Combined mnemonic strategy training and high-definition transcranial direct current stimulation for memory deficits in mild cognitive impairment

Introduction: Memory deficits characterize Alzheimer’s dementia and the clinical precursor stage known as mild cognitive impairment. Nonpharmacologic interventions hold promise for enhancing functioning in these patients, potentially delaying functional impairment that denotes transition to dementia. Previous findings revealed that mnemonic strategy training (MST) enhances long-term retention of trained stimuli and is accompanied by increased blood oxygen level–dependent signal in the lateral frontal and parietal cortices as well as in the hippocampus. The present study was designed to enhance MST generalization, and the range of patients who benefit, via concurrent delivery of transcranial direct current stimulation (tDCS). Methods: This protocol describes a prospective, randomized controlled, four-arm, double-blind study targeting memory deficits in those with mild cognitive impairment. Once randomized, participants complete five consecutive daily sessions in which they receive either active or sham high definition tDCS over the left lateral prefrontal cortex, a region known to be important for successful memory encoding and that has been engaged by MST. High definition tDCS (active or sham) will be combined with either MST or autobiographical memory recall (comparable to reminiscence therapy). Participants undergo memory testing using ecologically relevant measures and functional magnetic resonance imaging before and after these treatment sessions as well as at a 3-month follow-up. Primary outcome measures include face-name and object-location association tasks. Secondary outcome measures include self-report of memory abilities as well as a spatial navigation task (near transfer) and prose memory (medication instructions; far transfer). Changes in functional magnetic resonance imaging will be evaluated during both task performance and the resting-state using activation and connectivity analyses. Discussion: The results will provide important information about the efficacy of cognitive and neuromodulatory techniques as well as the synergistic interaction between these promising approaches. Exploratory results will examine patient characteristics that affect treatment efficacy, thereby identifying those most appropriate for intervention

Dynamic modeling of practice effects across the healthy aging-Alzheimer’s disease continuum

Standardized tests of learning and memory are sensitive to changes associated with both aging and superimposed neurodegenerative diseases. Unfortunately, repeated behavioral test administration can be confounded by practice effects (PE), which may obscure declines in level of abilities and contribute to misdiagnoses. Growing evidence, however, suggests PE over successive longitudinal measurements may differentially predict cognitive status and risk for progressive decline associated with aging, mild cognitive impairment (MCI), and dementia. Thus, when viewed as a reflection of neurocognitive plasticity, PE may reveal residual abilities that can add to our understanding of age- and disease-related changes in learning and memory. The present study sought to evaluate differences in PE and verbal recall in a clinically characterized aging cohort assessed on multiple occasions over 3 years. Participants included 256 older adults recently diagnosed as cognitively unimpaired (CU; n = 126), or with MCI of amnestic (n = 65) or non-amnestic MCI (n = 2085), and multi-domain amnestic dementia of the Alzheimer’s type (DAT; n = 45). We applied a continuous time structural equation modeling (ctsem) approach to verbal recall performance on the Hopkins Verbal Learning Test in order to distinguish PE from individual occasion performance, coupled random changes, age trends, and differing measurement quality. Diagnoses of MCI and dementia were associated with lower recall performance on all trials, reduced PE gain per occasion, and differences in non-linear dynamic parameters. Practice self-feedback is a dynamic measure of the decay or acceleration in PE process changes over longitudinal occasions. As with PE and mean recall, estimated practice self-feedback followed a gradient from positive in CU participants to null in participants with diagnosed MCI and negative for those with dementia diagnoses. Evaluation of sensitivity models showed this pattern of variation in PE was largely unmodified by differences in age, sex, or educational attainment. These results show dynamic modeling of PE from longitudinal performance on standardized learning and memory tests can capture multiple aspects of behavioral changes in MCI and dementia. The present study provides a new perspective for modeling longitudinal change in verbal learning in clinical and cognitive aging research

Dynamic modeling of practice effects across the healthy aging-Alzheimer’s disease continuum

Standardized tests of learning and memory are sensitive to changes associated with both aging and superimposed neurodegenerative diseases. Unfortunately, repeated behavioral test administration can be confounded by practice effects (PE), which may obscure declines in level of abilities and contribute to misdiagnoses. Growing evidence, however, suggests PE over successive longitudinal measurements may differentially predict cognitive status and risk for progressive decline associated with aging, mild cognitive impairment (MCI), and dementia. Thus, when viewed as a reflection of neurocognitive plasticity, PE may reveal residual abilities that can add to our understanding of age- and disease-related changes in learning and memory. The present study sought to evaluate differences in PE and verbal recall in a clinically characterized aging cohort assessed on multiple occasions over 3 years. Participants included 256 older adults recently diagnosed as cognitively unimpaired (CU; n = 126), or with MCI of amnestic (n = 65) or non-amnestic MCI (n = 2085), and multi-domain amnestic dementia of the Alzheimer’s type (DAT; n = 45). We applied a continuous time structural equation modeling (ctsem) approach to verbal recall performance on the Hopkins Verbal Learning Test in order to distinguish PE from individual occasion performance, coupled random changes, age trends, and differing measurement quality. Diagnoses of MCI and dementia were associated with lower recall performance on all trials, reduced PE gain per occasion, and differences in non-linear dynamic parameters. Practice self-feedback is a dynamic measure of the decay or acceleration in PE process changes over longitudinal occasions. As with PE and mean recall, estimated practice self-feedback followed a gradient from positive in CU participants to null in participants with diagnosed MCI and negative for those with dementia diagnoses. Evaluation of sensitivity models showed this pattern of variation in PE was largely unmodified by differences in age, sex, or educational attainment. These results show dynamic modeling of PE from longitudinal performance on standardized learning and memory tests can capture multiple aspects of behavioral changes in MCI and dementia. The present study provides a new perspective for modeling longitudinal change in verbal learning in clinical and cognitive aging research

O3‐06‐01: Nih Toolbox Cognition Tablet Battery In Identification Of Early Cognitive Impairment

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152934/1/alzjjalz2019064654.pd

Cognitive and Brain Activity Changes After Mnemonic Strategy Training in Amnestic Mild Cognitive Impairment: Evidence From a Randomized Controlled Trial

Background: Mnemonic strategy training (MST) has been shown to improve cognitive performance in amnestic mild cognitive impairment (a-MCI), however, several questions remain unresolved. The goal of the present study was to replicate earlier pilot study findings using a randomized controlled design and to evaluate transfer effects and changes in brain activation.Methods: Thirty patients with a-MCI were randomized into MST or education program. At baseline, participants completed clinical and neuropsychological assessments as well as structural and functional magnetic resonance imaging (fMRI). Interventions were administered individually and comprised four sessions, over 2 weeks. MST taught patients to use a three-step process to learn and recall face-name associations. Post-treatment assessment included fMRI, a separate face-name association task, neuropsychological tests, and measures of metamemory. Behavioral (i.e., non-fMRI) measures were repeated after one and 3-months.Results: Participants in the MST condition showed greater improvement on measures of face-name memory, and increased associative strategy use; effects that were accompanied by increased fMRI activation in the left anterior temporal lobe. While all participants reported greater contentment with their everyday memory following intervention, only the MST group reported significant improvements in their memory abilities. There was no clear indication of far-transfer effects to other neuropsychological tests.Conclusion: Results demonstrate that patients with a-MCI not only show stimulus specific benefits of MST, but that they appear capable of transferring training to at least some other cognitive tasks. MST also facilitated the use of brain regions that are involved in face processing, episodic and semantic memory, and social cognition, which are consonant with the cognitive processes engaged by training

Missense variants in ANKRD11 cause KBG syndrome by impairment of stability or transcriptional activity of the encoded protein

Purpose Although haploinsufficiency of ANKRD11 is among the most common genetic causes of neurodevelopmental disorders, the role of rare ANKRD11 missense variation remains unclear. We characterized clinical, molecular, and functional spectra of ANKRD11 missense variants. Methods We collected clinical information of individuals with ANKRD11 missense variants and evaluated phenotypic fit to KBG syndrome. We assessed pathogenicity of variants through in silico analyses and cell-based experiments. Results We identified 20 unique, mostly de novo, ANKRD11 missense variants in 29 individuals, presenting with syndromic neurodevelopmental disorders similar to KBG syndrome caused by ANKRD11 protein truncating variants or 16q24.3 microdeletions. Missense variants significantly clustered in repression domain 2 at the ANKRD11 C-terminus. Of the 10 functionally studied missense variants, 6 reduced ANKRD11 stability. One variant caused decreased proteasome degradation and loss of ANKRD11 transcriptional activity. Conclusion Our study indicates that pathogenic heterozygous ANKRD11 missense variants cause the clinically recognizable KBG syndrome. Disrupted transrepression capacity and reduced protein stability each independently lead to ANKRD11 loss-of-function, consistent with haploinsufficiency. This highlights the diagnostic relevance of ANKRD11 missense variants, but also poses diagnostic challenges because the KBG-associated phenotype may be mild and inherited pathogenic ANKRD11 (missense) variants are increasingly observed, warranting stringent variant classification and careful phenotyping

Dissociation of vascular dementia and Alzheimer’s disease using a sequential working memory and recognition task

Previous research suggests that it is possible to differentiate between patients with dementia due to subcortical ischemic white matter disease (i.e. vascular dementia – VaD) from those with Alzheimer’s disease (AD), as the former generally demonstrate executive dysfunction within the context of preserved recognition memory (i.e. encoding ability) whereas the opposite pattern is present in patients with AD. Executive abilities, specifically working memory, are important in utilizing the temporal aspects of memory (e.g. the sequence in which events occurred). Thus, a novel test was developed wherein participants were asked to sequence and then recognize a series of letters from among distracters with the expectation that the VaD patients would perform more poorly on the sequencing task whereas those with AD would do worse on the recognition component. Participants with mild AD (n=14), mild VaD (n=13), and healthy controls (n=10) were administered the experimental task and traditional neuropsychological tests of working memory and recognition memory. The patients were diagnosed with either AD or VaD and were required to have either low or high white matter damage, respectively, as evidenced by MRI scans. The VaD group performed worse during the sequencing task and also demonstrated difficulty utilizing the temporal aspects of memory. There was some evidence that encoding was relatively preserved in the VaD group compared to the AD patients following even the short delays used in this study (i.e. 15 seconds). Thus, the results support the relationship between executive abilities and the temporal aspects of memory and suggest that white matter damage can result in deficits analogous to those observed with cortical lesions. Additionally, the methods used in the experimental task may hold promise for examining such abilities within these and other populations.Ph.D., Clinical Psychology -- Drexel University, 200

O3‐05‐04: Task‐Related Fmri Change After High‐Definition Transcranial Direct Current Stimulation In Cognitively Intact Older Adults And Patients With Mci

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153127/1/alzjjalz2018062797.pd

Transcranial direct current stimulation (tDCS) in cognitively symptomatic older adults

BackgroundtDCS offers an inexpensive, portable, well-tolerated, and safe approach to neuromodulation. These benefits led to a rapid increase in its use as a potential treatment for those with Alzheimer’s disease and related dementias (ADRD), yet were accompanied by a number of methodological gaps that limit its current translational potential. This session will introduce and evaluate several such methodological factors including potential mechanisms of action, dose-response relationships, session frequency and duration, and individual factors that may account for variable treatment response.MethodData from over 300 participants across the ADRD spectrum and 2,500 tDCS sessions who were enrolled at the Research Program on Cognition and Neuromodulation Based Interventions will be used to demonstrate the potential impact of the above noted methodological factors. Structural and functional neuroimaging data will be included to demonstrate both theoretical and empirical effects of tDCS.ResultAcross studies, our results demonstrate that targeted, multi-electrode tDCS can alter underlying neurotransmitter levels and potentially “normalize” patterns of “activation” and functional connectivity in those with cognitive impairment. However, there is remarkable variability in the amount of electrical current delivered to the brain across participants (>600%) as well as the targeted brain region, which require reconsideration of the traditional dosing at the scalp approach. Moreover, there are apparent polarity-dependent effects as well as differences between passive versus active (i.e., cognitive task performance) measurements. Ongoing work evaluates the additional impact and nature of disease pathology on these factors.ConclusionThe combination of results highlights the complex and multifaceted nature of tDCS and may translate to other forms of neuromodulation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/175389/1/alz067610.pd