Phenotypes of hypofrontality in older female fragile X premutation carriers.

OBJECTIVE: To investigate the nature of cognitive impairments and underlying brain mechanisms in older female fragile X premutation carriers with and without fragile X-associated tremor/ataxia syndrome (FXTAS). METHODS: Extensive neuropsychological testing and cognitive event-related brain potentials (ERPs; particularly, the auditory P300) were examined in 84 female participants: 33 fragile X premutation carriers with FXTAS (mean age = 62.8 years), 25 premutation carriers without FXTAS (mean age = 55.4 years), and 26 normal healthy controls (mean age = 59.3 years). RESULTS: Both premutation groups exhibited executive dysfunction on the Behavioral Dyscontrol Scale, with subtle impairments in inhibition and performance monitoring in female carriers without FXTAS, and more substantial deficits in FXTAS women. However, the female carrier group without FXTAS showed more pronounced deficiencies in working memory. Abnormal ERPs were recorded over the frontal lobes, where FXTAS patients showed both P300 amplitude reduction and latency prolongation, whereas only decreased frontal P300 amplitudes were found in carriers without FXTAS. These frontal P300 measures correlated with executive function and information processing speed. INTERPRETATION: The neuropsychological testing and ERP results of the present study provide support for the hypothesis that executive dysfunction is the primary cognitive impairment among older female premutation carriers both with and without FXTAS, although these deficits are relatively mild compared to those in FXTAS males. These findings are consistent with a synergistic effect of the premutation and aging on cognitive impairment among older female fragile X premutation carriers, even in those without FXTAS symptoms.

Everyday cognition in older adults: associations with neuropsychological performance and structural brain imaging.

The recently developed Everyday Cognition scales (ECog) measure multiple cognitively relevant functional domains (e.g., Everyday Memory, Everyday Language, Everyday Visuospatial abilities, and three everyday executive domains). The present study further evaluated the validity of the ECog by examining its relationship with objective measures of neuropsychological function, and neurobiological markers of disease as reflected by structural neuroimaging. Participants included 474 older adults (244 normals, 142 with MCI, 88 with dementia). The neuropsychological domains measured were episodic memory, semantic memory, spatial ability, and executive functioning. Brain MRI volumes included total brain (BV), hippocampus (HC) and dorsolateral prefrontal cortex (DLPFC). Neuropsychological measures of episodic memory and executive function were most consistently related to the ECog domains; spatial abilities had a specific relationship to the Everyday Visuospatial ECog domain. HC and BV volumes were related to most ECog domains, while DLPFC volume was independently related to two everyday executive domains (Everyday Planning and Everyday Organization). The pattern of associations varied somewhat as a function of diagnosis. Episodic memory and HC had more consistent associations with the ECog domains in older adults with MCI/dementia than in cognitively normal elderly.

The role of cognitive reserve and memory self-efficacy in compensatory strategy use: A structural equation approach.

INTRODUCTION: The use of compensatory strategies plays an important role in the ability of older adults to adapt to late-life memory changes. Even with the benefits associated with compensatory strategy use, little research has explored specific mechanisms associated with memory performance and compensatory strategies. Rather than an individual's objective memory performance directly predicting their use of compensatory strategies, it is possible that some other variables are indirectly influencing that relationship. The purpose of this study was to: (a) examine the moderating effects of cognitive reserve (CR) and (b) evaluate the potential mediating effects of memory self-efficacy on the relationship between objective memory performance and compensatory strategy use. METHOD: Two structural equation models (SEM) were used to evaluate CR (latent moderator model) and memory self-efficacy (mediator model) in a sample of 155 community-dwelling older adults over the age of 55. RESULTS: The latent variable moderator model indicated that CR was not substantiated as a moderator variable in this sample (p = .861). However, memory self-efficacy significantly mediated the association between objective memory performance and compensatory strategy use (ß = .22, 95% confidence interval, CI [.002, .437]). More specifically, better objective memory was associated with lower compensatory strategy use because of its relation to higher memory self-efficacy. CONCLUSIONS: These findings provide initial support for an explanatory framework of the relation between objective memory and compensatory strategy use in a healthy older adult population by identifying the importance of an individual's memory perceptions.

Memantine Improves Attentional Processes in Fragile X-Associated Tremor/Ataxia Syndrome: Electrophysiological Evidence from a Randomized Controlled Trial.

Progressive cognitive deficits are common in patients with fragile X-associated tremor/ataxia syndrome (FXTAS), with no targeted treatment yet established. In this substudy of the first randomized controlled trial for FXTAS, we examined the effects of NMDA antagonist memantine on attention and working memory. Data were analyzed for patients (24 in each arm) who completed both the primary memantine trial and two EEG recordings (at baseline and follow-up) using an auditory "oddball" task. Results demonstrated significantly improved attention/working memory performance after one year only for the memantine group. The event-related potential P2 amplitude elicited by non-targets was significantly enhanced in the treated group, indicating memantine-associated improvement in attentional processes at the stimulus identification/discrimination level. P2 amplitude increase was positively correlated with improvement on the behavioral measure of attention/working memory during target detection. Analysis also revealed that memantine treatment normalized the P2 habituation effect at the follow-up visit. These findings indicate that memantine may benefit attentional processes that represent fundamental components of executive function/dysfunction, thought to comprise the core cognitive deficit in FXTAS. The results provide evidence of target engagement of memantine, as well as therapeutically relevant information that could further the development of specific cognitive or disease-modifying therapies for FXTAS.

Memantine effects on verbal memory in fragile X-associated tremor/ataxia syndrome (FXTAS): a double-blind brain potential study.

Older FMR1 premutation carriers may develop fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder manifesting cognitive deficits that often subsequently progress to dementia. To date, there is no specific treatment available for FXTAS. Studies have demonstrated the premutation-associated overactivation of glutamatergic receptors in neurons. Memantine, a NMDA receptor antagonist approved for treatment of Alzheimer's disease, thus was tested in the first placebo-controlled, double-blind, randomized clinical trial in FXTAS. Prior event-related brain potential (ERP) studies in FXTAS found reduced N400 repetition effect, a glutamate-related electrophysiological marker of semantic priming, and verbal memory processes. This substudy of the randomized clinical trial of memantine in FXTAS sought to use the N400 repetition effect to evaluate effects of chronic memantine treatment on verbal memory. Subsequent recall and recognition memory tests for the experimental stimuli were administered to characterize verbal memory. Data from 41 patients who completed the 1-year memantine trial (21 on memantine) and also completed longitudinal ERP studies were analyzed. Results showed treatment-associated benefits on both cued-recall memory and N400 repetition effect amplitude. Importantly, improvement in cued recall was positively correlated with amplitude increase of the N400 repetition effect. The placebo group, in contrast, displayed a significant reduction of the N400 repetition effect after 1 year. These results suggest that memantine treatment may have beneficial effects on verbal memory in FXTAS. Additional studies of memantine, perhaps in combination with other therapeutic agents, appear warranted, as symptomatic treatments and neuroprotective treatments are both needed for this recently recognized neurodegenerative disorder.

Idea density measured in late life predicts subsequent cognitive trajectories: implications for the measurement of cognitive reserve.

OBJECTIVE: The Nun Study showed that lower linguistic ability in young adulthood, measured by idea density (ID), increased the risk of dementia in late life. The present study examined whether ID measured in late life continues to predict the trajectory of cognitive change. METHOD: ID was measured in 81 older adults who were followed longitudinally for an average of 4.3 years. Changes in global cognition and 4 specific neuropsychological domains (episodic memory, semantic memory, spatial abilities, and executive function) were examined as outcomes. Separate random effects models tested the effect of ID on longitudinal change in outcomes, adjusted for age and education. RESULTS: Lower ID was associated with greater subsequent decline in global cognition, semantic memory, episodic memory, and spatial abilities. When analysis was restricted to only participants without dementia at the time ID was collected, results were similar. DISCUSSION: Linguistic ability in young adulthood, as measured by ID, has been previously proposed as an index of neurocognitive development and/or cognitive reserve. The present study provides evidence that even when ID is measured in old age, it continues to be associated with subsequent cognitive decline and as such may continue to provide a marker of cognitive reserve.