Inter- and Intra-Hemispheric Age-Related Remodeling in Visuo-Spatial Working Memory

Electroencephalography (EEG) studies investigating visuo-spatial working memory (vWM) in aging typically adopt an event-related potential (ERP) analysis approach that has shed light on the age-related changes during item retention and retrieval. However, this approach does not fully enable a detailed description of the time course of the neural dynamics related to aging. The most frequent age-related changes in brain activity have been described by two influential models of neurocognitive aging, the Hemispheric Asymmetry Reduction in Older Adults (HAROLD) and the Posterior-Anterior Shift in Aging (PASA). These models posit that older adults tend to recruit additional brain areas (bilateral as predicted by HAROLD and anterior as predicted by PASA) when performing several cognitive tasks. We tested younger (N = 36) and older adults (N = 35) in a typical vWM task (delayed match-to-sample) where participants have to retain items and then compare them to a sample. Through a data-driven whole scalp EEG analysis we aimed at characterizing the temporal dynamics of the age-related activations predicted by the two models, both across and within different stages of stimulus processing. Behaviorally, younger outperformed older adults. The EEG analysis showed that older adults engaged supplementary bilateral posterior and frontal sites when processing different levels of memory load, in line with both HAROLD and PASA-like activations. Interestingly, these age-related supplementary activations dynamically developed over time. Indeed, they varied across different stages of stimulus processing, with HAROLD-like modulations being mainly present during item retention, and PASA-like activity during both retention and retrieval. Overall, the present results suggest that age-related neural changes are not a phenomenon indiscriminately present throughout all levels of cognitive processing.

Dynamic Changes of Endogenic or Exogenic β-Carboline Alkaloid Harmine in Different Mammals and Human in vivo at Developmental and Physiological States

ObjectiveSeveral β-carboline alkaloids (βCBs), such as harmine, harmaline, harmane, and nor-harmane, are effective for Alzheimer’s disease mouse models. They can be found in some plants, common foodstuffs, and blank plasma of various mammals. However, whether these compounds in mammals are exogenous or endogenous remain unclear.MethodsThe exposure levels of βCBs and of neurotransmitters in plasma and tissues of pup rats, aging rats, mice of different physiological states, and healthy volunteers were detected by using UPLC-MS/MS. Plasma and tissue samples from 110 newborn rats up to 29 days old at 11 sampling points were collected and were analyzed to determine the concentration variation of βCBs in the developmental phase of newborn rats. The plasma of rats aged 2 to 18 months was used to detect the variation trend of βCBs and with some neurotransmitters. The plasma samples of normal C57BL/6 mice, APP/PS1 double transgenic mice, and scopolamine-induced memory impairment mice were collected and were analyzed to compare the difference of βCBs in different physiological states. The exposure levels of βCBs such as harmine, harmaline, and harmane in plasma of 550 healthy volunteers were also detected and analyzed on the basis of gender, race, and age.ResultsResults showed that harmine was the main compound found in rats, mice, and human, which can be detected in a newborn rat plasma (0.16 ± 0.03 ng/ml) and brain (0.33 ± 0.14 ng/g) without any exogenous consumption. The concentration of harmine in rat plasma showed a decreasing trend similar to the exposure levels of neurotransmitters such as 5-hydroxytryptamine, acetylcholine chloride, glutamic acid, tyrosine, and phenylalanine during the growth period of 18 months. The harmine exposure in rats and human indicates high dependence on the physiological and pathological status such as aging, gender, and race.ConclusionThe dynamic changes of harmine exposure in different animals and human, in vivo, at developmental and physiological states indicate that harmine is a naturally and widely distributed endogenous substance in different mammals and human. In addition to exogenous ingestion, spontaneous synthesis might be another important source of harmine in mammals, which should be verified by further experiment.

Low-Frequency vs. Theta Burst Transcranial Magnetic Stimulation for the Treatment of Chronic Non-fluent Aphasia in Stroke: A Proof-of-Concept Study

BackgroundAlthough low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) has shown promise in the treatment of poststroke aphasia, the efficacy of high-frequency rTMS (HF-rTMS) has yet to be determined.PurposeWe investigated the efficacy of intermittent theta burst stimulation (iTBS) in ameliorating chronic non-fluent aphasia and compared it with that of LF-rTMS.MethodsWe randomly assigned patients with poststroke non-fluent aphasia to an ipsilesional iTBS (n = 29), contralesional 1-Hz rTMS (n = 27), or sham (n = 29) group. Each group received the rTMS protocol executed in 10 daily sessions over 2 weeks. We evaluated language function before and after the intervention by using the Concise Chinese Aphasia Test (CCAT).ResultsCompared with the sham group, the iTBS group exhibited significant improvements in conversation, description, and expression scores (P = 0.0004–0.031), which characterize verbal production, as well as in auditory comprehension, reading comprehension, and matching scores (P < 0.01), which characterize language perception. The 1-Hz group exhibited superior improvements in expression, reading comprehension, and imitation writing scores compared with the sham group (P < 0.05). The iTBS group had significantly superior results in CCAT total score, matching and auditory comprehension (P < 0.05) relative to the 1-Hz group.ConclusionOur study findings contribute to a growing body of evidence that ipsilesional iTBS enhances the language recovery of patients with non-fluent aphasia after a chronic stroke. Auditory comprehension was more preferentially enhanced by iTBS compared with the 1-Hz protocol. Our findings highlight the importance of ipsilesional modulation through excitatory rTMS for the recovery of non-fluent aphasia in patients with chronic stroke.Clinical Trial Registration:[www.ClinicalTrials.gov], identifier [NCT03059225].

Awareness for People With Alzheimer’s Disease: Profiles and Weekly Trajectories

Objective: To understand awareness and fluctuations of awareness in Alzheimer’s disease (AD), it is fruitful to consider the objects of awareness, e.g., cognitive functioning or recognition of the disease, as well as the mechanisms and modes of expression underlying awareness. With a holistic and discourse-centered approach, we aimed to identify different awareness profiles and test whether these profiles were stable or whether transitions from one profile to another occurred over short time intervals.Methods: Twenty-eight residents of nursing homes with a diagnosis of AD participated in four semistructured interviews at biweekly intervals. These interviews were cluster analyzed to determine profiles of awareness. A Markov chain was applied to model their fluctuation.Results: Five awareness profiles were observed that differed in terms of objects and underlying processes. Awareness proved to be quite stable for four of the five profiles. Interindividual variability in awareness was also observed through numerous different trajectories that were identified.Discussion: Self-awareness and disease awareness are characterized by profiles that vary subtly between individuals. Fluctuations in awareness underscore the need to employ assessment intervals that closely reflect daily life in institutions.

Monthly At-Home Computerized Cognitive Testing to Detect Diminished Practice Effects in Preclinical Alzheimer's Disease

Introduction: We investigated whether monthly assessments of a computerized cognitive composite (C3) could aid in the detection of differences in practice effects (PE) in clinically unimpaired (CU) older adults, and whether diminished PE were associated with Alzheimer's disease (AD) biomarkers and annual cognitive decline.Materials and Methods:N = 114 CU participants (age 77.6 ± 5.0, 61% female, MMSE 29 ± 1.2) from the Harvard Aging Brain Study completed the self-administered C3 monthly, at-home, on an iPad for one year. At baseline, participants underwent in-clinic Preclinical Alzheimer's Cognitive Composite-5 (PACC5) testing, and a subsample (n = 72, age = 77.8 ± 4.9, 59% female, MMSE 29 ± 1.3) had 1-year follow-up in-clinic PACC5 testing available. Participants had undergone PIB-PET imaging (0.99 ± 1.6 years before at-home baseline) and Flortaucipir PET imaging (n = 105, 0.62 ± 1.1 years before at-home baseline). Linear mixed models were used to investigate change over months on the C3 adjusting for age, sex, and years of education, and to extract individual covariate-adjusted slopes over the first 3 months. We investigated the association of 3-month C3 slopes with global amyloid burden and tau deposition in eight predefined regions of interest, and conducted Receiver Operating Characteristic analyses to examine how accurately 3-month C3 slopes could identify individuals that showed >0.10 SD annual decline on the PACC-5.Results: Overall, individuals improved on all C3 measures over 12 months (β = 0.23, 95% CI [0.21–0.25], p < 0.001), but improvement over the first 3 months was greatest (β = 0.68, 95% CI [0.59–0.77], p < 0.001), suggesting stronger PE over initial repeated exposures. However, lower PE over 3 months were associated with more global amyloid burden (r = −0.20, 95% CI [−0.38 – −0.01], p = 0.049) and tau deposition in the entorhinal cortex (r = −0.38, 95% CI [−0.54 – −0.19], p < 0.001) and inferior-temporal lobe (r = −0.23, 95% CI [−0.41 – −0.02], p = 0.03). 3-month C3 slopes exhibited good discriminative ability to identify PACC-5 decliners (AUC 0.91, 95% CI [0.84–0.98]), which was better than baseline C3 (p < 0.001) and baseline PACC-5 scores (p = 0.02).Conclusion: While PE are commonly observed among CU adults, diminished PE over monthly cognitive testing are associated with greater AD biomarker burden and cognitive decline. Our findings imply that unsupervised computerized testing using monthly retest paradigms can provide rapid detection of diminished PE indicative of future cognitive decline in preclinical AD.

Aging Brain and Hearing: A Mini-Review

Brain reserve is a topic of great interest to researchers in aging medicine field. Some individuals retain well-preserved cognitive function until they fulfill their lives despite significant brain pathology. One concept that explains this paradox is the reserve hypothesis, including brain reserve that assumes a virtual ability to mitigate the effects of neuropathological changes and reduce the effects on clinical symptoms flexibly and efficiently by making complete use of the cognitive and compensatory processes. One of the surrogate measures of reserve capacity is brain volume. Evidence that dementia and hearing loss are interrelated has been steadily accumulating, and age-related hearing loss is one of the most promising modifiable risk factors of dementia. Research focused on the imaging analysis of the aged brain relative to auditory function has been gradually increasing. Several morphological studies have been conducted to understand the relationship between hearing loss and brain volume. In this mini review, we provide a brief overview of the concept of brain reserve, followed by a small review of studies addressing brain morphology and hearing loss/hearing compensation, including the findings obtained from our previous study that hearing loss after middle age could affect hippocampal and primary auditory cortex atrophy.

Brain Activity and Functional Connectivity Patterns Associated With Fast and Slow Motor Sequence Learning in Late Middle Adulthood

The human brain undergoes structural and functional changes across the lifespan. The study of motor sequence learning in elderly subjects is of particularly interest since previous findings in young adults might not replicate during later stages of adulthood. The present functional magnetic resonance imaging (fMRI) study assessed the performance, brain activity and functional connectivity patterns associated with motor sequence learning in late middle adulthood. For this purpose, a total of 25 subjects were evaluated during early stages of learning [i.e., fast learning (FL)]. A subset of these subjects (n = 11) was evaluated after extensive practice of a motor sequence [i.e., slow learning (SL) phase]. As expected, late middle adults improved motor performance from FL to SL. Learning-related brain activity patterns replicated most of the findings reported previously in young subjects except for the lack of hippocampal activity during FL and the involvement of cerebellum during SL. Regarding functional connectivity, precuneus and sensorimotor lobule VI of the cerebellum showed a central role during improvement of novel motor performance. In the sample of subjects evaluated, connectivity between the posterior putamen and parietal and frontal regions was significantly decreased with aging during SL. This age-related connectivity pattern may reflect losses in network efficiency when approaching late adulthood. Altogether, these results may have important applications, for instance, in motor rehabilitation programs.

Preservation of Retinal Function Through Synaptic Stabilization in Alzheimer's Disease Model Mouse Retina by Lycium Barbarum Extracts

In Alzheimer's disease (AD), amyloid β deposition-induced hippocampal synaptic dysfunction generally begins prior to neuronal degeneration and memory impairment. Lycium barbarum extracts (LBE) have been demonstrated to be neuroprotective in various animal models of neurodegeneration. In this study, we aimed to investigate the effects of LBE on the synapse loss in AD through the avenue of the retina in a triple transgenic mouse model of AD (3xTg-AD). We fed 3xTg-AD mice with low (200 mg/kg) or high (2 g/kg) dose hydrophilic LBE daily for 2 months from the starting age of 4- or 6-month-old. For those started at 6 month age, at 1 month (though not 2 months) after starting treatment, mice given high dose LBE showed a significant increase of a wave and b wave in scotopic ERG. After 2 months of treatment with high dose LBE, calpain-2, calpain-5, and the oxidative RNA marker 8-OHG were downregulated, and presynaptic densities in the inner plexiform layer but not the outer plexiform layer of the retina were significantly increased, suggesting the presynaptic structure of retina was preserved. Our results indicate that LBE feeding may preserve synapse stability in the retina of 3xTg-AD mice, probably by decreasing both oxidative stress and intracellular calcium influx. Thus, LBE might have potential as a neuroprotectant for AD through synapse preservation.

Impaired Glymphatic Function and Pulsation Alterations in a Mouse Model of Vascular Cognitive Impairment

Large vessel disease and carotid stenosis are key mechanisms contributing to vascular cognitive impairment (VCI) and dementia. Our previous work, and that of others, using rodent models, demonstrated that bilateral common carotid stenosis (BCAS) leads to cognitive impairment via gradual deterioration of the neuro-glial-vascular unit and accumulation of amyloid-β (Aβ) protein. Since brain-wide drainage pathways (glymphatic) for waste clearance, including Aβ removal, have been implicated in the pathophysiology of VCI via glial mechanisms, we hypothesized that glymphatic function would be impaired in a BCAS model and exacerbated in the presence of Aβ. Male wild-type and Tg-SwDI (model of microvascular amyloid) mice were subjected to BCAS or sham surgery which led to a reduction in cerebral perfusion and impaired spatial learning acquisition and cognitive flexibility. After 3 months survival, glymphatic function was evaluated by cerebrospinal fluid (CSF) fluorescent tracer influx. We demonstrated that BCAS caused a marked regional reduction of CSF tracer influx in the dorsolateral cortex and CA1-DG molecular layer. In parallel to these changes increased reactive astrogliosis was observed post-BCAS. To further investigate the mechanisms that may lead to these changes, we measured the pulsation of cortical vessels. BCAS impaired vascular pulsation in pial arteries in WT and Tg-SwDI mice. Our findings show that BCAS influences VCI and that this is paralleled by impaired glymphatic drainage and reduced vascular pulsation. We propose that these additional targets need to be considered when treating VCI.

Binocular Integrated Visual Field Deficits Are Associated With Changes in Local Network Function in Primary Open-Angle Glaucoma: A Resting-State fMRI Study

In glaucoma participants, both structural and functional brain changes have been observed, but we still have insufficient understanding of how these changes also affect the integrity of cortical functional networks, and how these changes relate to visual function. This is relevant, as functional network integrity may affect the applicability of future treatments, as well as the options for rehabilitation or training. Here, we compare global and local functional connectivity in local and global brain networks between glaucoma and control participants. Moreover, we study the relationship between functional connectivity and visual field (VF) loss. For our study, 20 subjects with primary open-angle glaucoma (POAG) and 24 age-similar healthy participants were recruited to undergo an ophthalmic assessment followed by two resting-state (RS) (f)MRI scans. For each scan and for each group, the ROIs with eigenvector centrality (EC) values higher than the 95th percentile were considered the most central brain regions (“hubs”). Hubs for which we found a significant difference in EC in both scans between glaucoma and healthy participants were considered to provide evidence for network changes. In addition, we tested the notion that a brain region's hub function in POAG might relate to the severity of a participant's VF defect, irrespective of which eye contributed mostly to this. To determine this, for each participant, eye-independent scores were derived for: (1) sensitivity of the worse eye – indicating disease severity, (2) sensitivity of both eyes combined – with one eye potentially compensating for loss in the other, or (3) difference in eye sensitivity – potentially requiring additional network interactions. By correlating each of these VF scores and the EC values, we assessed whether VF defects could be associated with centrality alterations in POAG. Our results show that no functional connectivity disruptions were found at the global brain level in POAG participants. This indicates that in glaucoma global brain network communication is preserved. Furthermore, for the Lingual Gyrus, identified as a brain hub, we found a positive correlation between the EC value and the VF sensitivity of both eyes combined. The fact that reduced local network functioning is associated with reduced binocular VF sensitivity suggests the presence of local brain reorganization that has a bearing on functional visual abilities.