Clinical trial NCT01055392: Disease-modifying Properties of Lithium in the Neurobiology of Alzheimer's Disease
Official title: Disease-modifying Properties of Lithium in the Neurobiology of Alzheimer's Disease: a Double-blind, Placebo-controlled Prevention Study in Elderly Patients With Mild Cognitive Impairment
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Cognitive Impairment
Alzheimer Disease
Keywords: mild cognitive impairment
Alzheimer's disease
Lithium
disease-modification
cognition
early Alzheimer's disease
Lead sponsor: University of Sao Paulo
Sponsor class: OTHER
First posted: 2010-01-25
Enrollment: 80
Sex: ALL
Minimum age (years): 60
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Lithium salts have been used for the treatment of psychiatric disorders for over five decades, mostly as a mood-stabilizing drug. Recent evidence points to the inhibition of the enzyme glycogen synthase kinase-3beta (GSK3) as one of its mechanisms of action. The overactivity of this enzyme has been implicated in the pathogenesis of Alzheimer's disease (AD), given its involvement in mechanisms related to the hyperphosphorylation of Tau protein and the production of beta-amyloid peptide. These are key events leading respectively to the formation of neurofibrillary tangles and senile plaques, which are the neuropathological hallmarks of the disease. Several in vitro and animal studies have shown that the inhibition of GSK3 by lithium and other agents attenuates these pathological processes, reinforcing the notion that GSK3 is a likely target for future disease-modifying therapies for AD. Indeed, a recent study published by our group showed that chronic lithium use is associated with a decrement in the expected prevalence of dementia, in a sample of elderly individuals with bipolar disorder. To investigate this putative neuroprotective effect in a prospective way, the investigators started 24-month randomized, double-blinded controlled trial of lithium for the prevention of dementia in a sample of elderly individuals with amnestic mild cognitive impairment (MCI), a condition associated with increased risk for the development of AD. The clinical and biological outcomes of this trial include the attenuation of cognitive deficits, and the modification of certain biological markers of the disease (as measured in the cerebrospinal fluid, leukocytes and platelets). The objective of the present application is to enable the extension of this ongoing trial to an additional 2-year follow-up. A longer follow-up (48 months) will increase the statistical power to ascertain the primary outcome variables of this study, particularly the con-version from MCI to Alzheimer's disease. This will warrant a more consistent conclusion about the potential of lithium treatment in the prevention of dementia, in addition to a better evaluation of safety and tolerability profiles of the long-term use of lithium in older individuals.


Eligibility criteria: Inclusion Criteria:

* patients with amnestic mild cognitive impairment;
* age: 60 to 80 years-old;

Exclusion Criteria:

* sensory deficiencies that might preclude the administration of cognitive tests;
* active major psychiatry disorder;
* unstable clinical conditions such as cardiac insufficiency, uncontrolled diabetes mellitus, renal failure;
* previous use of lithium salts;
* concurrent participation in other clinical trial or intervention studies;

Primary outcomes:
measure: effect of lithium to delay progression of cognitive deficits in patients with amnestic MCI
timeFrame: two year
Secondary outcomes:
measure: effect of lithium on CSF levels of Total Tau, Phosphorylated Tau and Amyloid-beta42
timeFrame: one year
measure: the effect of lithium on the activity of GSK3β in platelets and leukocytes drawn from peripheral blood.
timeFrame: one year
Other outcomes:
Locations:
city: Sao Paulo
country: Brazil
facility: Institute of Psychiatry, Faculty of Medicine - University of Sao Paulo
state: SP
Study officials:
affiliation: Department and Institute of Psychiatry, Faculty of Medicine - University of Sao Paulo
name: Orestes V Forlenza, Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Department and Institute of Psychiatry, Faculty of Medicine - University of Sao Paulo
name: Wagner F Gattaz, Ph.D.
role: STUDY_DIRECTOR
References:
citation: Forlenza OV, Radanovic M, Talib LL, Gattaz WF. Clinical and biological effects of long-term lithium treatment in older adults with amnestic mild cognitive impairment: randomised clinical trial. Br J Psychiatry. 2019 Nov;215(5):668-674. doi: 10.1192/bjp.2019.76.
citation: Aprahamian I, Santos FS, dos Santos B, Talib L, Diniz BS, Radanovic M, Gattaz WF, Forlenza OV. Long-term, low-dose lithium treatment does not impair renal function in the elderly: a 2-year randomized, placebo-controlled trial followed by single-blind extension. J Clin Psychiatry. 2014 Jul;75(7):e672-8. doi: 10.4088/JCP.13m08741.
citation: 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. doi: 10.1192/bjp.bp.110.080044.