C de Jager

Structural MRI changes detectable up to ten years before clinical Alzheimer's disease.

Structural brain changes have been described in both mild cognitive impairment (MCI) and Alzheimers disease (AD). However, less is known about whether structural changes are detectable earlier, in the asymptomatic phase. Using voxel-based morphometry (VBM) and shape analyses of magnetic resonance imaging (MRI) data, we investigated structural brain differences between groups of healthy subjects, stratified by subsequent diagnoses of MCI or AD during a 10-year follow-up. Images taken at baseline, at least 4 years before any cognitive symptoms, showed that subjects with future cognitive impairment (preclinical AD and MCI) had reduced brain volume in medial temporal lobes, posterior cingulate/precuneus, and orbitofrontal cortex, compared with matched subjects who remained cognitively healthy for 10 years (HC). For only those subjects later diagnosed as AD, significantly greater atrophy at baseline was detected in the right medial temporal lobe, which was also confirmed by shape analysis of the right hippocampus in these subjects. Our results demonstrate that structural brain changes occur years before clinical cognitive decline in AD and are localized to regions affected by AD neuropathology.

Plasma Total Homocysteine and Cognitive Performance in a Volunteer Elderly Population

Case-control studies have demonstrated associations between moderately elevated blood levels of total homocysteine (tHcy) and cerebrovascular disease,1 vascular dementia,2–4 and Alzheimer’s disease.3–5 Clarke et al.3 showed an association between elevated tHcy, low levels of folate and vitamin B12, and histopathologically confirmed Alzheimer’s disease. However, the influence of elevated tHcy levels or its biologic determinants on cognitive performance in the normal elderly and on the development of cognitive impairment or its progression to dementia is not well established. Riggs et al.6 and La Rue et al.7 have suggested that levels of plasma homocysteine, vitamin B12, and folate may exert differential effects on cognitive abilities. Recently, Jensen et al.8 reported negative relationships between elevated tHcy levels (>15 μmol/L) and a broad range of cognitive, quality of life, and psychologic variables in 80-year-old subjects. However, these studies could not assess whether these associations were independent of differences in age, gender, IQ, and depression. Furthermore, it is important to explore the relationship between tHcy and cognitive performance as continuous variables, rather than as dichotomous variables. The aim of this study was to examine the influence of plasma tHcy levels on global cognitive performance in 156 elderly community volunteers.

Differences in Cognitive Profile between TIA, Stroke and Elderly Memory Research Subjects: A Comparison of the MMSE and MoCA

Background: The Montreal Cognitive Assessment (MoCA) appears more sensitive to mild cognitive impairment (MCI) than the Mini-Mental State Examination (MMSE): over 50% of TIA and stroke patients with an MMSE score of ≥27 (‘normal’ cognitive function) at ≥6 months after index event, score <26 on the MoCA, a cutoff which has good sensitivity and specificity for MCI in this population. We hypothesized that sensitivity of the MoCA to MCI might in part be due to detection of different patterns of cognitive domain impairment. We therefore compared performance on the MMSE and MoCA in subjects without major cognitive impairment (MMSE score of ≥24) with differing clinical characteristics: a TIA and stroke cohort in which frontal/executive deficits were expected to be prevalent and a memory research cohort. Methods: The MMSE and MoCA were done on consecutive patients with TIA or stroke in a population-based study (Oxford Vascular Study) 6 months or more after the index event and on consecutive subjects enrolled in a memory research cohort (the Oxford Project to Investigate Memory and Ageing). Patients with moderate-to-severe cognitive impairment (MMSE score of <24), dysphasia or inability to use the dominant arm were excluded. Results: Of 207 stroke patients (mean age ± SD: 72 ± 11.5 years, 54% male), 156 TIA patients (mean age 71 ± 12.1 years, 53% male) and 107 memory research subjects (mean age 76 ± 6.6 years, 46% male), stroke patients had the lowest mean ± SD cognitive scores (MMSE score of 27.7 ± 1.84 and MoCA score of 22.9 ± 3.6), whereas TIA (MMSE score of 28.4 ± 1.7 and MoCA score of 24.9 ± 3.3) and memory subject scores (MMSE score of 28.5 ± 1.7 and MoCA score of 25.5 ± 3.0) were more similar. Rates of MoCA score of <26 in subjects with normal MMSE ( ≥27) were lowest in memory subjects, intermediate in TIA and highest after stroke (34 vs. 48 vs. 67%, p < 0.001). The cerebrovascular patients scored lower than the memory subjects on all MoCA frontal/executive subtests with differences being most marked in visuoexecutive function, verbal fluency and sustained attention (all p < 0.0001) and in stroke versus TIA (after adjustment for age and education). Stroke patients performed worse than TIA patients only on MMSE orientation in contrast to 6/10 subtests of the MoCA. Results were similar after restricting analyses to those with an MMSE score of ≥27. Conclusions: The MoCA demonstrated more differences in cognitive profile between TIA, stroke and memory research subjects without major cognitive impairment than the MMSE. The MoCA showed between-group differences even in those with normal MMSE and would thus appear to be a useful brief tool to assess cognition in those with MCI, particularly where the ceiling effect of the MMSE is problematic.

Profiles of cognitive subtest impairment in the Montreal Cognitive Assessment (MoCA) in a research cohort with normal Mini-Mental State Examination (MMSE) scores

The comparative ability of the Montreal Cognitive Assessment (MoCA) and MMSE to detect mild cognitive difficulties was investigated in 107 older adults. The sensitivity of the MoCA to detect cognitive impairment with a cutoff score of <26 was investigated, as compared to the MMSE across all scores, and at a cutoff of ≥27. Performance on MoCA subtests was compared at these MMSE cutoffs to determine profiles of early cognitive difficulties. The MoCA detected cognitive impairment not detected by the MMSE in a high proportion of participants, and this impairment was evident across various subtests. The MoCA appears to be a sensitive screening test for detection of early cognitive impairment.

Association of the androgen receptor CAG repeat polymorphism with Alzheimer's disease in men

We examined the CAG repeat polymorphism in exon 1 of the androgen receptor (AR) in an Oxford cohort of 150 cases (101 men) of definite or probable Alzheimers disease (AD) and 190 elderly controls (140 men). We found that short alleles (< or = 20 CAG repeats) were associated with AD (adjusted odds ratio = 2.5, 95% confidence intervals: 1.2-5.0) in men, but not in women. This association appeared stronger in early-onset AD (< 65 years). We conclude that this AR polymorphism is of potential relevance to the risk of AD in men.

Human hippocampal energy metabolism is impaired during cognitive activity in a lipid infusion model of insulin resistance.

Neuronal glucose uptake was thought to be independent of insulin, being facilitated by glucose transporters GLUT1 and GLUT3, which do not require insulin signaling. However, it is now known that components of the insulin‐mediated glucose uptake pathway, including neuronal insulin synthesis and the insulin‐dependent glucose transporter GLUT4, are present in brain tissue, particularly in the hippocampus. There is considerable recent evidence that insulin signaling is crucial to optimal hippocampal function. The physiological basis, however, is not clear. We propose that while noninsulin‐dependent GLUT1 and GLUT3 transport is adequate for resting needs, the surge in energy use during sustained cognitive activity requires the additional induction of insulin‐signaled GLUT4 transport. We studied hippocampal high‐energy phosphate metabolism in eight healthy volunteers, using a lipid infusion protocol to inhibit insulin signaling. Contrary to conventional wisdom, it is now known that free fatty acids do cross the blood–brain barrier in significant amounts. Energy metabolism within the hippocampus was assessed during standardized cognitive activity. 31Phosphorus magnetic resonance spectroscopy was used to determine the phosphocreatine (PCr)‐to‐adenosine triphosphate (ATP) ratio. This ratio reflects cellular energy production in relation to concurrent cellular energy expenditure. With lipid infusion, the ratio was significantly reduced during cognitive activity (PCr/ATP 1.0 ± 0.4 compared with 1.4 ± 0.4 before infusion, P = 0.01). Without lipid infusion, there was no reduction in the ratio during cognitive activity (PCr/ATP 1.5 ± 0.3 compared with 1.4 ± 0.4, P = 0.57). This provides supporting evidence for a physiological role for insulin signaling in facilitating increased neuronal glucose uptake during sustained cognitive activity. Loss of this response, as may occur in type 2 diabetes, would lead to insufficient neuronal energy availability during cognitive activity.

A comparison of screening tools for the assessment of Mild Cognitive Impairment: Preliminary findings

We report a pilot investigation into the utility of screening tools in Mild Cognitive Impairment (MCI). The Addenbrookes Cognitive Examination-Revised (ACE-R), Montreal Cognitive Assessment (MoCA) and the novel Computer-Administered Neuropsychological Screen for Mild Cognitive Impairment (CANS-MCI) were administered to 20 elderly controls and 15 MCI cases. Non-parametric Mann–Whitney U-tests showed significant differences between groups (p < .0001) on the CANS-MCI and MoCA. The ACE-R and MoCA total scores showed high sensitivity (90%) to MCI. Area under the curve was consistently significant in discriminating controls and MCI for memory scores across all screening instruments. A useful profile of quantitative and qualitative information pertaining to cognitive functioning in MCI can be obtained with the MoCA, ACE-R, and CANS-MCI.

Structural and functional bases of visuospatial associative memory in older adults

Impaired visuospatial associative memory may be one of the earliest changes predicting cognitive impairment and Alzheimers disease. We explored the relationship between performance on a visuospatial associative memory task (the Placing Test) and brain structure and function in cognitively healthy older adults. First, we performed a voxel-based morphometry correlational analysis on structural magnetic resonance imaging (MRI) data from 144 healthy older adults with their scores on the Placing Test. Second, we carried out a functional MRI study on another group of 28 healthy older adults who performed a similar task during functional MRI. Decreased performance on the Placing Test was associated with increased atrophy in medial-temporal regions. Functional activation of the same regions-controlling for the effect of atrophy-occurred during successful performance of the same task. The colocalization of structural and functional MRI correspondents of visuospatial associative test performance within medial-temporal regions validates multimodal imaging in describing behaviorally relevant variability in the aging brain and suggests that the Placing Test has the potential for detecting early cognitive changes occurring in preclinical phases of Alzheimers disease.