Improvement in executive function for older adults through smartphone apps: a randomized clinical trial comparing language learning and brain training.

Bilingualism has been linked to improved executive function and delayed onset of dementia, but it is unknown whether similar benefits can be obtained later in life through deliberate intervention. Given the logistical hurdles of second language acquisition in a randomized trial for older adults, few interventional studies have been done thus far. However, recently developed smartphone apps offer a convenient means to acquire skills in a second language and can be compared with brain training apps specifically designed to improve executive function. In a randomized clinical trial, 76 adults aged 65-75 were assigned to either 16 weeks of Spanish learning using the app Duolingo 30 minutes a day, an equivalent amount of brain training using the app BrainHQ, or a waitlist control condition. Executive function was assessed before and after the intervention with preregistered (NCT03638882) tests previously linked to better performance in bilinguals. For two of the primary measures: incongruent Stroop color naming and 2-back accuracy, Duolingo provided equivalent benefits as BrainHQ compared to a control group. On reaction time for N-back and Simon tests, the BrainHQ group alone experienced strong gains over the other two groups. Duolingo was rated as more enjoyable. These results suggest that app-based language learning may provide some similar benefits as brain training in improving executive function in seniors but has less impact on processing speed. However, future advancements in app design may optimize not only the acquisition of the target language but also the side benefits of the language learning experience.

Alpha-Synuclein Targeting Therapeutics for Parkinson's Disease and Related Synucleinopathies.

α-Synuclein (asyn) is a key pathogenetic factor in a group of neurodegenerative diseases generically known as synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Although the initial triggers of pathology and progression are unclear, multiple lines of evidence support therapeutic targeting of asyn in order to limit its prion-like misfolding. Here, we review recent pre-clinical and clinical work that offers promising treatment strategies to sequester, degrade, or silence asyn expression as a means to reduce the levels of seed or substrate. These diverse approaches include removal of aggregated asyn with passive or active immunization or by expression of vectorized antibodies, modulating kinetics of misfolding with small molecule anti-aggregants, lowering asyn gene expression by antisense oligonucleotides or inhibitory RNA, and pharmacological activation of asyn degradation pathways. We also discuss recent technological advances in combining low intensity focused ultrasound with intravenous microbubbles to transiently increase blood-brain barrier permeability for improved brain delivery and target engagement of these large molecule anti-asyn biologics.

Protein synthesis and actin polymerization in the rapid effects of 17ß-estradiol on short-term social memory and dendritic spine dynamics in female mice.

Estrogens rapidly facilitate learning and memory, including social recognition - the ability of an animal to recognize another. In ovariectomized female mice, systemic or dorsal hippocampal administration of 17ß-estradiol (E2) facilitates short-term social recognition memory within 40 min. Within the same timeframe, E2 increases dendritic spine density in CA1 dorsal hippocampal neurons of behavioural task-naïve mice and in hippocampal sections. Mechanisms underlying these effects remain unclear. Estrogens rapidly modulate actin cytoskeletal dynamics through actin polymerization and the translation of key synaptic proteins. We first determined doses of actin polymerization inhibitor latrunculin A (LAT) and protein synthesis inhibitor anisomycin (ANI) that would block short-term social recognition memory when infused into the dorsal hippocampus of ovariectomized female mice 15 min prior to testing. The highest doses that did not block social recognition prevented the facilitating effects of E2, whereas DNA transcription inhibitor, actinomycin D, could not block social recognition. As task performance may interfere with E2-facilitated increases in dendritic spine density, dendritic spine density and length were examined in task-performing and task-naïve mice. E2 increased dendritic spine density 15 but not 40 min following treatment, regardless of whether the animal had performed the social recognition task. This effect was blocked by LAT, but not ANI. Thus, both actin polymerization and protein synthesis are necessary for E2 to rapidly facilitate social recognition, whereas actin polymerization, but not protein synthesis, is required for the rapid increase in dendritic spine density brought on by E2.

High definition transcranial direct current stimulation modulates abnormal neurophysiological activity in post-stroke aphasia.

Recent findings indicate that measures derived from resting-state magnetoencephalography (rsMEG) are sensitive to cortical dysfunction in post-stroke aphasia. Spectral power and multiscale entropy (MSE) measures show that left-hemispheric areas surrounding the stroke lesion (perilesional) exhibit pathological oscillatory slowing and alterations in signal complexity. In the current study, we tested whether individually-targeted high-definition transcranial direct current stimulation (HD-tDCS) can reduce MEG abnormalities and transiently improve language performance. In eleven chronic aphasia survivors, we devised a method to localize perilesional areas exhibiting peak MSE abnormalities, and subsequently targeted these areas with excitatory/anodal-tDCS, or targeted the contralateral homolog areas with inhibitory/cathodal-tDCS, based on prominent theories of stroke recovery. Pathological MEG slowing in these patients was correlated with aphasia severity. Sentence/phrase repetition accuracy was assessed before and after tDCS. A delayed word reading task was administered inside MEG to assess tDCS-induced neurophysiological changes in relative power and MSE computed on the pre-stimulus and delay task time windows. Results indicated increases in repetition accuracy, decreases in contralateral theta (4-7 Hz) and coarse-scale MSE (slow activity), and increases in perilesional low-gamma (25-50 Hz) and fine-scale MSE (fast activity) after anodal-tDCS, indicating reversal of pathological abnormalities. RsMEG may be a sensitive measure for guiding therapeutic tDCS.