Kathleen Tingus

Lifespan trajectory of myelin integrity and maximum motor speed.

OBJECTIVE Myelination of the human brain results in roughly quadratic trajectories of myelin content and integrity, reaching a maximum in mid-life and then declining in older age. This trajectory is most evident in vulnerable later myelinating association regions such as frontal lobes and may be the biological substrate for similar trajectories of cognitive processing speed. Speed of movement, such as maximal finger tapping speed (FTS), requires high-frequency action potential (AP) bursts and is associated with myelin integrity. We tested the hypothesis that the age-related trajectory of FTS is related to brain myelin integrity. METHODS A sensitive in vivo MRI biomarker of myelin integrity (calculated transverse relaxation rates (R(2))) of frontal lobe white matter (FLwm) was measured in a sample of very healthy males (N=72) between 23 and 80 years of age. To assess specificity, R(2) of a contrasting early-myelinating region (splenium of the corpus callosum) was also measured. RESULTS FLwm R(2) and FTS measures were significantly correlated (r=.45, p<.0001) with no association noted in the early-myelinating region (splenium). Both FLwm R(2) and FTS had significantly quadratic lifespan trajectories that were virtually indistinguishable and both reached a peak at 39 years of age and declined with an accelerating trajectory thereafter. CONCLUSIONS The results suggest that in this very healthy male sample, maximum motor speed requiring high-frequency AP burst may depend on brain myelin integrity. To the extent that the FLwm changes assessed by R(2) contribute to an age-related reduction in AP burst frequency, it is possible that other brain functions dependent on AP bursts may also be affected. Non-invasive measures of myelin integrity together with testing of basic measures of processing speed may aid in developing and targeting anti-aging treatments to mitigate age-related functional declines.

Donepezil delays progression to AD in MCI subjects with depressive symptoms

Objective: To determine whether the presence of depression predicts higher rate of progression to Alzheimer disease (AD) in patients with amnestic mild cognitive impairment (aMCI) and whether donepezil treatment beneficially affect this relationship. Methods: The study sample was composed of 756 participants with aMCI from the 3-year, double-blind, placebo-controlled Alzheimers Disease Cooperative Study drug trial of donepezil and vitamin E. Beck Depression Inventory (BDI) was used to assess depressive symptoms at baseline and participants were followed either to the end of study or to the primary endpoint of progression to probable or possible AD. Results: Cox proportional hazards regression, adjusted for age at baseline, gender, apolipoprotein genotype, and NYU paragraph delayed recall score, showed that higher BDI scores were associated with progression to AD (p = 0.03). The sample was stratified into depressed (BDI score ≥10; n = 208) and nondepressed (BDI <10; n = 548) groups. Kaplan-Meier analysis showed that among the depressed subjects, the proportion progressing to AD was lower for the donepezil group than the combined vitamin E and placebo groups at 1.7 years (p = 0.023), at 2.2 years (p = 0.025), and remained marginally lower at 2.7 years (p = 0.070). The survival curves among the three treatment groups did not differ within the nondepressed participants. Conclusions: Results suggest that depression is predictive of progression from amnestic mild cognitive impairment (aMCI) to Alzheimer disease (AD) and treatment with donepezil delayed progression to AD among depressed subjects with aMCI. Donepezil appears to modulate the increased risk of AD conferred by the presence of depressive symptoms.

Gender and Iron Genes May Modify Associations Between Brain Iron and Memory in Healthy Aging

Brain iron increases with age and is abnormally elevated early in the disease process in several neurodegenerative disorders that impact memory including Alzheimers disease (AD). Higher brain iron levels are associated with male gender and presence of highly prevalent allelic variants in genes encoding for iron metabolism proteins (hemochromatosis H63D (HFE H63D) and transferrin C2 (TfC2)). In this study, we examined whether in healthy older individuals memory performance is associated with increased brain iron, and whether gender and gene variant carrier (IRON+) vs noncarrier (IRON−) status (for HFE H63D/TfC2) modify the associations. Tissue iron deposited in ferritin molecules can be measured in vivo with magnetic resonance imaging utilizing the field-dependent relaxation rate increase (FDRI) method. FDRI was assessed in hippocampus, basal ganglia, and white matter, and IRON+ vs IRON− status was determined in a cohort of 63 healthy older individuals. Three cognitive domains were assessed: verbal memory (delayed recall), working memory/attention, and processing speed. Independent of gene status, worse verbal-memory performance was associated with higher hippocampal iron in men (r=−0.50, p=0.003) but not in women. Independent of gender, worse verbal working memory performance was associated with higher basal ganglia iron in IRON− group (r=−0.49, p=0.005) but not in the IRON+ group. Between-group interactions (p=0.006) were noted for both of these associations. No significant associations with white matter or processing speed were observed. The results suggest that in specific subgroups of healthy older individuals, higher accumulations of iron in vulnerable gray matter regions may adversely impact memory functions and could represent a risk factor for accelerated cognitive decline. Combining genetic and MRI biomarkers may provide opportunities to design primary prevention clinical trials that target high-risk groups.

Age-related slowing in cognitive processing speed is associated with myelin integrity in a very healthy elderly sample

Performance on measures of cognitive processing speed (CPS) slows with age, but the biological basis associated with this cognitive phenomenon remains incompletely understood. We assessed the hypothesis that the age-related slowing in CPS is associated with myelin breakdown in late-myelinating regions in a very healthy elderly population. An in vivo magnetic resonance imaging (MRI) biomarker of myelin integrity was obtained from the prefrontal lobe white matter and the genu of the corpus callosum for 152 healthy elderly adults. These regions myelinate later in brain development and are more vulnerable to breakdown due to the effects of normal aging. To evaluate regional specificity, we also assessed the splenium of the corpus callosum as a comparison region, which myelinates early in development and primarily contains axons involved in visual processing. The measure of myelin integrity was significantly correlated with CPS in highly vulnerable late-myelinating regions but not in the splenium. These results have implications for the neurobiology of the cognitive changes associated with brain aging.

Persistence of neuropsychological testing deficits in mild cognitive impairment.

Background: The significant variability across studies of mild cognitive impairment (MCI) in rates of progression to Alzheimer’s disease (AD) and reversion to normal cognition may be due to differences in specific neuropsychological tests and thresholds used to define MCI. Methods: We assessed 115 subjects with amnestic (AMN) or non-amnestic (NON) MCI on a standardized neuropsychological battery at baseline and after a mean follow-up of 16.4 months to determine the prevalence and persistence of deficits identified with specific tests. Results: The prevalence of impaired performance varied widely across tests. Deficits were more persistent in the AMN group than in the NON group. Baseline deficits in Visual Reproduction II and the California Verbal Learning Test were the best predictors of persistent memory impairment. Subjects who at baseline were impaired on multiple memory tests or had poorer overall memory performance were more likely to exhibit persistent memory deficits. Conclusions: The use of different neuropsychological tests and thresholds to diagnose MCI identified subsets of subjects with different rates of persistence of cognitive impairment. Standardization of the operational definition of cognitive impairment in MCI may result in more consistent predictions of progression to AD.

Normative data for healthy older adults and an abbreviated version of the Stroop test

Normative data for the Kaplan version of the Stroop Test are presented for 153 healthy, cognitively intact older adults aged 50–89 years. Increasing age was associated with decreased performance on all three subtests (Stroop A, Stroop B, and Stroop C), while years of education was only associated with Stroop B performance. Hence the normative data were stratified by age into three groups (50–64, 65–74, 75–89). Completion times for the first half of each trial (half-time scores) were found to have good split-half reliability and correlated highly with the original full administration scores. Means and standard deviations for the half-time administration are also presented for this sample. The current study provides more comprehensive normative data for older adults than previously available, as well as normative information for half-time scores that may have future clinical utility as an alternative, abbreviated version of the Kaplan Stroop Test.

Myelin integrity mediates age-related slowing in cognitive processing speed in a sample of healthy elderly men

concerned the subiculum (r1⁄4 0.64; p< 10-5), a slighter effectwas found for CA1 (r 1⁄4 0.36; p 1⁄4 0.004), whereas the other subfields were spared (r 1⁄4 0.02; p 1⁄4 0.90). Subicular volume positively correlated to WM density in the posterior CC, the cingulum bundle and the fornix (Figure b). This association was still significant when controlling for age. No significant correlation was found for CA1 nor the Other subfields. Conclusions: We showed that with aging, WM undergoes extensive changes encompassing frontal but also limbic areas. Besides, WM density in limbic areas is correlated to the shrinkage of the subiculum, the major hippocampal output sending fibres through the fornix and to the retrosplenial cortex. It is thus likely that age-related alterations in the subiculum and in these WM tracts are related, and together participate to the impairment of a common brain network.

Influence of iron genes and gender on brain iron and cognition

Background: Brain iron increases with age and is abnormally elevated early in the disease process in several neurodegenerative disorders including Alzheimer’s disease (AD). Studies have liked higher iron levels in males with younger age at onset and presence of the HFE hemochromatosis and transferrin C2 gene variants (iron genes) with AD. Objective: Examine whether cognitive performance in healthy older individuals is associated with increased brain ferritin iron and highly prevalent iron genes. Methods: Ferritin iron can be measured with specificity in vivo with MRI utilizing the Field Dependent Relaxation Rate Increase (FDRI) method. FDRI was assessed in basal ganglia, hippocampus, and white matter. Results: 48% of the sample carried neither gene (the IRONgroup) and 52% carried one and/or the other (IRONþ group). A robust gender by gene group interaction was observed. IRONþ men had significantly higher FDRI compared to the IRONgroup but in secondary analyses only the caudate nucleus showed a significant FDRI increase in IRONþ compared to IRONmen (t1⁄42.31, p1⁄4.027). This gene effect was not observed in women. Independent of genes, memory performance was significantly associated with hippocampal iron in men but not in women. Conclusions: This is the first evidence that these prevalent mutations can influence brain iron levels in men. Irrespective of gene status, verbal memory is negatively associated with hippocampal iron accumulation in men. Clinical phenomena such as gender-associated risk of developing neurodegenerative diseases and age at onset may be associated with the interactions between iron genes and brain ferritin iron accumulation. Reducing brain iron accumulations in old age may be a worthwhile therapeutic target for age-related neurodegenerative diseases.

IC-P-075: Cognitive processing speed and myelin breakdown in older individuals

Background: The process of myelination peaks in middle age followed by myelin breakdown and loss. Investigations of information processing speed performance across the lifespan reveal a trajectory that parallels myelination and subsequent myelin breakdown. Myelin breakdown may result in a progressive “disconnection” of widely distributed neural networks and may underlie age-related cognitive decline and Alzheimer’s disease (AD). Objective(s): This study tests the “myelin model”/hypothesis that in older individuals, myelin breakdown in late-myelinating regions is associated with slowed processing speed and contributes to the continuum of cognitive decline that ultimately results in AD. Methods: Healthy older ( 55 years) individuals (N 92) and 8 subjects with Alzheimer’s disease (AD) had neurocognitive testing. The late-myelinating frontal lobe white matter (Fwm) as well as earlyand later-myelinating regions of the corpus callosum, the splenium (Swm) and genu (Gwm) respectively, were assessed using MRI and transverse relaxation rates (R2) were calculated. R2 is an indirect measure of white matter structural integrity; it declines with age-related myelin breakdown and is significantly lower in AD. Results: As hypothesized, cognitive processing speed tasks (Trails A and Digit Symbol) were significantly associated with R2 in late-myelinating regions (Fwm, p .0001 and Gwm, p .004) but not in the early myelinating Swm region (p .2). Conclusions: These data suggest that myelin breakdown in healthy older individuals underlies the age-related cognitive decline that ultimately results in AD. MRI measures of myelin breakdown and cognitive measures may be useful in AD primary prevention studies.