disorder (3), amyotrophic lateral sclerosis (4) and Alzheimer’s disease (1). We hypothesise that the inhibition of GSK-3B by lithium is more specific to processes that ultimately lead to the formation of neuritic plaques and neurofibrillary tangles. According to the 'GSK3 hypothesis of Alzheimer’s disease', over-active GSK-3B accounts for memoryimpairment, Tau hyper-phosphorylation, increased beta-amyloid production and local plaque-associated inflammatory responses mediated by the microglia (5). The inhibition of GSK-3B is currently regarded as a candidate disease-modifying approach for the treatment and prevention of Alzheimer’s disease, and specific inhibitors such as NP-031112 are being tested in phase-II clinical trials (www.clinicaltrials.gov).Therefore, lithium may contribute to the attenuation of the pathological process in Alzheimer’s disease through inhibition of GSK-3B, and deliver additional, unspecific benefits via modification of other signaling pathways that favor autophagy, preclude apoptosis and up-regulate the secretion of neurotrophic factors in the brain. Presumably, the interplay of complementary mechanisms is necessary to warrant clinically relevant benefits, which we were able to show in our study (1). We thus speculate that the effects of lithium on multiple homeostatic systems downstream from membrane receptor-based neurotransmission, may in fact represent an advantage as a candidate drug for the treatment of complex neurobiologicaldiseases. In our study, the doses of lithium used were very well tolerated. This, together with its wide availability and the low cost, warrant the further investigation of the potential protective effect of lithium in Alzheimer’s disease.

References:1. Forlenza OV, Diniz BS, Radanovic M, Santos FS, Talib LL and Gattaz WF. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. Br J Psychiatry 2011;198:351-3562. de Sousa RT, van de Bilt MT, Diniz BS, Ladeira RB, Portela LV, Souza DO, Forlenza OV, Gattaz WF and Machado-Vieira R. Lithium increases plasmabrain-derived neurotrophic factor in acute bipolar mania: a preliminary 4-week study. Neurosci Lett 2011;494(1):54-56.3. Nunes PV, Forlenza OV and Gattaz WF. Lithium and risk for Alzheimer's disease in elderly patients with bipolar disorder. Br J Psychiatry 2007;190:359-3604. Aggarwal SP, Zinman L, Simpson E, McKinley J, Jackson KE, Pinto H, Kaufman P, Conwit RA, Schoenfeld D, Shefner J, Cudkowicz M; Northeast and Canadian Amyotrophic Lateral Sclerosis consortia. Safety and efficacy of lithium in combination with riluzole for treatment of amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2010;9(5):481-4885. Hooper C, Killick R, Lovestone S. The GSK3 hypothesis of Alzheimer's disease. J Neurochem. 2008;104(6):1433-1439

Declaration of Interest: There is no conflict of interest related to the contents of this letter. Funding for the present work provided by Conselho Nacional de Pesquisa Científica (CNPq, Project 554535/2005-0), Alzheimer’s Association (NIRG-08-90688), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, Project 02/13633-7) and Associação Beneficente Alzira Denise Hertzog da Silva (ABADHS).

Authors’ affiliations: Laboratory of Neuroscience (LIM-27), Department and Institute of Psychiatry, Faculty of Medicine, University ofSao Paulo. O.V.F.: MD, PhD, Associate Professor; B.S.D.: MD, PhD; W.F.G.: MD, PhD, Full Professor.

Corresponding address: Orestes V. Forlenza, Rua Dr. Ovídio Pires de Campos 785, 05403-010, Sao Paulo, SP, Brazil, email: forlenza@usp.br
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Conflict of interest: None Declared

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Understanding the neuroprotective mechanisms of lithium may have clinical significance

Benjamin R Underwood, Consultant psychiatrist
26 May 2011

The article by Forlenze et al (1) is a useful addition to the literature. Disease modifying drugs for dementia, and in particular Alzheimer’s disease, are sorely needed. Despite very strong pre-clinical science, translational studies have been relatively limited, so this sort of interventional trial is welcome.

The authors highlight the inhibition of glycogen synthase kinase 3 beta (GSK3B), a serine/threonine kinase involved in the regulation of numerous intracellular signalling pathways, as the likely mechanism for any neuroprotective effects. Whilst it is true that there is a literaturesupporting this pathway, other potential disease modifying pathways are influenced by lithium. For example, up-regulation of autophagy, an intracellular protein degradation pathway which is able to degrade mutant proteins associated with neurodegeneration, can rescue a variety of animalmodels of neurodegenerative disease (2). In fact, GSK3B inhibition inhibits autophagy via its effect on the mTOR (mammalian target of rapamycin) pathway. Despite this, lithium ultimately induces autophagy via a dominant mechanism involving inositol monophsphatase inhibition (3).These distinctions are not trivial, as understanding the interactions of these pathways allows for more rational treatment design. For example, lithium and rapamycin (a drug which inhibits mTOR) provides greater neuroprotection in fly models of Huntington’s disease than either drug alone (4). Furthermore, numerous FDA approved drugs which are autophagy up-regulators have been identified. Many of these may have a more favourable side effect profile than lithium, and preclinical work suggeststheir efficacy in animal models of neurodegenerative disease (5).

The potential mechanisms for neuroprotection by lithium extend well beyond inhibition of GSK3B. Working out which are most important is of more than scientific interest as it is likely to allow rational drug design and better selection of currently available drugs with neuroprotective potential.

1)Forlenza, O, Diniz, B, Radanovic M, Santos F, Talib L and Gattaz W. Disease-modifying properties of long term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. Br J Psychiatry 2011; 198: 351-6.2)Garcia-Arencibia M, Hochfeld W, Toh P and Rubinsztein DC. Autophagy, aguardian against neurodegeneration. Semin Cell Dev Biol. 2010;7:691-8.3)Sarkar S, Floto RA, Berger Z, Imarisio S, ordenier A et al. Lithium induces autophagy by inhibiting inositol monophosphatase. J Cell Biol. 2005;7:1101-114)Sarkar S, Krishna G, Imarisio S, Saiki S, O’Kane CJ and Rubinsztein DC.A rational mechanism for combination treatment of Huntington’s disease using lithium and rapamycin. Hum Mol Genet 2008 2;170-8.5)Williams A, Sarkar S, Cuddon P, Ttofi EK, Saiki S et al. Novel targetsfor Huntington’s disease in an m-TOR-independent autophagy pathway. Nat Chem Biol. 2008;5:295-305
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Conflict of interest: None Declared

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