Alastair Mander

Increased Risk of Cognitive Impairment in Patients With Diabetes Is Associated With Metformin

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. Prospective 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.

A double-blind, placebo-controlled trial of diclofenac/misoprostol in Alzheimer’s disease

Background: Previous studies suggest a potential benefit from nonsteroidal anti-inflammatory drugs (NSAIDs) in Alzheimer’s disease (AD). Prescribing NSAIDs, however, carries the risk of significant gastrointestinal adverse events. Objectives: To study whether treatment with an NSAID prevents expected decline in AD patients and evaluate whether co-administration of the gastro-protective agent, misoprostol, with an NSAID is safe in AD. Methods: The efficacy and safety of diclofenac in combination with misoprostol (D/M) was evaluated in 41 patients with mild-moderate AD in a prospective 25-week, randomized, double-blind placebo-controlled trial. Efficacy measures comprised the Alzheimer’s Disease Assessment Scale cognitive and noncognitive subsections, Global Deterioration Scale, Clinical Global Impression of Change, Mini-Mental State Examination, Instrumental Activities of Daily Living, Physical Self-Maintenance Scale, and a caregiver-rated Global Impression of Change. Results: There were no group differences with any of the outcome measures in an intent-to-treat analysis. There were some nonsignificant trends for the placebo group to have deteriorated more than the D/M-treated patients. Withdrawal rates were 12 of 24 in the D/M group and 2 of 17 in the placebo group. There were no serious drug-related adverse events. Conclusions: This pilot study, with small treatment numbers, did not demonstrate a significant effect of NSAID treatment in AD, but the trends observed justify further investigations with a larger number of participants. D/M is safe in AD patients, but its tolerability is not optimal.

Cognitive impairment and vitamin B12: a review

BACKGROUND This review examines the associations between low vitamin B12 levels, neurodegenerative disease, and cognitive impairment. The potential impact of comorbidities and medications associated with vitamin B12 derangements were also investigated. In addition, we reviewed the evidence as to whether vitamin B12 therapy is efficacious for cognitive impairment and dementia. METHODS A systematic literature search identified 43 studies investigating the association of vitamin B12 and cognitive impairment or dementia. Seventeen studies reported on the efficacy of vitamin B12 therapy for these conditions. RESULTS Vitamin B12 levels in the subclinical low-normal range (<250 ρmol/L) are associated with Alzheimers disease, vascular dementia, and Parkinsons disease. Vegetarianism and metformin use contribute to depressed vitamin B12 levels and may independently increase the risk for cognitive impairment. Vitamin B12 deficiency (<150 ρmol/L) is associated with cognitive impairment. Vitamin B12 supplements administered orally or parenterally at high dose (1 mg daily) were effective in correcting biochemical deficiency, but improved cognition only in patients with pre-existing vitamin B12 deficiency (serum vitamin B12 levels <150 ρmol/L or serum homocysteine levels >19.9 μmol/L). CONCLUSION Low serum vitamin B12 levels are associated with neurodegenerative disease and cognitive impairment. There is a small subset of dementias that are reversible with vitamin B12 therapy and this treatment is inexpensive and safe. Vitamin B12 therapy does not improve cognition in patients without pre-existing deficiency. There is a need for large, well-resourced clinical trials to close the gaps in our current understanding of the nature of the associations of vitamin B12 insufficiency and neurodegenerative disease.

Serum interleukin-6 and interleukin-6 soluble receptor in Alzheimer's disease

Serum levels of interleukin-6 (IL-6) and interleukin-6 soluble receptor (IL-6sR) were measured in 41 patients (23 female and 18 male, mean age 72.5 years) with Alzheimers disease (AD) and in 32 controls (14 women and 18 men, mean age 69.2 years) using enzyme-linked immunosorbent assays (ELISA). Proportions of individuals with detectable serum IL-6 concentrations did not differ significantly between patients and controls. There was however, a significant decrease in IL-6sR levels in Alzheimers patients when compared with controls. Our results suggest that there is a dysregulation of IL-6 and its soluble receptor in AD.

Among vitamin B12 deficient older people, high folate levels are associated with worse cognitive function: combined data from three cohorts.

BACKGROUND Folate fortification of food aims to reduce the number of babies born with neural tube defects, but has been associated with cognitive impairment when vitamin B12 levels are deficient. Given the prevalence of low vitamin B12 levels among the elderly, and the global deployment of food fortification programs, investigation of the associations between cognitive impairment, vitamin B12, and folate are needed. OBJECTIVE To investigate the associations of serum vitamin B12, red cell folate, and cognitive impairment. METHODS Data were collected on 1,354 subjects in two studies investigating cognitive impairment, and from patients attending for assessment or management of memory problems in the Barwon region of south eastern Australia between 2001 and 2011. Eligible subjects who had blood measurements of vitamin B12 and red cell folate taken within six months of cognitive testing were included. Subjects with stroke or neurodegenerative diseases other than Alzheimers disease were excluded. A Mini-Mental State Examination score of <24 was used to define impaired cognitive function. RESULTS Participants with low serum vitamin B12 (<250 pmol/L) and high red cell folate (>1,594 nmol/L) levels were more likely to have impaired cognitive performance (adjusted odds ratio (AOR) 3.45, 95% confidence interval (CI): 1.60-7.43, p = 0.002) when compared to participants with biochemical measurements that were within the normal ranges. Participants with high folate levels, but normal serum vitamin B12, were also more likely to have impaired cognitive performance (AOR 1.74, 95% CI: 1.03-2.95, p = 0.04). CONCLUSIONS High folate or folic acid supplements may be detrimental to cognition in older people with low vitamin B12 levels. This topic is of global significance due to the wide distribution of food fortification programs, so prospective studies should be a high priority.

Fluoxetine induced dyskinesia

A case of fluoxetine induced dyskinesia in an elderly woman with previous use of low dose haloperidol is described. In contrast to neuroleptic induced tardive dyskinesia it was characterised by a rapid onset after commencing fluoxetine and rapid resolution on cessation. In the case discussion we describe other cases of fluoxetine induced extrapyramidal syndromes and possible mechanisms.

Response to comment on Moore et al. Increased risk of cognitive impairment in patients with diabetes is associated with metformin. Diabetes care 2013;36:2981-2987.

We thank Goodarzi (1) for his interest in our work (2) and recognize that we agree with most of the criticisms leveled at our study. Indeed, most of the points raised were acknowledged in our original work. There is a need to test the issues raised more robustly—a point on which we agree. Goodarzi highlights that B12 levels may be unrelated to the association of metformin with cognitive function. We do …

Vitamin B12 and Cognitive Impairment

Vitamin B12 is an essential vitamin required for neurological health. The main causes of deficiency (hypoacidity of the stomach, pernicious anemia, and lack of dietary intake) are more prevalent with increasing age. This chapter discusses the epidemiological evidence that suggests an association between low vitamin B12 levels and cognitive decline. To date, short term clinical trials have only shown B12 supplementation to be effective in improving cognition in those with preexisting deficiency (<150. ρmol/L). Improving dietary B12 intake by better food selection, fortified foods, or supplements, may have a role in maintaining cognitive function in those who are at risk of developing B12 deficiency. To be effective, such intervention may need to be commenced before the onset of neuronal damage in middle age, particularly in those with a B12 level of less than 250. ρmol/L. Trials to study when and for how long to provide B12 supplementation are needed.

A revolution in drug approval practices is required.

This is a topic that requires a revolution in practices.1 Currently, when manufacturers submit data to the regulator, they have to provide data on all completed trials. The regulator may ask for further data but once satisfied gives approval or denial for marketing. The data then provided to the public and …