Ross Carne

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.

Cerebral cortex : an MRI-based study of volume and variance with age and sex

The aim of the present study was to examine quantitative differences in lobar cerebral cortical volumes in a healthy adult population. Quantitative volumetric MRI of whole brain, cerebral and cerebellar volumes was performed in a cross-sectional analysis of 97 normal volunteers, with segmented frontal, temporal, parietal and occipital cortical volumes measured in a subgroup of 60 subjects, 30 male and 30 female, matched for age and sex. The right cerebral hemisphere was larger than the left across the study group with a small (<1%) but significant difference in symmetry (P<0.001). No difference was found between volumes of right and left cerebellar hemispheres. Rightward cerebral cortical asymmetry (right larger than left) was found to be significant across all lobes except parietal. Males had greater cerebral, cerebellar and cerebral cortical lobar volumes than females. Larger male cerebral cortical volumes were seen in all lobes except for left parietal. Females had greater left parietal to left cerebral hemisphere and smaller left temporal to left cerebral hemisphere ratios. There was a mild reduction in cerebral volumes with age, more marked in males. This study confirms and augments past work indicating underlying structural asymmetries in the human brain, and provides further evidence that brain structures in humans are differentially sensitive to the effects of both age and sex.

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.

Depression in temporal lobe epilepsy surgery patients: An FDG-PET study

Summary:  Purpose: Depression is common in temporal lobe epilepsy (TLE) and after temporal lobectomy, and its etiology is obscure. In nonepileptic depression (including depression associated with other neurologic disorders), a consistent PET imaging finding is frontal lobe hypometabolism. Many TLE patients have hypometabolism involving frontal regions. Thus in data available from routine clinical assessments in an epilepsy surgery unit, we tested the hypothesis that the pattern of hypometabolism, particularly in the frontal lobe, may be associated with the depression seen in patients with TLE and TLE surgery.

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.

The multiple mini‐interview: how long is long enough?

Objectives  The multiple mini‐interview (MMI) overcomes the limitations of the traditional panel interview by multiple sampling to provide improved objectivity and reliability. Reliability of the MMI is affected by number of stations; however, there are few data reporting the influence of interview duration on MMI outcome and reliability. We aimed to determine whether MMI stations can be shortened without affecting applicant rankings or compromising test reliability.

Hippocampal deformation mapping in MRI negative PET positive temporal lobe epilepsy

Objectives: To compare hippocampal surface structure, using large deformation high dimensional mapping (HDM-LD), in subjects with temporal lobe epilepsy (TLE) with (HS+ve) and without (HS−ve) hippocampal sclerosis. Methods: The study included 30 HS−ve subjects matched with 30 HS+ve subjects from the previously reported epilepsy patient cohort. To control for normal right–left asymmetries of hippocampal surface structure, subjects were regrouped based on laterality of onset of epileptic seizures and presence of HS. Gender ratio, age, duration of epilepsy and seizure frequency were calculated for each of the four groups. Final HDM-LD surface maps of the right and left TLE groups were compared to define differences in subregional hippocampal involvement within the groups. Results: There were no significant differences in comparisons of the left TLE (left HS−ve compared with HS+ve) or right TLE (right HS−ve compared with HS+ve) groups with respect to age, duration of epilepsy or seizure severity scores. HDM-LD maps showed accentuated surface changes over the lateral hippocampal surface, in the region of the Sommer sector, in the hippocampi affected by HS. However, HS−ve hippocampi showed maximal surface changes in a different pattern, and did not involve the region of Sommer sector. Conclusion: We conclude that differences in segmental volume loss between the HS−ve and HS+ve groups are suggestive that the underlying pathophysiology of hippocampal changes in the two groups is different, and not related to chronic seizure duration or severity.

Magnetic resonance imaging negative positron emission tomography positive temporal lobe epilepsy: FDG-PET pattern differs from mesial temporal lobe epilepsy.

PurposeSome patients with temporal lobe epilepsy (TLE) lack evidence of hippocampal sclerosis (HS) on MRI (HS-ve). We hypothesized that this group would have a different pattern of 2-deoxy-2-[F-18]fluoro-d-glucose (FDG)-positron emission tomography (PET) hypometabolism than typical mesial TLE/HS patients with evidence of hippocampal atrophy on magnetic resonance imaging (MRI) (HS+ve), with a lateral temporal neocortical rather than mesial focus.ProceduresThirty consecutive HS-ve patients and 30 age- and sex-matched HS+ve patients with well-lateralized EEG were identified. FDG-PET was performed on 28 HS-ve patients and 24 HS+ve patients. Both groups were compared using statistical parametric mapping (SPM), directly and with FDG-PET from 20 healthy controls.ResultsBoth groups showed lateralized temporal hypometabolism compared to controls. In HS+ve, this was antero–infero–mesial (T = 17.13); in HS-ve the main clustering was inferolateral (T = 17.63). When directly compared, HS+ve had greater hypometabolism inmesial temporal/hippocampal regions (T = 4.86); HS-ve had greater inferolateral temporal hypometabolism (T = 4.18).ConclusionsThese data support the hypothesis that focal hypometabolism involves primarily lateal neocortical rather than mesial temporal structures in ‘MRI-negative PET-positive TLE.’

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 …

Characteristics of motor vehicle crashes associated with seizure: Car crash semiology

Objective To examine the characteristics of seizure-related vehicle crashes (SRC). Method Using a nested case-control design, we identified and compared cases of SRC involving confirmed epilepsy patients with 137,126 non-seizure-related crash controls (NSRC) in the Australian state of Victoria. SRC were identified from approximately 20,000 epileptologist medical records by cross-referencing this source with the Victorian Police Traffic Incident database and the Road Crash Information System Database (RCISD). Results Seventy-one SRC involving 62 patients with epilepsy were identified. Thirty-seven SRC resulted in injury and could be identified in the RCISD and compared to NSRC. Seizure-related crashes typically involved a single vehicle (57% vs 29%, p < 0.001) carrying a sole occupant (95% vs 48%, p = 0.001). Most SRC began with an “out of control movement” (51% vs 10%, p < 0.001) and the subsequent collision type differed significantly between the groups (p < 0.001). The majority of SRC were a “collision with a fixed object” (54% vs 17%, p < 0.001) involving an “off path on straight” mechanism (48% vs 10%, p < 0.001). Regarding all 71 SRC, generalized as compared with focal epilepsy crashes involved younger drivers (p < 0.001), seizure-provoking factors (p = 0.033), and occurred earlier in the day (p = 0.004). Conclusions Given the distinct SRC features, we propose that clinicians, crash investigators, and driver licensing authorities incorporate collision characteristics into the overall assessment of suspected SRC. Further research should examine restricting driving immediately after risk periods as a harm-minimization strategy.