***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: OBJECTIVE To investigate the associations of metformin , serum vitamin B12 , calcium supplements , and cognitive impairment in patients with diabetes . RESEARCH DESIGN AND METHODS Participants were recruited from the Primary Research in Memory ( PRIME ) clinics study , the Australian Imaging , Biomarkers and Lifestyle ( AIBL ) study of aging , and the Barwon region of southeastern Australia . Patients with Alzheimer disease ( AD ) ( n = 480 ) or mild cognitive impairment ( n = 187 ) and those who were cognitively intact ( n = 687 ) were included ; patients with stroke or with neurodegenerative diseases other than AD were excluded . Subgroup analyses were performed for participants who had either type 2 diabetes ( n = 104 ) or impaired glucose tolerance ( n = 22 ) . RESULTS Participants with diabetes ( n = 126 ) had worse cognitive performance than participants who did not have diabetes ( n = 1,228 ; adjusted odds ratio 1.51 [ 95 % CI 1.03–2.21 ] ) . Among participants with diabetes , worse cognitive performance was associated with metformin use ( 2.23 [ 1.05–4.75 ] ) . After adjusting for age , sex , level of education , history of depression , serum vitamin B12 , and metformin  use , participants with diabetes who were taking calcium supplements had better cognitive performance ( 0.41 [ 0.19–0.92 ] ) . CONCLUSIONS Metformin use was associated with impaired cognitive performance . Vitamin B12 and calcium supplements may alleviate metformin-induced vitamin B12 deficiency and were associated with better cognitive outcomes . Prospect i ve trials are warranted to assess the beneficial effects of vitamin B12 and calcium use on cognition in older people with diabetes who are taking metformin Epidemiological studies have identified a robust association between type II diabetes mellitus and Alzheimer disease ( AD ) , and neurobiological studies have suggested the presence of central nervous system insulin resistance in individuals with AD . Given this association , we hypothesized that the central nervous system – penetrant insulin-sensitizing medication metformin would be beneficial as a disease-modifying and /or symptomatic therapy for AD , and conducted a placebo-controlled crossover study of its effects on cerebrospinal fluid ( CSF ) , neuroimaging , and cognitive biomarkers . Twenty nondiabetic subjects with mild cognitive impairment or mild dementia due to AD were r and omized to receive metformin then placebo for 8 weeks each or vice versa . CSF and neuroimaging ( Arterial Spin Label MRI ) data were collected for biomarker analyses , and cognitive testing was performed . Metformin was found to be safe , well-tolerated , and measureable in CSF at an average steady-state concentration of 95.6 ng/mL. Metformin was associated with improved executive functioning , and trends suggested improvement in learning/memory and attention . No significant changes in cerebral blood flow were observed , though post hoc completer analyses suggested an increase in orbitofrontal cerebral blood flow with metformin exposure . Further study of these findings is warranted INTRODUCTION Type 2 diabetes ( DM-2 ) increases the risk of developing Alzheimer´s disease ( AD ) , and patients with AD are more likely to develop DM-2 . DM-2 and AD share some pathophysiological features . In AD , amyloid-β ( Aβ ) is accumulated as extracellular plaques in the gray matter of the brain , while in DM-2 islet amyloid polypeptide ( IAPP ) is accumulated in the pancreas . Premature cellular degeneration is seen in both diseases . Glucagon-like peptide-1 ( GLP-1 ) reduces the amount of Aβ and improves cognition in animal studies . The present study tests the hypothesis that treatment with the long-acting GLP-1 receptor agonist liraglutide affects the accumulation of Aβ in patients with AD . MATERIAL AND METHODS This is a r and omized , controlled , double-blinded intervention study with AD patients treated for six months with liraglutide ( n = 20 ) or placebo ( n = 20 ) . The primary outcome is change in deposition of Aβ in the central nervous system ( CNS ) by Pittsburgh compound B positron emission tomography ( PET )  . The secondary outcome is evaluation of cognition using a neuro-psychological test battery , and examination of changes in glucose uptake in the CNS by 18F-fluoro-deoxy-glucose PET  . Finally , a perfusion-weighted magnetic resonance imaging with contrast will be performed to evaluate blood flow . CONCLUSION No registered drug affects the deposition of Aβ in the brain of AD patients . Our goal is to find a new therapeutic agent that alters the pathophysiology in AD patients by decreasing the formation of Aβ plaques and thereby presumably improves the cognitive function . FUNDING The trial is investigator-initiated and investigator-driven and is supported by Novo Nordisk Sc and inavia . TRIAL REGISTRATION Clinical Trials.gov : NCT01469351 OBJECTIVE To examine the effects of intranasal insulin administration on cognition , function , cerebral glucose metabolism , and cerebrospinal fluid biomarkers in adults with amnestic mild cognitive impairment or Alzheimer disease ( AD ) . DESIGN R and omized , double-blind , placebo-controlled trial . SETTING Clinical research unit of a Veterans Affairs medical center . PARTICIPANTS The intent-to-treat sample consisted of 104 adults with amnestic mild cognitive impairment ( n = 64 ) or mild to moderate AD ( n = 40 ) . Intervention Participants received placebo ( n = 30 ) , 20 IU of insulin ( n = 36 ) , or 40 IU of insulin ( n = 38 ) for 4 months , administered with a nasal drug delivery device ( Kurve Technology , Bothell , Washington ) . MAIN OUTCOME MEASURES Primary measures consisted of delayed story recall score and the Dementia Severity Rating Scale score , and secondary measures included the Alzheimer Disease 's Assessment Scale-cognitive subscale ( ADAS-cog ) score and the Alzheimer 's Disease Cooperative Study -activities of daily living ( ADCS-ADL ) scale . A subset of participants underwent lumbar puncture ( n = 23 ) and positron emission tomography with fludeoxyglucose F 18 ( n = 40 ) before and after treatment . RESULTS Outcome measures were analyzed using repeated- measures analysis of covariance . Treatment with 20 IU of insulin  improved delayed memory ( P < .05 ) , and both doses of insulin ( 20 and 40 IU ) preserved caregiver-rated functional ability ( P < .01 ) . Both insulin doses also preserved general cognition as assessed by the ADAS-cog score for younger participants and functional abilities as assessed by the ADCS-ADL scale for adults with AD ( P < .05 ) . Cerebrospinal fluid biomarkers did not change for insulin-treated participants as a group , but , in exploratory analyses , changes in memory and function were associated with changes in the Aβ42 level and in the tau protein-to-Aβ42 ratio in cerebrospinal fluid . Placebo-assigned participants showed decreased fludeoxyglucose F 18 uptake in the parietotemporal , frontal , precuneus , and cuneus regions and insulin-minimized progression . No treatment-related severe adverse events occurred . CONCLUSIONS These results support longer trials of intranasal insulin therapy for patients with amnestic mild cognitive impairment and patients with AD . Trial Registration clinical trials.gov Identifier : NCT00438568 
    Output:
    
The results of 29 pairwise comparisons indicated that cognition was significantly improved in subjects treated with antidiabetic agents compared with placebo .
Pioglitazone 15 to 30 mg demonstrated the greatest efficacy compared to placebo in network meta- analysis .
No significant differences in acceptability were identified when comparing agents with each other and with placebo .
The current findings indicate a pro-cognitive class effect of antidiabetic agents in AD/MCI .