Relationship of Parieto-Occipital Brain Energy Phosphate Metabolism and Cognition Using 31P MRS at 7-Tesla in Amnestic Mild Cognitive Impairment.

BACKGROUND: The human brain has high energy requirements that continuously support healthy neuronal activity and cognition. A disruption in brain energy metabolism (BEM) may contribute to early neuropathological changes such as accumulation of ß-amyloid and tau in vulnerable populations. One such population is amnestic mild cognitive impairment (aMCI) where some individuals are at risk for developing dementia, i.e. Alzheimer's disease (AD). Recent advances in imaging technology are providing new avenues to measure BEM accurately using 31phosphorus magnetic resonance spectroscopy (31P MRS) at ultra-high-field (UHF) magnetic strength 7-Tesla. This study investigates whether a methodology using partial volume-coil 31P MRS at 7T over parieto-occipital lobes can accurately quantify high-energy phosphate and membrane phospholipid metabolites in aMCI. A secondary objective was to explore BEM and membrane phospholipid indices' correspondence with cognitive performance in domains of executive function (EF), memory, attention, and visuospatial skills in aMCI, a heterogeneous population. METHODS: 19 aMCI participants enrolled in the study completed cognitive assessment and 31P MRS scan. BEM indices were measured using three energy indicators: energy reserve (PCr/t-ATP), energy consumption (intracellular_Pi/t-ATP), and metabolic state (PCr/intracellular_Pi) along with regulatory co-factors of BEM-intracellular Mg2 + and pH; whereas the ratio of phosphomonoesters (PMEs) to phosphodiesters (PDEs) - membrane phospholipid indicator. RESULTS: 31P MRS scan showed thirteen well-resolved peaks with precise quantification of the phosphorus metabolites at UHF. The higher BEM indices were associated with lower cognitive performance of memory [(energy reserve indicator: CVLT p = 0.004), (metabolic state indicator: CVLT p = 0.007)], executive function [(metabolic state indicator: TOSL (p = 0.044)], and attention [(pH: selective auditory task, p = 0.044)]. The finding of an inverse relationship observed in the parieto-occipital lobes suggests an association between neuronal energy markers with cognition in aMCI. CONCLUSION: The significant contribution of this preliminary research was to establish the feasibility of utilizing a methodology at UHF to accurately measure high-energy phosphate and membrane phospholipid metabolites in a population with heterogeneous outcomes. This work offers a novel approach for future work to further elucidate early dementia biomarkers or precursors to the downstream accumulation of amyloid and tau using the combination of MRS-PET imaging modalities in AD.

Cognitive Training and Transcranial Direct Current Stimulation in Mild Cognitive Impairment: A Randomized Pilot Trial.

BACKGROUND: Transcranial direct current stimulation (tDCS), a non-invasive stimulation, represents a potential intervention to enhance cognition across clinical populations including Alzheimer's disease and mild cognitive impairment (MCI). This randomized clinical trial in MCI investigated the effects of anodal tDCS (a-tDCS) delivered to left inferior frontal gyrus (IFG) combined with gist-reasoning training (SMART) versus sham tDCS (s-tDCS) plus SMART on measures of cognitive and neural changes in resting cerebral blood flow (rCBF). We were also interested in SMART effects on cognitive performance regardless of the tDCS group. METHODS: Twenty-two MCI participants, who completed the baseline cognitive assessment (T1), were randomized into one of two groups: a-tDCS + SMART and s-tDCS + SMART. Of which, 20 participants completed resting pCASL MRI scan to measure rCBF. Eight SMART sessions were administered over 4 weeks with a-tDCS or s-tDCS stimulation for 20 min before each session. Participants were assessed immediately (T2) and 3-months after training (T3). RESULTS: Significant group × time interactions showed cognitive gains at T2 in executive function (EF) measure of inhibition [DKEFS- Color word (p = 0.047)], innovation [TOSL (p = 0.01)] and on episodic memory [TOSL (p = 0.048)] in s-tDCS + SMART but not in a-tDCS + SMART group. Nonetheless, the gains did not persist for 3 months (T3) after the training. A voxel-based analysis showed significant increase in regional rCBF in the right middle frontal cortex (MFC) (cluster-wise p = 0.05, k = 1,168 mm3) in a-tDCS + SMART compared to s-tDCS + SMART. No significant relationship was observed between the increased CBF with cognition. Irrespective of group, the combined MCI showed gains at T2 in EF of conceptual reasoning [DKEFS card sort (p = 0.033)] and category fluency [COWAT (p = 0.055)], along with gains at T3 in EF of verbal fluency [COWAT (p = 0.009)]. CONCLUSION: One intriguing finding is a-tDCS to left IFG plus SMART increased blood flow to right MFC, however, the stimulation seemingly blocked cognitive benefits of SMART on EF (inhibition and innovation) and episodic memory compared to s-tDCS + SMART group. Although the sample size is small, this paper contributes to growing evidence that cognitive training provides a way to significantly enhance cognitive performance in adults showing memory loss, where the role of a-tDCS in augmenting these effects need further study.

Event-related neural oscillation changes following reasoning training in individuals with Mild Cognitive Impairment.

Emerging evidence suggests cognitive training programs targeting higher-order reasoning may strengthen not only cognitive, but also neural functions in individuals with Mild Cognitive Impairment (MCI). However, research on direct measures of training-induced neural changes, derivable from electroencephalography (EEG), is limited. The current pilot study examined effects of Gist Reasoning training (n = 16) compared to New Learning training (n = 16) in older adults with amnestic MCI on measures of event-related neural oscillations (theta and alpha band power) corresponding to Go/NoGo tasks during basic and superordinate semantic categorization. EEG data were recorded while participants performed the Go/NoGo task pre- and post-training, and power in theta and alpha frequency bands was examined. Both groups were comparable at pre-training on all measures and both groups showed greater event-related theta synchronization post-training. Furthermore, the Gist Reasoning group had enhanced event-related desynchronization in low-frequency alpha band (8-10 Hz) on response inhibition (NoGo) trials and high-frequency alpha band (11-13 Hz) on response execution (Go) trials during superordinate categorization, relative to the New Learning group. These findings suggest that Gist Reasoning training in MCI impacted neural processing linked to strategic processing of Go and NoGo trials during the more complex superordinate categorization task. Targeting higher-order top-down cognitive processing seems to better harness residual neuroplastic potential in MCI. ClinicalTrials.gov ID: NCT02588209.

Enhancing latent cognitive capacity in mild cognitive impairment with gist reasoning training: a pilot study.

OBJECTIVE: Cognitive training offers a promising way to mitigate cognitive deterioration in individuals with mild cognitive impairment (MCI). This randomized control pilot trial examined the effects of Gist Reasoning Training on cognition as compared with a training involving New Learning in a well-characterized MCI group. METHODS: Fifty participants with amnestic MCI were randomly assigned to the experimental Gist Training group or an active control New Learning group. Both groups received 8 h of training over a 4-week period. We compared pre-training with post-training changes in cognitive functions between the two training groups. RESULTS: The Gist Training group showed higher performance in executive function (strategic control and concept abstraction) and memory span compared with the New Learning group. Conversely, the New Learning group showed gains in memory for details. CONCLUSION: These findings suggest that cognitive training in general yields benefits, and more specifically, training programs that target top-down cognitive functions such as gist reasoning may have a broad impact on improving cognition in MCI. © 2016 The Authors. International Journal of Geriatric Psychiatry Published by John Wiley & Sons Ltd.

Gist reasoning training in cognitively normal seniors.

OBJECTIVE: Cognitive impairment is a key factor that threatens functionality and quality of life in seniors. Given the projection that the population of individuals 65 years of age and older will double within the next 25 years, a critical need exists to identify and test effectiveness of protocols that target higher-order cognitive skills such as gist reasoning to maximize cognitive capacity in later life. METHODS: This study examined the effects of eight hours of gist reasoning training in 26 cognitively normal seniors between the ages of 64-85 years (M = 74.23, SD = 6.67). RESULTS: Findings suggest that top-down strategy-based gist reasoning training significantly improved abstraction ability, a skill relevant to everyday life, as well as generalized to untrained measures of executive function including concept abstraction, cognitive switching, and verbal fluency. Individuals with lower baseline ability to abstract gist showed the greatest gain in the target domain trained. CONCLUSIONS: These findings highlight the potential value of engaging in cognitively challenging activities that involve gist reasoning, to strengthen and preserve cognitive capacity with aging.

Effects of cognitive-communication stimulation for Alzheimer's disease patients treated with donepezil.

This randomized study evaluated the combined effect of a cognitive-communication program plus an acetylcholinesterase inhibitor (donepezil; donepezil-plus-stimulation group; n = 26), as compared with donepezil alone (donepezil-only group; n = 28) in 54 patients with mild to moderate Alzheimer's disease (AD; Mini-Mental Status Examination score of 12- 28) ranging in age from 54 to 91 years. It was hypothesized that cognitive-communication stimulation in combination with donepezil would positively affect the following: (a) relevance of discourse, (b) performance of functional abilities, (c) emotional symptoms, (d) quality of life, and (e) overall global function, as measured by caregiver and participant report and standardized measures. Cognitive-communication, neuropsychiatric, functional performance, and quality of life evaluations were conducted at baseline and Month 4, the month after the 2-month active stimulation period. Follow-up evaluations were performed at Months 8 and 12. The stimulation program consisted of 12 hr of intervention over an 8-week period and involved participant-led discussions requiring homework, interactive sessions about AD, and discussions using salient life stories. Additive effects of active stimulation with donepezil were examined in 2 ways: (1) comparing mean group performance over time and (2) evaluating change scores from baseline. A Group x Time interaction was found for the donepezil-plus-stimulation group in the emotional symptoms of apathy and irritability as compared with the donepezil-only group. Evaluation of change scores from baseline to 12 months revealed a positive effect for the donepezil-plus-stimulation group on discourse and functional abilities with a trend on apathy, irritability, and patient-reported quality of life. In sum, the research revealed benefits to the donepezil-plus-stimulation group in the areas of discourse abilities, functional abilities, emotional symptoms, and overall global performance. This study adds to growing evidence that active cognitive stimulation may slow the rate of verbal and functional decline and decrease negative emotional symptoms in AD when combined with acetylcholinesterase inhibitors, indicating a need to advance research in the area of cognitive treatments. The fact that AD is a progressive brain disease should not preclude ameliorative treatment.